Comparison of spontaneous intracerebral hemorrhage treatment in Germany between 1999 and 2009: results of a survey.

BACKGROUND AND PURPOSE: The aim of our study was to examine surgical practice in the therapy of spontaneous intracerebral hemorrhage in Germany over a period of 10 years. METHODS: In 1999 and 2009 a questionnaire with 10 different cases of spontaneous intracerebral hemorrhage was sent to all neurosurgical centers in Germany. It included a cranial CT as well as a case description. The question asked if a conservative or surgical procedure was most suitable. When choosing surgery, the participants could decide between large open approach or microsurgery as well as stereotactic aspiration or external ventricular drainage. RESULTS: In 1999, 85 of 121 (70%) and in 2009 111 of 125 (89%) questionnaires could be evaluated. The results of the questionnaires from 1999 and 2009 showed no difference in the decision for or against a surgical procedure, except for a move toward conservative treatment in 1 patient with a massive spontaneous intracerebral hemorrhage. In 2 cases of isolated basal ganglia bleeding, a conservative approach was chosen by approximately 98% of the participants both in 1999 and in 2009. In all other cases of spontaneous intracerebral hemorrhage, in particular when the patient was in poor clinical condition, the decision was very heterogeneous. CONCLUSIONS: Despite new studies, there were no significant differences regarding the decision for or against a surgical procedure in 1999 and 2009. Although clearly unfavorable prognostic factors are known, many patients still undergo a surgical procedure. It appears that at least spontaneous intracerebral hemorrhage in the area of the basal ganglia is a unique domain of conservative treatment.

Pituitary insufficiency after operation of supratentorial intra- and extraaxial tumors outside of the sellar-parasellar region?

Recent studies investigating pituitary function after non-sellar brain tumor surgery showed that up to 38.2% of patients have pituitary insufficiency (PI). It has been assumed that the operation causes the PI, but preoperative hormone testing, which would have been necessary to prove this assumption, was not performed. The objective of this study is to answer the question if indeed microsurgery is the culprit of PI in patients with operatively treated non-sellar brain tumors. In this prospective trial, 54 patients with supratentorial non-sellar tumors were included. The basal levels of cortisol, prolactin, testosterone, estrogen, IGF-1, fT3, fT4, STH, TSH, ACTH, FSH, and LH were recorded preoperatively on days 1 and 7 after surgery. If basal hormone screening revealed an abnormality, a releasing hormone assay was performed. Before surgery, 24 of the 54 patients (44.4%) already had PI. Additional 25 patients showed either hypocortisolism or hypothyreoidism. As those patients had been pre-treated with dexamethasone and L-thyroxine, these findings were considered not to represent PI but drug effects. Hormone testing on days 1 and 7 after surgery revealed no changes. With 44.4% PI is a frequent finding in brain tumor patients already before surgery. The factors causing preoperative PI remain yet to be identified. The endocrine results after surgery are unchanged which rules out that surgery is the cause of PI.

2-Octyl-cyanoacrylate for wound closure in cervical and lumbar spinal surgery.

It is claimed that wound closure with 2-octyl-cyanoacrylate has the advantages that band-aids are not needed in the postoperative period, that the wound can get in contact with water and that removal of stitches is not required. This would substantially enhance patient comfort, especially in times of reduced in-hospital stays. Postoperative wound infection is a well-known complication in spinal surgery. The reported infection rates range between 0% and 12.7%. The question arises if the advantages of wound closure with 2-octyl-cyanoacrylate in spinal surgery are not surpassed by an increase in infection rate. This study has been conducted to identify the infection rate of spinal surgery if wound closure was done with 2-octyl-cyanoacrylate. A total of 235 patients with one- or two-level surgery at the cervical or lumbar spine were included in this prospective study. Their pre- and postoperative course was evaluated. Analysis included age, sex, body mass index, duration and level of operation, blood examinations, 6-week follow-up and analysis of preoperative risk factors. The data were compared to infection rates of similar surgeries found in a literature research and to a historical group of 503 patients who underwent wound closure with standard skin sutures after spine surgery. With the use of 2-octyl-cyanoacrylate, only one patient suffered from postoperative wound infection which accounts for a total infection rate of 0.43%. In the literature addressing infection rate after spine surgery, an average rate of 3.2% is reported. Infection rate was 2.2% in the historical control group. No risk factor could be identified which limited the usage of 2-octyl-cyanoacrylate. 2-Octyl-cyanoacrylate provides sufficient wound closure in spinal surgery and is associated with a low risk of postoperative wound infection.

