Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial.

BACKGROUND: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. Clinically, PARP inhibitors exacerbate the hematological side effects of TMZ. The OPARATIC trial was conducted to measure penetration of recurrent glioblastoma by olaparib and assess the safety and tolerability of its combination with TMZ. METHODS: Preclinical pharmacokinetic studies evaluated olaparib tissue distribution in rats and tumor-bearing mice. Adult patients with recurrent glioblastoma received various doses and schedules of olaparib and low-dose TMZ in a 3 + 3 design. Suitable patients received olaparib prior to neurosurgical resection; olaparib concentrations in plasma, tumor core and tumor margin specimens were measured by mass spectrometry. A dose expansion cohort tested tolerability and efficacy of the recommended phase II dose (RP2D). Radiosensitizing effects of olaparib were measured by clonogenic survival in glioblastoma cell lines. RESULTS: Olaparib was a substrate for multidrug resistance protein 1 and showed no brain penetration in rats but was detected in orthotopic glioblastoma xenografts. Clinically, olaparib was detected in 71/71 tumor core specimens (27 patients; median, 496 nM) and 21/21 tumor margin specimens (9 patients; median, 512.3 nM). Olaparib exacerbated TMZ-related hematological toxicity, necessitating intermittent dosing. RP2D was olaparib 150 mg (3 days/week) with TMZ 75 mg/m2 daily for 42 days. Fourteen (36%) of 39 evaluable patients were progression free at 6 months. Olaparib radiosensitized 6 glioblastoma cell lines at clinically relevant concentrations of 100 and 500 nM. CONCLUSION: Olaparib reliably penetrates recurrent glioblastoma at radiosensitizing concentrations, supporting further clinical development and highlighting the need for better preclinical models.

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.

Intracranial WHO grade I meningioma: a competing risk analysis of progression and disease-specific survival.

BACKGROUND: Studies on meningioma are reported with inadequate allowance for competing causes of progression or death. The aim of this study was to describe the outcome of patients with intracranial WHO grade I meningioma and identify factors that may influence disease progression and cause-specific survival. METHODS: Pathology reports and clinical data of 505 WHO grade I meningiomas treated between January 2003 and December 2017 were retrospectively reviewed at a single institution. We estimated a cumulative incidence function for progression and cause-specific mortality. A competing risk analysis was conducted on clinical and histological criteria. Median follow-up was 6.2 years. RESULTS: A total of 530 surgical resections were performed on 505 cases. Forty-one patients received radiotherapy (RT). At data collection, 84 patients had died of their meningioma disease or demonstrated a recurrence eventually treated by redo surgery or RT. The risks of recurrence or meningioma-related death at 5 years were 16.2%, 95%CI[12.5, 20], whereas 5-year overall survival was 86.1%, 95%CI[82.8, 89.6]. In the multivariable Fine-Gray regression for a competing risk model, venous sinus invasion (SHR = 1.8, 95%CI[1.1, 2.9], p0.028), extent of resection (SHR = 0.2, 95%CI[0.1, 0.3], p < 0.001), and progressing meningioma (SHR = 7, 95%CI[3.3, 14.8], p < 0.001) were established as independent prognostic factors of cause-specific death or meningioma progression. In contrast, age at diagnosis < 65 years (HR = 1.1, 95%CI[1, 1.1], p < 0.001) and redo surgery for meningioma recurrence (HR = 2.6, 95%CI[1.4, 5], p = 0.00252) were predictors of the overall survival. CONCLUSIONS: In this large series, WHO grade I meningioma treatment failure correlated with venous sinus invasion, incomplete resection, and progressing tumour; shorter survival correlated with increased age and redo surgery for recurrence. We recommend the cumulative incidence competing risk approach in WHO grade I meningioma studies where unrelated mortality may be substantial, as this approach results in more accurate estimates of disease risk and associated predictors.

