Byron Young

A Randomized Trial of Surgery in the Treatment of Single Metastases to the Brain

To assess the efficacy of surgical resection of brain metastases from extracranial primary cancer, we randomly assigned patients with a single brain metastasis to either surgical removal of the brain tumor followed by radiotherapy (surgical group) or needle biopsy and radiotherapy (radiation group). Forty-eight patients (25 in the surgical group and 23 in the radiation group) formed the study group; 6 other patients (11 percent) were excluded from the study because on biopsy their lesions proved to be either second primary tumors or inflammatory or infectious processes. Recurrence at the site of the original metastasis was less frequent in the surgical group than in the radiation group (5 of 25 [20 percent] vs. 12 of 23 [52 percent]; P less than 0.02). The overall length of survival was significantly longer in the surgical group (median, 40 weeks vs. 15 weeks in the radiation group; P less than 0.01), and the patients treated with surgery remained functionally independent longer (median, 38 weeks vs. 8 weeks in the radiation group; P less than 0.005). We conclude that patients with cancer and a single metastasis to the brain who receive treatment with surgical resection plus radiotherapy live longer, have fewer recurrences of cancer in the brain, and have a better quality of life than similar patients treated with radiotherapy alone.

Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial

BACKGROUND The standard treatment for spinal cord compression caused by metastatic cancer is corticosteroids and radiotherapy. The role of surgery has not been established. We assessed the efficacy of direct decompressive surgery. METHODS In this randomised, multi-institutional, non-blinded trial, we randomly assigned patients with spinal cord compression caused by metastatic cancer to either surgery followed by radiotherapy (n=50) or radiotherapy alone (n=51). Radiotherapy for both treatment groups was given in ten 3 Gy fractions. The primary endpoint was the ability to walk. Secondary endpoints were urinary continence, muscle strength and functional status, the need for corticosteroids and opioid analgesics, and survival time. All analyses were by intention to treat. FINDINGS After an interim analysis the study was stopped because the criterion of a predetermined early stopping rule was met. Thus, 123 patients were assessed for eligibility before the study closed and 101 were randomised. Significantly more patients in the surgery group (42/50, 84%) than in the radiotherapy group (29/51, 57%) were able to walk after treatment (odds ratio 6.2 [95% CI 2.0-19.8] p=0.001). Patients treated with surgery also retained the ability to walk significantly longer than did those with radiotherapy alone (median 122 days vs 13 days, p=0.003). 32 patients entered the study unable to walk; significantly more patients in the surgery group regained the ability to walk than patients in the radiation group (10/16 [62%] vs 3/16 [19%], p=0.01). The need for corticosteroids and opioid analgesics was significantly reduced in the surgical group. INTERPRETATION Direct decompressive surgery plus postoperative radiotherapy is superior to treatment with radiotherapy alone for patients with spinal cord compression caused by metastatic cancer.

A multi-institutional analysis of complication outcomes after arteriovenous malformation radiosurgery

PURPOSE To better understand radiation complications of arteriovenous malformation (AVM) radiosurgery and factors affecting their resolution. METHODS AND MATERIALS AVM patients (102/1255) who developed neurological sequelae after radiosurgery were studied. The median AVM marginal dose (Dmin) was 19 Gy (range: 10-35). The median volume was 5.7 cc (range: 0.26-143). Median follow-up was 34 months (range: 9-140). RESULTS Complications consisted of 80/102 patients with evidence of radiation injury to the brain parenchyma (7 also with cranial nerve deficits, 12 also with seizures, 5 with cyst formation), 12/102 patients with isolated cranial neuropathies, and 10/102 patients with only new or worsened seizures. Severity was classified as minimal in 39 patients, mild in 40, disabling in 21, and fatal in 2 patients. Symptoms resolved completely in 42 patients for an actuarial resolution rate of 54% +/- 7% at 3 years post-onset. Multivariate analysis identified significantly greater symptom resolution in patients with no prior history of hemorrhage (p = 0.01, 66% vs. 41%), and in patients with symptoms of minimal severity: headache or seizure as the only sequelae of radiosurgery (p < 0.0001, 88% vs. 34%). CONCLUSION Late sequelae of radiosurgery manifest in varied ways. Further long-term studies of these problems are needed that take into account symptom severity and prior hemorrhage history.

Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma

In Brain Tumor Cooperative Group Study 77-02, eleven institutions randomized 603 adult patients with supratentorial malignant glioma to one of four treatment groups following surgery: conventional radiotherapy (6000 cGy in 30-35 fractions) + BCNU, conventional radiotherapy + streptozotocin, hyperfractionated (twice daily) radiotherapy (6600 cGy in 60 fractions) + BCNU, and conventional radiotherapy with misonidazole followed by BCNU. Data were analyzed for the total randomized population and for the 557 patients (86% with glioblastoma multiforme) who met protocol eligibility specifications (including confirmed histopathology on central review). Median survival was approximately 10 months following randomization. Overall there was no statistically significant difference in survival among the four groups. Among non-glioblastoma patients, the misonidazole group appeared to have poor survival. Peripheral neuropathy was a dose-limiting toxicity with misonidazole. It is concluded that neither the addition of misonidazole nor hyperfractionated radiotherapy as given in this protocol offered any advantage over conventional radiotherapy plus either BCNU or streptozotocin for treatment of malignant glioma.

Relationship between admission hyperglycemia and neurologic outcome of severely brain-injured patients.

Severe head injury is associated with a stress response that includes hyperglycemia, which has been shown to worsen outcome before or during cerebral ischemia. To better define the relationship between human head injury and hyperglycemia, glucose levels were followed in 59 consecutive brain-injured patients from hospital admission up to 18 days after injury. The patients who had the highest peak admission 24-hour serum glucose levels had the worse 18-day neurologic outcome (p = 0.01). Patients with peak 24-hour admission glucose levels greater than 200 mg/dL had a two-unit increase in Glasgow Coma Scale score while patients with admission peak 24-hour serum glucose levels less than or equal to 200 mg/dL had a four-unit increase in Glasgow Coma Scale score during the 18-day study period (p = 0.04). There was a significant relationship between 3-month and 1-year outcome and peak admission 24-hour serum glucose level (p = 0.02 and p = 0.02, respectively). Those patients with admission peak 24-hour serum glucose levels less than or equal to 200 mg/dL had a greater percentage of favorable outcome at 18 days, 3 months, and 1 year than those with admission peak 24-hour glucose levels greater than 200 mg/dL (p = 0.0007, p = 0.03, and p = 0.005, respectively). A significant relationship between admission peak 24-hour Glasgow Coma Scale score and 18-day, 3-month, and 1-year outcomes was found (p = 0.0001, p = 0.0002, and p = 0.0002, respectively). Patients with mean admission peak 24-hour Glasgow Coma Scale scores of 3.5, 6, and 10 had mean admission 24-hour peak serum glucose levels of 252 +/- 23.5, 219.1 +/- 19, and 185.8 +/- 21, respectively (p = 0.05). These relationships were not significantly altered when confounding variables such as the amount of glucose given over the initial 24-hour postinjury period, the presence of diabetes or multiple injuries, and whether patients were given steroids, dilantin, or insulin were statistically incorporated. These data suggest that admission hyperglycemia is a frequent component of the stress response to head injury, a significant indicator of severity of injury, and a significant predictor of outcome from head injury.

Controllable Lifestyle: A New Factor in Career Choice by Medical Students.

Abstract To determine whether control of work hours (controllable lifestyle) was becoming an increasingly important factor in choices of specialties by medical students, data from three medical schools over the past ten, ten, and six years, respectively, were reviewed for the types of specialty training entered by students in the top 15% of their classes. Since students in the upper 15% of the class are likely to obtain the specialties of their choice, any change in the pattern of their specialty preferences probably reflects a general trend. Specialties that feature a controllable lifestyle (CL) were defined as anesthesiology, dermatology, emergency medicine, neurology, ophthalmology, otolaryngology, pathology, psychiatry, and radiology. Non‐CL specialties were surgery, medicine, family practice, pediatrics, and obstetrics‐gynecology. The results showed that the percentages of students entering CL specialties increased significantly at all three schools, the percentages of students entering non‐CL specialties decreased significantly at all three schools, and there was no significant change in the percentage of students entering surgical specialties. Acad. Med. 64(1989):606–609.: To determine whether control of work hours (controllable lifestyle) was becoming an increasingly important factor in choices of specialties by medical students, data from three medical schools over the past ten, ten, and six years, respectively, were reviewed for the types of specialty training entered by students in the top 15% of their classes. Since students in the upper 15% of the class are likely to obtain the specialties of their choice, any change in the pattern of their specialty preferences probably reflects a general trend. Specialties that feature a controllable lifestyle (CL) were defined as anesthesiology, dermatology, emergency medicine, neurology, ophthalmology, otolaryngology, pathology, psychiatry, and radiology. Non-CL specialties were surgery, medicine, family practice, pediatrics, and obstetrics-gynecology. The results showed that the percentages of students entering CL specialties increased significantly at all three schools, the percentages of students entering non-CL specialties decreased significantly at all three schools, and there was no significant change in the percentage of students entering surgical specialties.