The prediction of long-term outcome after subarachnoid hemorrhage as measured by the Short Form-36 Health Survey.

The Glasgow Outcome Scale (GOS) score is widely used to assess outcome after a subarachnoid hemorrhage (SAH). Patients who have recovered fully or with a mild disability (GOS scores 4 and 5) frequently complain about difficulties in conducting their daily activities. The Short Form-36 (SF-36) Health Survey is a questionnaire that assesses outcomes in multiple categories. This study was conducted to compare the quality of outcome assessment between the SF-36 Health Survey and GOS scores. A total of 128 patients with SAH (all data expressed as mean+/-standard deviation) aged 53.1+/-12.1 years, and a mean Hunt and Hess grade on admission of 2+/-1, were retrospectively included in the study. Medical charts were reviewed to assess previous medical history, location of the aneurysm and the presence of vasospasm. The SF-36 and GOS scores were collected in structured interviews approximately 5 years (+/-2 years) after the SAH. The SF-36 data were compared to a historical healthy control cohort of 2,474 individuals. The results showed that 52% of patients experienced a favourable outcome after SAH (GOS scores 4 and 5). Vasospasm was recorded in 25% of patients. However, the average SF-36 results were lower in all tested categories for patients after SAH than the healthy normal controls. None of the SF-36 categories except physical function correlated significantly with the GOS score. Aneurysm location did not have an impact on SF-36 data. Patients after a SAH assessed as GOS score 5 are significantly impaired in social functioning and general health. We conclude that patients continue to suffer neuropsychological deficits years after a SAH. The GOS score is a rough outcome measure that primarily focuses on physical functioning. SF-36 is a useful tool to include in the neuropsychological outcome assessment of patients with SAH.

Pituitary insufficiency after traumatic brain injury.

After traumatic brain injury (TBI), patients present with psychological disorders that may be explained by post-traumatic pituitary insufficiency (PI). The goal of this study was to determine the relationship between hypopituitarism, neuropsychological changes and findings on CT scans after TBI. Hospital charts of 55 TBI patients were screened for age, Glasgow Coma Scale (GSC) score, hypoxia or hypotension. The first two CT scans were analyzed for hemorrhagic lesions. Basal levels of the following hormones were recorded: cortisol, prolactin, estradiol, testosterone, insulin-like growth factor 1 and free thyroxine. Hormonal stimulation tests were performed either if the basal hormone screening revealed an abnormality or if the patient answered "yes" to at least one question in the non-evaluated neuropsychological questionnaire. Overall, 14 out of 55 patients (25.4%) presented with PI; one of them with two hormonal deficits. Growth hormone deficit, hypothyroidism and hypocortisolism were found in one, one and two patients, respectively. Neuropsychological complaints were present in 67% of the patients and were associated with intracerebral hemorrhagic lesions and not PI. Neuropsychological complaints after TBI are more frequent than PI. Brain tissue damage is most important than PI in the development of psychological changes after TBI.

Arteriovenous differences of oxygen and transcranial Doppler sonography in the management of aneurysmatic subarachnoid hemorrhage.

After subarachnoid hemorrhage (SAH) the detection of hemodynamically significant vasospasm is frequently difficult, especially in comatose patients. Most clinicians use transcranial Doppler sonography (TCD) to detect increasing mean blood flow velocities in the basal arteries as markers of cerebral vasospasm, without accounting for the effects of sedation and variations in blood pressure or pCO(2). This study was conducted to test the hypothesis that the arteriovenous difference of oxygen (avDO(2); in terms of % volume) could also be useful for the evaluation of vasospasm. A total of 22 SAH patients (M : F = 1 : 1.75, age 58+/-10 years, median Hunt and Hess grade 4) were prospectively enrolled. All patients were sedated with continuous doses of midazolam/fentanyl and/or propofol. TCD studies and avDO(2) measurements were conducted at the same time or in close succession. The blood flow velocity of the middle cerebral artery was recorded. A cranial CT scan was conducted if the avDO(2) increased by at least 0.8%. Overall, 82 measurements were recorded in 22 patients between days 1 and 13 after SAH. TCD mean flow velocities increased as expected. In contrast, avDO(2) decreased until post-hemorrhage day 4 before it increased again. Overall, after SAH, avDO(2) was significantly lower than in normal individuals. Cerebral infarction occurred primarily in patients with a maximal change of avDO(2) of more than 1%. TCD velocities alone are poor indicators of the severity of vasospasm. In contrast, daily avDO(2) seems to be a more robust parameter. However, collection of additional metabolic information is warranted.