Malignant Meningioma: An International Multicentre Retrospective Study.

BACKGROUND: In contrast to benign meningiomas, malignant meningiomas (MM) are rare and associated with an unfavourable prognosis. Reports on MM concern fairly small cohorts, often comprising less than 30 cases. OBJECTIVE: To describe the outcome MM and identify factors that may influence survival. METHODS: Pathology reports and clinical data of 178 patients treated between 1989 and 2017 for a MM at 6 different international institutions were retrospectively reviewed. Seventy-six patients (42.7%) had a previous history of grade I or grade II meningioma. The patients underwent a total of 380 surgical resections and 72.5% received radiotherapy. Median follow-up was 4.5 yr. RESULTS: At data collection, 111 patients were deceased (63.4%) and only 23 patients (13.7%) were alive without any residual tumor on the most recent scan. Median overall survival was 2.9 yr, 95% confidence interval [CI; 2.4, 4.5]. Overall survival rates at 1, 5, and 10 yr, respectively, were: 77.7%, 95% CI [71.6, 84.3], 40%, 95% CI [32.7, 49], and 27.9%, 95% CI [20.9, 37.3]. In the multivariable analysis, age at MM surgery <65 yr (hazard ratio [HR] = 0.44, 95% CI [0.29, 0.67], P < .001), previous benign or atypical meningioma surgery (HR = 1.9, 95% CI [1.23, 2.92], P = .004), completeness of resection (HR = 0.51, 95% CI [0.34, 0.78], P = .002), and adjuvant radiotherapy (HR = 0.64, 95% CI [0.42, 0.98], P = .039) were established as independent prognostic factors for survival. CONCLUSION: This large series confirms the poor prognosis associated with MM, the treatment of which remains challenging. Patients under 65-yr-old with primary MM may live longer after complete resection and postoperative radiotherapy. Even with aggressive treatments, local control remains difficult to achieve.

Meningeal haemangiopericytoma and solitary fibrous tumour: a retrospective bi centre study for outcome and prognostic factor assessment.

To describe the outcome of patients diagnosed with central nervous system haemangiopericytoma (HPC) or solitary fibrous tumour (SFT) and identify factors that may influence recurrence and survival. Between January 2000 and September 2016, a retrospective search identified 55 HPCs/SFTs. The patients underwent a total of 101 surgical resections and 56.9% received radiation therapy. Median follow-up was 7.8 years. 28 patients (50.9%) were re-operated for tumour recurrence. At the end of the study, 21 patients (42%) had no residual tumour on the last scan. Surgical recurrence-free survival at 5 years was 75.2%, 95% CI [63.3-89.3] and, the median surgical recurrence-free survival was 7.4 years. In the adjusted analysis, venous sinus invasion (present vs. absent) (HR 3.39, 95% CI [1.16, 9.93], p = 0.026), completeness of resection (HR 0.38, 95% CI [0.15-0.97], p = 0.042) and tumour subtype (SFT vs. HPC) (HR 3.02, 95% CI[1.02, 8.91], p = 0.045) were established as independent prognostic factors. At the end of the study, 25 patients were deceased (45.5%). and only 15 patients (27.3%) had no residual tumour on the last scan and were alive. Overall survival at 5 years was 80.2, 95% CI [69.3-92.8] and the median overall survival was 13.1 years. None of the investigated variables was associated with overall survival. Patients who received radiation therapy demonstrated neither a reduced risk of surgical recurrence (p = 0.370) nor a longer overall survival (p = 1.000). SFTs/HPCs are associated with a significant risk of recurrence that may reduce the survival of the patients. Total tumour resection upon initial surgery is associated with a lower risk of relapse but not with a prolonged survival. We did not observe a significant improvement in any of the clinical outcomes after radiation therapy.

Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study.

BACKGROUND: CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. METHODS: We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2-4) 6-60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov, number NCT01151124. FINDINGS: 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60-82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6-8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. INTERPRETATION: Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. FUNDING: ReNeuron Limited.

