Mark E. Shaffrey

Decompressive Bifrontal Craniectomy in the Treatment of Severe Refractory Posttraumatic Cerebral Edema

OBJECTIVE The management of malignant posttraumatic cerebral edema remains a frustrating endeavor for the neurosurgeon and the intensivist. Mortality and morbidity rates remain high despite refinements in medical and pharmacological means of controlling elevated intracranial pressure; therefore, a comparison of medical management versus decompressive craniectomy in the management of malignant posttraumatic cerebral edema was undertaken. METHODS At the University of Virginia Health Sciences Center, 35 bifrontal decompressive craniectomies were performed on patients suffering from malignant posttraumatic cerebral edema. A control population was formed of patients whose data was accrued in the Traumatic Coma Data Bank. Patients who had undergone surgery were matched with one to four control patients based on sex, age, preoperative Glasgow Coma Scale scores, and maximum preoperative intracranial pressure (ICP). RESULTS The overall rate of good recovery and moderate disability for the patients who underwent craniectomies was 37% (13 of 35 patients), whereas the mortality rate was 23% (8 of 35 patients). Pediatric patients had a higher rate of favorable outcome (44%, 8 of 18 patients) than did adult patients. Postoperative ICP was lower than preoperative ICP in patients who underwent decompression (P = 0.0003). Postoperative ICP was lower in patients who underwent surgery than late measurements of ICP in the matched control population. A statistically significant increased rate of favorable outcomes was seen in the patients who underwent surgery compared to the matched control patients (15.4%) (P = 0.014). All patients who exhibited sustained ICP values above 40 torr and those who underwent surgery more than 48 hours after the time of injury did poorly. Evaluation of the 20 patients who did not fit into either of those categories revealed a 60% rate of favorable outcome and a statistical advantage over control patients (P = 0.0001). CONCLUSION Decompressive bifrontal craniectomy provides a statistical advantage over medical treatment of intractable posttraumatic cerebral hypertension and should be considered in the management of malignant posttraumatic cerebral swelling. If the operation can be accomplished before the ICP value exceeds 40 torr for a sustained period and within 48 hours of the time of injury, the potential to influence outcome is greatest.

Imaging Tumor Angiogenesis With Contrast Ultrasound and Microbubbles Targeted to αvβ3

Background Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrastenhanced ultrasound (CEU) with microbubbles targeted to &agr;v‐integrins expressed on the neovascular endothelium could be used to image angiogenesis. Methods and Results Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to &agr;v&bgr;33 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular &agr;v‐integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2±1 versus 35±14 mm2, P<0.001). Tumor blood volume increased by ≈35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, &agr;v&bgr;3‐targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from &agr;v&bgr;3‐targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7±0.4 versus 3.3±1.0 relative units, P<0.05). CEU signal from &agr;v&bgr;3‐targeted microbubbles was greatest at the periphery of tumors, where &agr;v‐integrin expression was most prominent, and correlated well with tumor microvascular blood volume (r=0.86). Conclusions CEU with microbubbles targeted to &agr;v&bgr;3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications. (Circulation. 2003;108:336‐341.)

Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma †

Convection-enhanced delivery (CED) of cintredekin besudotox (CB) was compared with Gliadel wafers (GW) in adult patients with glioblastoma multiforme (GBM) at first recurrence. Patients were randomized 2:1 to receive CB or GW. CB (0.5 microg/mL; total flow rate 0.75 mL/h) was administered over 96 hours via 2-4 intraparenchymal catheters placed after tumor resection. GW (3.85%/7.7 mg carmustine per wafer; maximum 8 wafers) were placed immediately after tumor resection. The primary endpoint was overall survival from the time of randomization. Prestated interim analyses were built into the study design. Secondary and tertiary endpoints were safety and health-related quality-of-life assessments. From March 2004 to December 2005, 296 patients were enrolled at 52 centers. Demographic and baseline characteristics were balanced between the 2 treatment arms. Median survival was 36.4 weeks (9.1 months) for CB and 35.3 weeks (8.8 months) for GW (P = .476). For the efficacy evaluable population, the median survival was 45.3 weeks (11.3 months) for CB and 39.8 weeks (10 months) for GW (P = .310). The adverse-events profile was similar in both arms, except that pulmonary embolism was higher in the CB arm (8% vs 1%, P = .014). This is the first randomized phase III evaluation of an agent administered via CED and the first with an active comparator in GBM patients. There was no survival difference between CB administered via CED and GW. Drug distribution was not assessed and may be crucial for evaluating future CED-based therapeutics.