Cerebral energy failure after subarachnoid hemorrhage: the role of relative hyperglycolysis.

After subarachnoid hemorrhage (SAH) cerebral metabolism is significantly impaired. Hyperglycolysis describes the reduction of oxidative metabolism followed by a relative increase of anaerobic glycolysis to maintain energy supply. This phenomenon is known in head injury but has not as yet been shown after SAH. This study was conducted to test the hypothesis that hyperglycolysis is present in SAH patients and is associated with vasospasm. A total of 105 measurements were conducted on 21 SAH patients (age 49+/-15 years, median World Federation of Neurosurgical Societies Grade 4) over the first 5 days following admission. Arteriovenous differences were calculated for oxygen (avDO2) and glucose (avDGlc). Relative hyperglycolysis was defined as metabolic ratio (MR=avDO2[mmol/L]/avDGlc[mmol/L])<3.44. Jugular-venous saturation for oxygen (SjvO2), mean arterial blood pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP) were monitored. Relative hyperglycolyis was recorded in 34% of studies after SAH. In hyperglycolytic studies both jugular-venous lactate and SjvO2 were significantly elevated (jugular-venous lactate 14.9+/-9.9 vs. 11.8+/-5.5 mg/dL, p=0.04; SjvO2: 70.0+/-18% vs. 81.7+/-9%, p=0.002). Relative hyperglycolysis is associated with outcome after SAH. In patients who died after SAH almost 50% of studies showed hyperglycolysis, whereas patients who survived without neurological deficit had no hyperglycolytic events. Relative hyperglycolysis is a common event after SAH. It may be associated with relative hyperemia but most importantly with outcome.

Dysplasia of C-1 and craniocervical instability in patients with Shprintzen-Goldberg syndrome. Case report and review of the literature.

Shprintzen-Goldberg syndrome is a rare connective tissue disorder characterized by marfanoid habitus and additional dysmorphic stigmata. Craniocervical anomalies occur in fewer than 30% of cases. Serious vertebral instability can also occur, albeit rarely. The authors report on the first patient treated with surgical fusion at the craniocervical junction because of a C-1 dysplasia and severe instability. The skeletal and cardiovascular anomalies that can pose additional problems for surgical treatment and perioperative care are discussed in detail.

S-100B and NSE: markers of initial impact of subarachnoid haemorrhage and their relation to vasospasm and outcome.

S100-B and neuron specific enolase (NSE) are known predictors of outcome in head injured and stroke patients. This study was conducted to test the hypothesis that S-100B and NSE can predict the development of vasospasm and outcome within the first 3 days after subarachnoid haemorrhage (SAH). Fifty-one SAH patients (mean age 51+/-11 years, male : female ratio 1.0 : 1.6, mean World Federation of Neurological Surgeons [WFNS] Grade 3+/-1.5) were included in the study. S100-B and NSE were recorded in venous blood across the first 3 days post-SAH. Vasospasm was diagnosed if mean blood flow velocity of the middle cerebral artery was greater than 120 cm/s and Lindegaard ratio >3. Glasgow Outcome Score (GOS) and cranial CT scans were recorded at 6 months. Normal, intermediate and high S-100B values were seen in 24%, 51% and 25% of patients, respectively. In patients with S-100B>1 microg/L, Fisher Grade 4 and WFNS 4-5 were both seen in 77% of cases. S-100B was significantly higher in those patients who did not develop vasospasm. In addition, S-100B values were significantly higher in those patients who died than in those with unfavourable or favourable outcome. NSE was normal, intermediate and high in 82%, 8% and 10% of patients, respectively. Patients with WFNS 4-5 and/or Fisher Grade 4 had significantly higher NSE values than all others. Across the first 3 days after SAH, measuring S-100B is useful to predict outcome and vasospasm.

Surgical treatment for ulnar nerve entrapment at the elbow.