World Health Organization grade II meningiomas.

BACKGROUND: We analyzed WHO grade II meningioma cases to identify factors influencing survival. MATERIALS AND METHODS: Between January 2000 and August 2015, 206 cases of World Health Organization (WHO) grade II meningioma were operated at our institution. This population underwent a total of 298 surgical resections and 55 patients received a radiotherapy. A Cox multivariate regression was conducted on clinical and histological criteria. RESULTS: Sixty-four patients were deceased (31.1 %), of which 38 died following the disease progression (18.4 %). Overall survival probability at 1, 5, and 10 years were 95.4 %, 95 % CI [92.5, 98.4]; 84 %, 95 % CI [78.3, 90.2], and 72.9 %, 95 % CI [64.5, 82.4], respectively (Fig. 1a). At the end of the study, only 87 patients (42.2 %) were alive with no tumor residual or recurrence on the last scan. Age at diagnosis (hazard ratio (HR) = 0.31, 95 % CI [0.15, 0.63], p < 0.001), extent of resection (HR = 0.25, 95 % CI [0.12, 0.49], p < 0.001), and tumoral brain invasion (HR = 0.49, 95 % CI [0.25, 0.98], p = 0.040) were independent factors associated with the overall survival. The patients who received radiotherapy did not demonstrate a longer overall survival (p = 0.540). CONCLUSIONS: WHO grade II meningioma significantly impaired the survival of the patients. In the adjusted Cox regression, a macroscopic gross total resection (Simpson grades 1, 2, and 3), an age below 62 years at diagnosis and the absence of brain invasion were independent factors associated with a longer survival. Radiotherapy may not increase the overall survival after complete or incomplete resection.

World Health Organization Grade II Meningioma: A 10-Year Retrospective Study for Recurrence and Prognostic Factor Assessment.

BACKGROUND: We analyzed the characteristics of patients with World Health Organization (WHO) Grade II meningioma to identify factors that may influence recurrence. MATERIALS AND METHODS: Between January 2000 and August 2015, 178 cases of WHO Grade II meningioma were operated at our institution. This population underwent a total of 224 surgical resections, and 36 patients received radiotherapy. Median follow-up was 3.6 years, and interquartile range was 1.5-6.2. RESULTS: A total of 28 patients (16.1%) were re operated for a relapse of their Grade II meningioma. The median time between the first and the second surgery was 4.2 years [interquartile range 1.4-5.3]. Surgical recurrence-free survival at 1, 2, 5, and 10 years were: 96.9% (95% confidence interval [95% CI] 94.2-99.6; 91.7%, 95% CI 87.3-96.3; 85%, 95% CI 78.6-92; and 70.8%, 95% CI 60.1-83.5), respectively. At the end of the study, 93 patients (57.8%) had no residual tumor on the last scan. Age at diagnosis (hazard ratio [HR] 0.17, 95% CI 0.05-0.56, P < 0.001), extent of resection (HR 0.22, 95% CI 0.08-0.64, P = 0.01), and Ki-67 index (HR 0.18, 95% CI 0.06-0.56, P < 0.001) were independent factors associated with the surgical recurrence-free survival. CONCLUSIONS: Younger patients with a lower proliferation rate and gross total resection are less likely to undergo a reintervention for WHO Grade II meningioma recurrence. Observation rather than systematic adjuvant radiotherapy may be preferred. If possible, a redo surgery may be considered in case of relapse or tumor residual progression, because radiotherapy may not decrease the surgical recurrence-free survival after complete or incomplete resection.

Initial experience of 3 Tesla versus conventional field strength magnetic resonance imaging of small functioning pituitary tumours.