The Controllable Lifestyle Factor and Students' Attitudes about Specialty Selection.

Questionnaires were distributed to 346 fourth-year students in nine medical schools. The students were asked to state their selected specialty and to rank the importance that each of 25 influences, listed as questionnaire items, had had in making their choice of specialty. Factor analysis showed that particular items were significantly associated with particular factors. The first factor emphasized perceived lifestyle (items in this category gave importance to remuneration, personal time, and prestige); the second factor emphasized cerebral activities and a practice orientation; and the third factor stressed altruistic values and attitudes. The authors classified the selected specialties into three groups: those characterized as having a non-controllable lifestyle (NCL), those with a controllable lifestyle (CL), and surgery. (CL specialties were defined as those that allow the physician to control the number of hours devoted to practicing the specialty.) Data were analyzed using factor analysis, and analysis of variance, and the Scheffe method. Analysis indicated that the perceived lifestyle factor was most closely associated with the responses of those students choosing CL specialties. Furthermore, this factor received the highest total loading of the three factors from all the students, thus indicating the level of interest in lifestyle factors. Responses to items that defined the cerebral and practice factor were highest from the group of students choosing CL specialties and lowest from the group choosing NCL specialties. The NCL students scored highest in the altruism factor and the CL students scored the lowest. The surgery and NCL groups were similar in attitude patterns, and both were substantially different in attitude patterns from those of the CL groups. (ABSTRACT TRUNCATED AT 250 WORDS)

Gamma knife radiosurgery using 90 Gy for trigeminal neuralgia.

The purpose of this paper was to note a potential source of error in magnetic resonance (MR) imaging. Magnetic resonance images were acquired for stereotactic planning for GKS of a vestibular schwannoma in a female patient. The images were acquired using three-dimensional sequence, which has been shown to produce minimal distortion effects. The images were transferred to the planning workstation, but the coronal images were rejected. By examination of the raw data and reconstruction of sagittal images through the localizer side plate, it was clearly seen that the image of the square localizer system was grossly distorted. The patient was returned to the MR imager for further studies and a metal clasp on her brassiere was identified as the cause of the distortion.A-60-year-old man with medically intractable left-sided maxillary division trigeminal neuralgia had severe cardiac disease, was dependent on an internal defibrillator and could not undergo magnetic resonance imaging. The patient was successfully treated using computerized tomography (CT) cisternography and gamma knife radiosurgery. The patient was pain free 2 months after GKS. Contrast cisternography with CT scanning is an excellent alternative imaging modality for the treatment of patients with intractable trigeminal neuralgia who are unable to undergo MR imaging.The authors describe acute deterioration in facial and acoustic neuropathies following radiosurgery for acoustic neuromas. In May 1995, a 26-year-old man, who had no evidence of neurofibromatosis Type 2, was treated with gamma knife radiosurgery (GKS; maximum dose 20 Gy and margin dose 14 Gy) for a right-sided intracanalicular acoustic tumor. Two days after the treatment, he developed headache, vomiting, right-sided facial weakness, tinnitus, and right hearing loss. There was a deterioration of facial nerve function and hearing function from pretreatment values. The facial function worsened from House-Brackmann Grade 1 to 3. Hearing deteriorated from Grade 1 to 5. Magnetic resonance (MR) images, obtained at the same time revealed an obvious decrease in contrast enhancement of the tumor without any change in tumor size or peritumoral edema. Facial nerve function improved gradually and increased to House-Brackmann Grade 2 by 8 months post-GKS. The tumor has been unchanged in size for 5 years, and facial nerve function has also been maintained at Grade 2 with unchanged deafness. This is the first detailed report of immediate facial neuropathy after GKS for acoustic neuroma and MR imaging revealing early possibly toxic changes. Potential explanations for this phenomenon are presented.In clinical follow-up studies after radiosurgery, imaging modalities such as computerized tomography (CT) and magnetic resonance (MR) imaging are used. Accurate determination of the residual lesion volume is necessary for realistic assessment of the effects of treatment. Usually, the diameters rather than the volume of the lesion are measured. To determine the lesion volume without using stereotactically defined images, the software program VOLUMESERIES has been developed. VOLUMESERIES is a personal computer-based image analysis tool. Acquired DICOM CT scans and MR image series can be visualized. The region of interest is contoured with the help of the mouse, and then the system calculates the volume of the contoured region and the total volume is given in cubic centimeters. The defined volume is also displayed in reconstructed sagittal and coronal slices. In addition, distance measurements can be performed to measure tumor extent. The accuracy of VOLUMESERIES was checked against stereotactically defined images in the Leksell GammaPlan treatment planning program. A discrepancy in target volumes of approximately 8% was observed between the two methods. This discrepancy is of lesser interest because the method is used to determine the course of the target volume over time, rather than the absolute volume. Moreover, it could be shown that the method was more sensitive than the tumor diameter measurements currently in use. VOLUMESERIES appears to be a valuable tool for assessing residual lesion volume on follow-up images after gamma knife radiosurgery while avoiding the need for stereotactic definition.This study was conducted to evaluate the geometric distortion of angiographic images created from a commonly used digital x-ray imaging system and the performance of a commercially available distortion-correction computer program. A 12 x 12 x 12-cm wood phantom was constructed. Lead shots, 2 mm in diameter, were attached to the surfaces of the phantom. The phantom was then placed inside the angiographic localizer. Cut films (frontal and lateral analog films) of the phantom were obtained. The films were analyzed using GammaPlan target series 4.12. The same procedure was repeated with a digital x-ray imaging system equipped with a computer program to correct the geometric distortion. The distortion of the two sets of digital images was evaluated using the coordinates of the lead shots from the cut films as references. The coordinates of all lead shots obtained from digital images and corrected by the computer program coincided within 0.5 mm of those obtained from cut films. The average difference is 0.28 mm with a standard deviation of 0.01 mm. On the other hand, the coordinates obtained from digital images with and without correction can differ by as much as 3.4 mm. The average difference is 1.53 mm, with a standard deviation of 0.67 mm. The investigated computer program can reduce the geometric distortion of digital images from a commonly used x-ray imaging system to less than 0.5 mm. Therefore, they are suitable for the localization of arteriovenous malformations and other vascular targets in gamma knife radiosurgery.