The outcomes of 81 operations were assessed for the treatment of ulnar nerve entrapment at the elbow performed on 55 males (bilateral operations in one) and 25 females during the period from January 1995 to December 2000. Before operation, neurophysiological examination was performed in all patients. Simple ulnar nerve decompression or anterior transposition of the ulnar nerve (subcutaneous or intramuscular) was performed with or without the operating microscope. Nine patients were lost to follow up. The outcome was excellent or good in 63 of 72 cases, no change in eight cases, and poor in one case. The outcomes of procedures performed with the operating microscope tended to be superior.

Intraorbital mucocele associated with old minor trauma--case report.

A 46-year-old white man complained of swelling in the left orbital region. The only significant event in his medical history was minor trauma which occurred during ice hockey 15 years previously. On admission, the only clinical finding was left-sided exophthalmos. Computed tomography and magnetic resonance imaging revealed a left intraorbital cystic mass lesion. The cystic mass was completely removed through a left subfrontal extradural approach. There was no anatomical contact with the paranasal sinuses and the orbital walls were intact. The cystic mass was isolated in the orbital cavity. Histological examination confirmed the diagnosis of mucocele. Generally, the cause of mucocele is chronic sinusitis, but we suspect that the old minor trauma was the most likely cause in the present case.

A case of basilar impression complicated with left frontal meningioma.

CASE REPORT: A 75-year-old baikarian woman was admitted to our hospital for treatment of seizures. From the results of neurological and radiological examination, a left frontal meningioma was suspected and the patient was referred to our department for neurosurgical intervention. At admission, the MRI showed a basilar impression accompanied by Klippel-Feil syndrome of C4/5/6/7, but neurological symptoms of basilar impression were absent. Subsequently, the tumor was resected via the left frontal approach using microsurgical technique. Histological examination disclosed fibroblastic meningioma. DISCUSSION: The coincidence of basilar impression with a brain tumor is a relatively rare occurrence. There are a few reports about craniovertebral junction anomaly including basilar impression associated with spinal or cerebral tumor. This time, we present an interesting combined case of BI and Klippel-Feil syndrome associated with left frontal meningioma.

Risk factors for outcome and complications of dorsal foraminotomy in cervical disc herniation.

BACKGROUND: Dorsal foraminotomy is a standard operative procedure for lateral cervical disc herniation. Factors associated with surgical complications and clinical outcome in dorsal foraminotomy of cervical disc herniation were evaluated in a retrospective cohort study. METHOD: Thirty-nine patients were operated upon for unilateral, monosegmental, mediolateral cervical disc herniation (+/- associated spondylosis) from 1997 to 1999. Preoperative radiologic imaging and surgical reports were analyzed. Motor disfunction, neck irritation, and radicular pain were evaluated. Outcome was ranked according to modified Odom's criteria at 6 weeks and 1 year postoperatively. RESULTS: Six weeks after injury 7 of 39 patients (18%) showed neck irritation. No new neurologic deficit was seen. All patients with preoperative paresis improved; two had early relapses of a medial soft disc prolapse (2/39). Residual radicular pain was seen in 3 of 39 patients (8%) within 30 days postoperatively, necessitating surgical revision. Factors of surgical failure were associated spondylosis (2/3) and residual mediolateral disc protrusion (1/3). In one patient with associated spondylosis, local pain due to a symptomatic fracture of the lateral process of D1 resolved after revision. Duration of preoperative radicular pain was identified as a risk factor for unfavorable outcome. CONCLUSION: In lateral cervical disc herniation, associated spondylosis or medial disc protrusion poses a significant risk of surgical failure and complications of dorsal foraminotomy. Reducing the radicular failure rate by enlarging the bony decompression may lead to local failure. In well-selected patients with a lateral cervical free disc fragment, dorsolateral foraminotomy is successful and safe.

Vertebral artery complications in anterior approaches to the cervical spine: report of two cases and review of literature.