BACKGROUND: Higher field strength magnetic resonance imaging (MRI) is becoming increasingly available and offers improved image quality; however, the clinical usefulness of this technique for the demonstration of surgically treatable functional pituitary adenomas has not been clearly established. OBJECTIVE: To determine whether 3 Tesla (3T) MRI improves the detection of ACTH- and GH-secreting microadenomas over conventional imaging at field strengths of up to 1·5 Tesla (1·5T). DESIGN: Data sets from postgadolinium T1-weighted MRI at 1·5T and 3T were blinded, randomly ordered and assessed for the presence of pituitary tumour by two radiologists. Where possible, lesion signal difference to noise ratio (SDNR) was calculated for quantitative comparison. Imaging diagnoses were correlated with subsequent surgical and histological findings. PATIENTS: Twenty-four patients (10 men, 14 women) with biochemical evidence of Cushing's disease (19) or acromegaly (5) were identified over a 5-year period. RESULTS: 1·5T MRI gave a clear diagnosis of 12 pituitary tumours, all confirmed at 3T. Four additional definite lesions and one suspicious case were correctly identified at 3T. Histological correlation in 21 cases showed sensitivity improving from 54% with 1·5T to 85% with 3T. Radiologists' subjective image preference favoured 3T in 92%. Quantitative difference between tumour and parenchymal signal was significantly greater at 3T (mean SDNR -7·9 [3T] and -2·8 [1·5T], paired t-test P < 0·05). CONCLUSIONS: 3T MRI appears to offer increased conspicuity and detection of GH- and ACTH-secreting pituitary microadenomas. It is potentially clinically useful when 1·5T imaging is negative or equivocal.

Intracranial delivery of stem cells.

The method of delivery of stem cells is a major factor to consider in the design of clinical trials of cell therapy. Different methods of delivery will be associated with different risks to the patient, and may also be associated with different potential for benefit. Current approaches are partly informed by the routes selected for study in animal models of focal ischaemia and CNS transplantation, but there has been little work comparing the efficacy of different routes of administration. Direct intraparenchymal delivery of cells has been employed in several preliminary clinical trials, and data on the safety of this approach are reviewed.

A patient with thyrotropinoma cosecreting growth hormone and follicle-stimulating hormone with low alpha-glycoprotein: a new subentity?

BACKGROUND: Thyrotropinomas are rare pituitary tumors. In 25 percent of cases there is autonomous secretion of a second pituitary hormone, adding to the clinical complexity. We report a patient with thyrotropin (TSH)-dependant hyperthyroidism along with growth hormone (GH) and follicle-stimulating hormone (FSH) hypersecretion but low alpha-glycoprotein (alpha-subunit) concentrations, a hitherto unique constellation of findings. SUMMARY: A 67-year-old Scottish lady presented with longstanding ankle edema, paroxysmal atrial fibrillation, uncontrolled hypertension, fine tremors, warm peripheries, and agitation. Initial findings were a small goiter, elevated serum TSH of 7.37 mU/L (normal range, 0.30-6.0 mU/L), a free-thyroxine concentration of 34.9 pmol/L (normal range, 9.0-24.0 pmol/L), a flat TSH response to TSH-releasing hormone, and serum alpha-subunit of 3.1 IU/L (normal, <3.0 IU/L). There was no evidence of an abnormal thyroid hormone beta receptor by genotyping. Serum FSH was 56.8 U/L, but the luteinizing hormone (LH) was 23.6 U/L (postmenopausal FSH and LH reference ranges both >30 U/L) Basal insulin-like growth factor I was elevated to 487 microg/L with the concomitant serum GH being 14.1 mU/L, and subsequent serum GH values 30 minutes after 75 g oral glucose being 19.1 mU/L and 150 minutes later being 13.7 mU/L. An magnetic resonance imaging pituitary revealed a macroadenoma. Pituitary adenomectomy was performed with the histology confirming a pituitary adenoma, and the immunohistochemistry staining showed positive reactivity for FSH with scattered cells staining for GH and TSH. Staining for other anterior pituitary hormones was negative. After pituitary surgery she became clinically and biochemically euthyroid, the serum IFG-1 became normal, but the pattern of serum FSH and LH did not change. CONCLUSION: This case of plurihormonal thyrotropinoma is unique in having hypersecretion of TSH, GH, and FSH with low alpha-subunit. Such a combination may represent a new subentity of TSHomas.