Neurosurgical applications of fibrin glue: augmentation of dural closure in 134 patients

In a wide variety of neurosurgical procedures performed on 134 patients over a 3-year period, fibrin glue has been applied as an adjunct to dural closure. Overall success at preventing cerebrospinal fluid (CSF) leakage was 90% (121 of 134, 90% effective). In patients considered to be at high risk for CSF leakage intraoperatively but without pre-established fistulae (Group 1), the success rate was higher (111 of 119, 93% effective). In patients with pre-established CSF fistulae (Group 2), the success rate was lower (10 of 15, 67% effective). As single donor sources of concentrated fibrinogen are now available with reduced risks of blood-borne disease transmission, fibrin glue may be a valuable clinical tool for the neurosurgeon.

Poor drug distribution as a possible explanation for the results of the PRECISE trial

OBJECT Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial. METHODS Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution. RESULTS Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score. CONCLUSIONS The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme

Malignant gliomas are thought to be highly dependent on the mevalonate pathway for cell growth. Lovastatin, a cholesterol-lowering drug, inhibits not only the rate-limiting step in the mevalonate pathway (hepatic hydroxymethyl glutaryl coenzyme A reductase), but also the prenylation of several key regulatory proteins including ras and the small guanosine triphosphate binding proteins. Therefore, from August 1994 through March 1996, 18 patients with either anaplastic glioma or glioblastoma multiforme were entered into a trial testing the safety of high-dose lovastatin with or without radiation. Although the response data is too premature to evaluate activity, the fact that high doses of lovastatin are well tolerated with concurrent radiation suggests that central nervous system toxicity will not be a significant limiting toxicity as more selective farnesyltransferase inhibitors are brought into the clinic as radiation sensitizers.

Gamma Knife radiosurgery to the surgical cavity following resection of brain metastases.

OBJECT This study evaluated the efficacy of postoperative Gamma Knife surgery (GKS) to the tumor cavity following gross-total resection of a brain metastasis. METHODS A retrospective review was conducted of 700 patients who were treated for brain metastases using GKS. Forty-seven patients with pathologically confirmed metastatic disease underwent GKS to the postoperative resection cavity following gross-total resection of the tumor. Patients who underwent subtotal resection or who had visible tumor in the resection cavity on the postresection neuroimaging study (either CT or MR imaging with and without contrast administration) were excluded. Radiographic and clinical follow-up was assessed using clinic visits and MR imaging. The radiographic end point was defined as tumor growth control (no tumor growth regarding the resection cavity, and stable or decreasing tumor size for the other metastatic targets). Clinical end points were defined as functional status (assessed prospectively using the Karnofsky Performance Scale) and survival. Primary tumor pathology was consistent with lung cancer in 19 cases (40%), melanoma in 10 cases (21%), renal cell carcinoma in 7 cases (15%), breast cancer in 7 cases (15%), and gastrointestinal malignancies in 4 cases (9%). The mean duration between resection and radiosurgery was 15 days (range 2-115 days). The mean volume of the treated cavity was 10.5 cm3 (range 1.75-35.45 cm3), and the mean dose to the cavity margin was 19 Gy. In addition to the resection cavity, 34 patients (72%) underwent GKS for 116 synchronous metastases observed at the time of the initial radiosurgery. RESULTS The mean radiographic follow-up duration was 14 months (median 10 months, range 4-37 months). Local tumor control at the site of the surgical cavity was achieved in 44 patients (94%), and tumor recurrence at the surgical site was statistically related to the volume of the surgical cavity (p=0.04). During follow-up, 34 patients (72%) underwent additional radiosurgery for 140 new (metachronous) metastases. At the most recent follow-up evaluation, 11 patients (23%) were alive, whereas 36 patients had died (mean duration until death 12 months, median 10 months). Patients who showed good systemic control of their primary tumor tended to have longer survival durations than those who did not (p=0.004). At the last clinical follow-up evaluation, the mean Karnofsky Performance Scale score for the overall group was 78 (median 80, range 40-100). CONCLUSION Radiosurgery appears to be effective in terms of providing local tumor control at the resection cavity following resection of a brain metastasis, and in the treatment of synchronous and metachronous tumors. These data suggest that radiosurgery can be used to prevent recurrence following gross-total resection of a brain metastasis.