BACKGROUND: Cases of lesions to either the carotid artery or the vertebral artery in anterior approaches to the cervical spine are rarely found in medical literature. Two cases of vertebral artery injury in anterior approaches as well as a review of the pertinent literature are presented. In cases of arterial injury, appropriate management strategies are necessary to avoid or minimize harm to the patient. CASE REPORTS: In the first case, the vertebral artery was injured during decompression of a cervical spinal stenosis while drilling the neuroforamen. Local compression provided sufficient control of hemorrhage. Nevertheless, rebleeding from a pseudoaneurysm occurred 2 days later. After removal of the hematoma, the pseudoaneurysm was treated successfully with coils by an endovascular approach. In the second case, misplacement of one screw in screw-fixation of a type II odontoid fracture caused a pseudoaneurysm of the vertebral artery. This led to a fatal subarachnoid hemorrhage 4 days later. CONCLUSIONS: In ventral approaches to the cervical spine, precise preoperative planning and a detailed knowledge of the surgical anatomy are mandatory. In cases of injury to the vertebral arteries, direct surgical repair is most appropriate to prevent complications arising from fistulas, late-onset hemorrhages, pseudoaneurysms, thrombosis, and emboli. Alternatively, endovascular techniques or even clipping or ligation of the affected artery should be considered.

Endoscopic surgical anatomy of the paediatric third ventricle studied using virtual neuroendoscopy based on 3-D ultrasonography.

INTRODUCTION: Endoscopic treatment for occlusive hydrocephalus requires knowledge of individual ventricular and vascular anatomies of the ventricular system. METHODS: We studied the feasibility of virtual neuroendoscopy (VNE) based on 3-D ultrasonography (3-D US) for the identification of parenchymal and vascular anatomical landmarks of the third ventricle and its impact on the surgical planning of endoscopic third ventriculostomy (ETV) in paediatric patients. 3-D US was performed through the anterior fontanel in four infants with hydrocephalus. RESULTS: Virtual neuroendoscopy revealed the size of the foramen of Monro, anatomical landmarks of the floor of the third ventricle crucial for correct fenestration during ETV, but not the premesencephalic cistern. The basilar bifurcation was identified in relation to the floor of the third ventricle by VNE (power-Doppler ultrasonography) and confirmed intraoperatively after ETV. CONCLUSION: 3-D US-based VNE reveals detailed anatomical information on the ventricular system including the foramen of Monro and the floor of the third ventricle. Within the premesencephalic cistern vascular anatomy can be visualized, but not non-vascular structures.

Virtual endoscopy of the cerebral ventricles based on 3-D ultrasonography.

Virtual endoscopy enables preoperative surgical planning based on "surgeons' view" information in the individual patient. In neurosurgery, magnetic resonance (MR) images are mainly used for planning of virtual neuroendoscopy (VNE). We studied the feasibility of three-dimensional (3-D) ultrasonography as the imaging modality for VNE in pediatric patients with hydrocephalus. 3-D ultrasonography data sets were obtained through the open anterior fontanelle and analyzed using perspective volume rendering, with delineation of the ventricular system for anatomical details in relation to standard ultrasonography and intraoperative anatomy, during endoscopy in two infants with hydrocephalus. VNE clarified anatomical variants seen on standard ultrasonography images, anticipated ventricular dysmorphia seen during neuroendosopy and enabled a realistic impression of an endoscopic inspection into the ventricular system of the two infants studied. Based on 3-D ultrasonography, VE enables detailed information on ventricular anatomy in pediatric patients for planning of endoscopic interventions.

Monitoring of brain tissue oxygenation during aneurysm surgery: prediction of procedure-related ischemic events.