Implications of full compliance with the computed tomography scanning recommendations of the National Institute for Clinical Excellence and Scottish Intercollegiate Guidelines Network guidelines for the management of head injury.

A prospective study was conducted to examine clinical practices in the management of head-injured patients preinception and postinception of the Scottish Intercollegiate Guidelines Network guidelines. Comparison was made between the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence guidelines on their indications for computed tomography scanning. Information was available on 2827 adult patients. Two hundred and thirty-two patients satisfied one or more Scottish Intercollegiate Guidelines Network criteria for computed tomography scanning. Four hundred and seventy-eight patients fulfilled one or more National Institute for Clinical Excellence criteria for scanning. No patient with Scottish Intercollegiate Guidelines Network or National Institute for Clinical Excellence indications for computed tomography scanning and who was not scanned, subsequently required neurosurgical treatment for a complication related to their injury. Full compliance with the scanning recommendations in the Scottish Intercollegiate Guidelines Network and National Institute for Clinical Excellence guidelines will require a significant increase in scanning resource and is unlikely to lead to the identification of a significant additional number of patients with intracranial lesions requiring neurosurgical intervention.

Apo E genotype not associated with intravascular coagulation in traumatic brain injury.

There is considerable evidence linking both genotype and coagulopathy to vascular complications of traumatic brain injury (TBI) and other cerebral insults. The authors explored a possible connection between the apolipoprotein E (Apo E) genotype, coagulopathy and intravascular microthombosis (IMT) in TBI. The predicted association was not confirmed.

Premorbid intelligence and brain injury.

OBJECTIVES: To determine whether NART scores are associated with severity of brain injury and therefore presumably affected by brain injury. In addition, to compare the Cambridge Contextual Reading Test (CCRT) with injury severity in head-injured individuals. DESIGN AND METHODS: Participants were 55 survivors of traumatic head injury, who completed the NART and the CCRT. The scores on these premorbid measures were then compared with indices of injury severity from their initial neurosurgical admission. RESULTS: The NART was significantly correlated with Glasgow coma scale, with greater severity of injury associated with poorer performance. Poorer NART performance was also significantly more likely amongst those whose injury resulted in coma. The CCRT was preferred by patients, though it was also significantly associated with Glasgow coma scale and presence of coma. CONCLUSIONS: The data suggest that performance on both the NART and the CCRT are affected by brain injury severity and thus may underestimate true premorbid ability in these individuals. Similar findings would be likely with the conceptually identical WTAR measure. These measures should be used with appropriate caution and may be usefully supplemented by predictions based on demographic information.

Apolipoprotein E polymorphism and neuropsychological outcome following subarachnoid haemorrhage.

OBJECTIVES: To investigate the association between APOE genotype and cognitive and emotional outcome following spontaneous subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Neuropsychological assessments were conducted with 70 SAH survivors derived from a consecutive series of neurosurgical admissions. Outcomes, including cognitive tests, health questionnaires and Glasgow Outcome Scale at a mean of 16 months after SAH, were compared with presence or absence of the epsilon4 allele. RESULTS: There was no evidence that SAH survivors possessing the epsilon4 allele had poorer outcome. The only suggestion of an association between the epsilon4 allele and outcome was in a subgroup of patients with a Fisher grade 4 haemorrhage, although this trend did not reach statistical significance. CONCLUSIONS: Overall, possession of the APOE epsilon4 allele is not significantly associated with neuropsychological outcome following SAH. However, there may be an effect amongst those with a Fisher grade 4 haemorrhage.