Convection-enhanced delivery of cintredekin besudotox (interleukin-13- PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: Phase 1 study of final safety results

OBJECTIVECintredekin besudotox (CB), a recombinant cytotoxin consisting of interleukin-13 and truncated Pseudomonas exotoxin, binds selectively to interleukin-13Rα2 receptors overexpressed by malignant gliomas. This study assessed the safety of CB administered by convection-enhanced delivery followed by standard external beam radiation therapy (EBRT) with or without temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) in patients with newly diagnosed malignant gliomas. METHODSAfter gross total resection of the tumor, two to four intraparenchymal catheters were stereotactically placed and CB (0.25 or 0.5 μg/mL) was infused for 96 hours. This was followed, 10 to 14 days later, by EBRT (5940–6100 cGy, 5 d/wk for 6–7 wk) with or without temozolomide (75 mg/m2/d, 7 d/wk during EBRT). Safety was assessed during an 11-week observation period after catheter placement RESULTSTwenty-two patients (12 men, 10 women; median age, 55 yr; 21 with glioblastoma multiforme and one with an anaplastic mixed oligoastrocytoma) were enrolled. None of the patients experienced dose-limiting toxicities in the first two cohorts (0.25 μg/mL CB + EBRT [n = 3] and 0.25 μg/mL CB + EBRT + temozolomide [n = 3]). One patient experienced a dose-limiting toxicity (Grade 4 seizure) in the third cohort (0.5 μg/mL CB + EBRT [n = 6]). Six patients in the final cohort (0.5 μg/mL CB + EBRT + temozolomide [n = 10]) completed treatment, and one patient experienced a dose-limiting toxicity (Grade 3 aphasia and confusion). Four patients were not considered evaluable for a dose decision and were replaced. CB related adverse events occurring in more than one patient were fatigue, gait disturbance, nystagmus, and confusion. No Grade 3 to 4 hematological toxicities were observed. CONCLUSIONCB (0.5 μg/mL) administered via convection-enhanced delivery before standard radiochemotherapy seems to be well tolerated in adults with newly diagnosed malignant gliomas. Further clinical study assessment is warranted.

Gastrointestinal myoelectric and clinical patterns of recovery after laparotomy.

The objective of this study was to define the patterns of myoelectric activity that occur throughout the gastrointestinal tract during normal recovery from laparotomy. Electrodes were placed on the stomach, jejunum, and transverse colon of 44 patients undergoing laparotomy. Basal electric rhythms in all areas showed no changes in frequency after operation (up to 1 month). Gastric spike wave activity showed a gradient of increasing activity from fundus to antrum. Antral spike activity was unchanged during the study. Jejunal spike activity was present in the earliest recordings and occurred in 45.9% +/- 3.5% to 59.9% +/- 5.5% of slow waves. Recovery of normal colon discrete and continuous electric response activity occurred on postoperative day 5.9 +/- 1.5. Bowel sounds returned on day 2.4 +/- 0.5 and passage of flatus and stool occurred on day 5.1 +/- 0.2. The myoelectric parameters measured are not absolutely predictive of uneventful recovery from postoperative ileus but they are, as a group, more informative than any currently available clinical criteria.

Metastasis to nervous system : spinal epidural and intramedullary metastases

SummarySpinal cord epidural metastasis (SEM) is a common complication of systemic cancer with an increasing incidence. Prostate, breast and lung cancer are the most common offenders. Metastasis usually arises in the posterior aspect of vertebral body with later invasion of epidural space. Pathophysiologically, vascular insufficiency is more important than direct spinal cord compression. The most common complaint is pain, and two thirds of patients with SEM have motor signs at initial diagnosis. Currently magnetic resonance imaging is the most sensitive diagnostic tool. The optimal management of SEM is still arguable, but recent advances in surgical management of SEM and higher complication rate of surgery following radiotherapy should persuade clinicians to consider de novo surgery where possible. Radiotherapy has an important role, particularly in treatment of radiosensitive tumors and in patients who are not candidates for surgery. Novel approaches such as stereotactic radiosurgery are promising; however, response to chemotherapy depends on inherent properties of primary tumor. Recurrent SEM is a substantial problem for which surgery or repeat radiotherapy may be options. Intramedullary metastasis is rare but should be considered in patients with systemic malignancy and asymmetrical presentation of myelopathic symptoms. The prognosis is usually poor and preferred modality of treatment is radiotherapy.