OBJECT: The aim of this study was to evaluate the feasibility of monitoring brain tissue oxygenation (PO2) during aneurysm surgery for the detection of procedure-related ischemia. METHODS: Between 1997 and 1998, PO2 was monitored prospectively in a cohort of 40 patients (42 recordings) during aneurysm surgery in the anterior circulation within the vascular territory of the aneurysm-bearing artery. The position of the probe used to measure oxygenation levels was verified on computerized tomography (CT) scanning on the 1st postoperative day. Because of the mislocation of one probe and the malfunction of another, data from only 38 patients (40 recordings) were suitable for analysis. Relative changes from baseline to absolute nadir values of intraoperative PO2 were correlated with simultaneously recorded somatosensory evoked potentials (SSEPs), and cardiovascular and ventilatory parameters. The frequency of ischemic events was evaluated with the aid of CT on the 1st postoperative day as a substitute parameter for intraoperative ischemia. Clinical outcome was evaluated 30 days postoperatively based on the Glasgow Outcome Scale. Except for three, all patients underwent surgery for treatment of a symptomatic aneurysm. Mean baseline PO2 was 23.9 mm Hg (range 2-67.2 mm Hg) before clip application. A relative decrease in PO2 (20% decrease in value compared with baseline) occurred in 12 patients and was a sensitive indicator for the risk of ischemia during temporary arterial occlusion, but was less predictive of nonocclusive ischemia (sensitivity 0.5; positive predictive value [PPV] 0.42; p > 0.05). Results of receiver operating characteristic analysis demonstrated a postclipping PO2 nadir of 15 mm Hg as a dichotomizing threshold for the prediction of ischemia. This threshold rendered an improved sensitivity (0.9) and PPV (0.56) for procedure-related ischemia (p = 0.0003). The results of utility analysis revealed this monitoring parameter to be clinically diagnostic. Only PO2 monitoring, and not SSEP at the tibial nerve, was predictive of ischemia within the anterior cerebral artery territory. CONCLUSIONS: Using 15 mm Hg as a dichotomizing threshold, intraoperative PO2 monitoring enables one to identify patients at risk for procedure-related ischemia during aneurysm surgery and surpasses SSEP monitoring. This newly defined threshold based on intraoperative PO2 monitoring provides a basis for studies on treatments for procedure-related ischemia during aneurysm surgery.

PMMA vertebroplasty in patients with malignant vertebral destruction of the thoracic and lumbar spine.

OBJECT: Patients with osteolytic metastases frequently suffer from serious local and radicular pain. Pathophysiologically, local pain arises from skeletal instability, whereas radicular pain originates from compression of nerve roots by local tumor growth. Causal treatment of osteolytic metastases in disseminated malignant disease is very difficult. Resection of vertebrae, in combination with ventro-dorsal stabilization, is a complex treatment for patients with a limited life expectancy. Percutaneous polymethylmethacrylate (PMMA) vertebroplasty is a new and easy method of relieving patients' pain. In addition, it is both cost effective and safe. Pain is reduced immediately after treatment. Due to the regained vertebral stability, early mobilization of the patients is possible. METHODS: A total of 22 patients with osteolytic malignancies of the thoracic and lumbar spine were treated with PMMA vertebroplasty. Prior to and after surgery, then six weeks and six months after discharge from hospital, patients answered the Oswestry Low Back Pain Disability (OLBPD) Questionnaire for assessment of treatment-related change in disability. Percutaneous vertebroplasty was performed in a total of 19 patients. In three patients with tumor related compression of nerve roots an open neurolysis was performed followed by vertebroplasty. RESULTS: A total of 86% of patients reported a significant pain reduction. Vertebroplasty was highly beneficial for patients with pain related to local instability of the spine, but less so in patients with additional nerve root compression. Extravasation of PMMA beyond the vertebral margins was observed in 23% of the cases. No treatment-related clinical or neurological complications were seen. CONCLUSIONS: PMMA vertebroplasty is a useful and safe method of pain relief for patients with malignant osteolytic diseases of the thoracic and lumbar spine.

The tissue level of dexamethasone in human brain tumors is about 1000 times lower than the cytotoxic concentration in cell culture.

In glioblastoma patients dexamethasone is routinely administered as an antiedematous drug. In contrast to its empirically proven effect, the biochemical way of action remains poorly understood. In order to assess whether a direct cytotoxic effect is present in vivo we compared dexamethasone levels in brain tumor specimens with its cytotoxic concentrations in cell culture. Biopsy specimens were taken during microsurgical tumor removal, homogenized and dexamethasone levels were measured by high pressure liquid chromatography. In cell culture we tested different concentrations of dexamethasone on A172, U87, U373 cells and on eleven primary glioblastoma cell lines. Furthermore a pilocytic astrocytoma I, an astrocytoma II and an oligodendroglioma III and a meningioma were examined. Cell viability was assessed using the Alamar Blue assay and the concentrations resulting in loss of 50% of the cell population were calculated (LD50). The average brain tumor tissue concentration of dexamethasone was 225 nanogram g(-1). The mean LD50 in cell culture ranged at 222 microgram ml(-1). We conclude that a direct cytotoxic effect of dexamethasone on brain tumor cells is not present in vivo because the tissue levels of the drug are about 1000 times lower than the LD50 in cell culture.