Arachidonic Acid‐Induced Oxidative Injury to Cultured Spinal Cord Neurons

Abstract : Spinal cord trauma can cause a marked release of free fatty acids, in particular, arachidonic acid (AA), from cell membranes. Free fatty acids, and AA by itself, may lead to secondary damage to spinal cord neurons. To study this hypothesis, cultured spinal cord neurons were exposed to increasing concentrations of AA (0.01‐10 μM). AA‐induced injury to spinal cord neurons was assessed by measurements of cellular oxidative stress, intracellular calcium levels, activation of nuclear factor‐κB (NF‐κB), and cell viability. AA treatment increased cell intracellular calcium concentrations and decreased cell viability. Oxidative stress increased significantly in neurons exposed to 1 and 10 μM AA. In addition, AA treatment activated NF‐κB and decreased levels of the inhibitory subunit, IκB. It is interesting that manganese superoxide dismutase protein levels and levels of intracellular total glutathione increased in neurons exposed to this fatty acid for 24 h, consistent with a compensatory response to increased oxidative stress. These results strongly support the hypothesis that free fatty acids contribute to the tissue injury observed following spinal cord trauma.

Metabolic and nutritional sequelae in the non-steroid treated head injury patient.

Energy production, substrate oxidation, serum protein levels, and weight change were studied in 16 non-steroid treated patients with severe head injury. Patients were evaluated during an average of 31.3 days from hospital admission to discharge. The mean measured energy expenditure (MEE) was 1.40 +/- 0.5 times predicted energy expenditure. Caloric balance [calories received = calories expended] was achieved by the 2nd week. Despite caloric balance and the administration of at least 1.5 g of protein per kg of body weight per day, the mean nitrogen balance was negative. There was a positive nitrogen balance in only 2 patients. These patients received a mean of 1.43 times the MEE in total kilocalories and 2.3 g of protein per kg of body weight. Fat and protein oxidation exceeded protein and fat administration for 3 weeks postinjury. Albumin levels dropped from a mean of 3.09 +/- 0.2 on admission to 1.98 +/- 0.4 within 2 weeks. The initial retinol binding protein levels were within the normal range, and the levels increased over time. There was marked weight loss (mean, 15.6 +/- 5.9 lb). Head injury induces a profound traumatic response identified by increased energy expenditure, a negative nitrogen balance, weight loss, hypoalbuminemia, and altered substrate oxidation. This response seems to be caused by the head injury alone and is not due to the administration of corticosteroids.