Anxiety and depression after spontaneous subarachnoid hemorrhage.

OBJECTIVE: Relatively little attention has been paid to emotional outcome after subarachnoid hemorrhage (SAH). This study assessed levels of anxiety and depression among SAH survivors and related these to clinical indices. METHODS: Seventy SAH patients from a consecutive series of neurosurgical admissions participated in semistructured assessments of functional outcome; 52 of the patients also returned standardized measures of emotional outcome. These data were compared with clinical indices collected during the initial hospital admission. RESULTS: Moderate to severe levels of anxiety were present in approximately 40% of patients 16 months after hemorrhage, with approximately 20% experiencing moderate to severe levels of depression. Although anxiety was more likely to be reported at interview by those with an SAH of Fisher Grade 4, the standardized measures of anxiety and depression were not associated with severity of hemorrhage or any other clinical variables. Both anxiety and depression were significantly associated with outcome indices such as return to work and engagement in social activities. CONCLUSION: Anxiety is a significant and lasting problem for approximately 40% of survivors of SAH. It is suggested that measures taken to prevent or treat such anxiety among survivors of SAH may serve to significantly improve functional outcome.

Patients with a head injury who "talk and die" in the 1990s.

BACKGROUND: Patients who "talk and die" after head injury may represent a group who suffer delayed and therefore potentially preventable complications after injury. We have compared the clinical and pathologic features of patients who talk and die with those who "talk and live" after head injury. METHODS: Data collected prospectively by the Scottish Trauma Audit Group were used to identify patients with a head injury and classify them according to verbal response at admission to hospital. All "talking" patients in the catchment area of a regional neurosurgical center were selected and those who died were compared with those who survived. RESULTS: Seven hundred eighty-nine talking patients were identified. Seven hundred twenty-seven patients survived and 62 died. Patients who talked and died were older, had more severe extracranial injuries, had lower consciousness levels, and reached theater more quickly than those who talked and lived. Thirty-one of the patients that died had extra-axial hematomas. CONCLUSION: Even with increased availability of computed tomographic scanning, some patients still talk and die after head injury.

Effect of apolipoprotein E genotype on hematoma volume after trauma.

OBJECT: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is associated with poor outcome after head injury and spontaneous intracerebral hemorrhage (SICH). The aims of this study were to determine if patients in whom one or more APOE-epsilon4 alleles are present are more likely to sustain intracranial mass lesions after head injury and to determine whether there is an isoform-specific effect on the size of the intracranial hematoma. METHODS: The authors performed a computerized volumetric analysis of 142 hematomas visible on computerized tomography (CT) scans obtained in 129 patients. The APOE genotype was determined by subjecting buccal smear samples to polymerase chain reaction and restriction enzyme digestion. Allele frequencies were similar in head-injured patients with and without intracranial hematomas (p = 0.36). Univariate analysis revealed that in those patients with one or more APOE-epsilon4 alleles hematoma volume was greater (cube root-transformed values) than that found in patients without the APOE-epsilon4 allele (3.1 cm compared with 2.5 cm, p = 0.0039). The results of univariate analysis also suggested significant effects of patient age, injury severity (mild, moderate, or severe according to admission Glasgow Coma Scale scores) and hematoma location (extraaxial, intraaxial, or both) on hematoma volume. The mechanism of injury (assault, fall, or other) was marginally associated with hematoma volume (p = 0.052). Time from injury to CT scan, hypoxia, and hypotension had no significant effect on hematoma volume. The results of multiple linear regression analysis showed that the presence of an APOE-epsilon4 allele and an extraaxial hematoma location were independent predictors of hematoma volume, after adjusting for patient age, hours between injury and CT scan, injury severity, and injury mechanism. CONCLUSIONS: Larger hematomas were found in head-injured patients with one or more APOE-epsilon4 alleles than in patients without the allele. This may contribute to the poorer outcomes observed in these patients.