Practice choices and challenges in the current intrathecal therapy environment: an online survey.

OBJECTIVE: The objective of this study was to evaluate current practice characteristics, treatment choices, clinical experiences, and economic concerns associated with intrathecal therapy. DESIGN: Health care professionals in the United States, who were known to actively use intrathecal therapy in their practices, were recruited to participate in an online survey; contact information was obtained via Internet searches, university Websites, association memberships, industry databases, and personal contacts. Survey responses were summarized descriptively. RESULTS: Of the 329 practitioners who were contacted, 87 participated in the survey. Most participants specialized in anesthesiology (77.0%), worked in a private practice or private hospital (74.7%), and had been practicing pain management for more than 10 years (64.4%). Morphine was the most frequently used opioid for the initiation of intrathecal therapy (80.7% of practitioners), and 81.9% had used ziconotide in their practice. Most practitioners (63.9%) had treated at least one patient who developed a granuloma, and 66.0% of those practitioners had a patient experience permanent or temporary neurological injury due to a granuloma. Fewer than half of practitioners were satisfied with reimbursement from private insurance companies (25.3%) or workers compensation (34.9%), and 90.5% believed reimbursement rates for filling, refilling, and programming patient pumps are not adequate to cover practice costs. The majority of practitioners (56.6%) use fewer pumps in their practices because of reimbursement issues. CONCLUSIONS: Intrathecal pain management practices continue to evolve as the options for treatment increase, and the body of applicable scientific literature grows; however, economic considerations can influence clinical decisions and may interfere with treatment choice and patient access to therapy.

Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study.

Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemotherapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery.

Stereotactic radiosurgical treatment of cerebral metastases arising from breast cancer.

OBJECTIVE: This study was undertaken to evaluate the outcome of patients undergoing stereotactic radiosurgery (SRS) as primary or salvage treatment of brain metastases arising from breast cancer. MATERIALS AND METHODS: Between July 2000 and September 2005, the medical records of 49 breast cancer patients who underwent SRS for 84 brain metastases were reviewed retrospectively. Thirty-four patients received SRS as primary brain metastasis treatment and 15 patients received SRS as salvage treatment of brain metastasis recurrence following prior whole-brain radiation therapy. The Kaplan-Meier method, univariate comparisons with log-rank test, and multivariate analysis were performed. RESULTS: Median follow-up was 12 months (range, 5-50 months) and median survival was 19 months for all patients. The 1- and 2-year overall survival (OS) rates were 60%, 56%, and 55%, 23% for initial SRS alone and SRS salvage groups, respectively (P = 0.99). A multivariate analysis showed that a high KPS score (KPS > or =90 vs. <90; P = 0.02), a higher SIR value (SIR > or =6 vs. <6; P = 0.001), postmenopausal status (P = 0.003), and positive estrogen receptor status (P = 0.04) were predictive of better survival. The 1- and 2-year local control rates were 79%, 49%, and 77%, 46% for SRS alone and SRS salvage group, respectively. CONCLUSION: SRS can be used as primary treatment of brain metastases or salvage of recurrences after whole-brain radiation therapy to achieve good local control on the order of close to 80% at 1 year. The median survival of brain metastasis patients with breast cancer of 19 months appears favorable compared with the general brain metastasis population.

A pilot study of neurocognitive function in patients with one to three new brain metastases initially treated with stereotactic radiosurgery alone.

OBJECTIVE: Whether to administer or omit adjuvant whole-brain radiation therapy in conjunction with stereotactic radiosurgery (SRS) in the initial management of patients with one to three newly diagnosed brain metastases is the subject of debate. This report provides data from a pilot study in which neurocognitive function (NCF) was prospectively measured for patients with one to three newly diagnosed brain metastases treated with initial SRS alone. METHODS: Fifteen patients were prospectively treated with initial SRS alone. Assessment of NCF and magnetic resonance imaging scans were performed. RESULTS: At baseline, 67% of the patients had impairment on one or more tests of NCF. The domains most frequently impaired at baseline were executive function, motor dexterity, and learning/memory with an incidence of 50, 40, and 27% respectively. Brain metastasis volume (.3 cm3) measured at the time of initial SRS treatment was associated with worse performance on a measure of attention (P < 0.05). At 1 month, declines in the learning/memory and motor dexterity domains were most common. In a subgroup of five patients still alive 200 days after enrollment, four patients (80%) demonstrated stable or improved learning/memory, three (60%) demonstrated stable or improved executive function, and three (60%) demonstrated stable or improved motor dexterity relative to their baseline evaluation. CONCLUSION: Although two-thirds of the brain metastasis patients had impaired NCF at baseline, the majority of five long-term survivors had stable or improved NCF performance across executive function, learning/memory, and motor dexterity.

Polyanalgesic consensus conference 2007: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel.

Background. Expert panels of physicians and nonphysicians in the field of intrathecal therapies convened in 2000 and 2003 to make recommendations for the rational use of intrathecal analgesics based on the preclinical and clinical literature known up to those times. An expert panel of physicians convened in 2007 to update previous recommendations and to form guidelines for the rational use of intrathecal opioid and nonopioid agents. Methods. A review of preclinical and clinical published relevant studies from 2000 to 2006 was undertaken and disseminated to a convened expert panel of physicians and nonphysicians. Focused discussions were held on the rational use of intrathecal agents and a survey asking questions regarding intrathecal therapies management was given to the panelists. Results. The panelists, after review of the literature from 2000 to 2006 and discussion, created an updated algorithm for the rational use of intrathecal opioid and nonopioid agents in patients with nonmalignant and end-of-life pain. Of note is that the panelists felt that ziconotide, based on new and relevant literature and experience, should be updated to a line one intrathecal drug.

Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis.

BACKGROUND: Solitary brain metastases occur in about 50% of patients with brain metastases from nonsmall cell lung cancer (NSCLC). The standard of care is surgical resection of solitary brain metastases, or stereotactic radiosurgery (SRS) plus whole brain radiation therapy (WBRT). However, the optimal treatment for the primary site of newly diagnosed NSCLC with a solitary brain metastasis is not well defined. The goal was to distinguish which patients might benefit from aggressive treatment of their lung primary in patients whose solitary brain metastasis was treated with surgery or SRS. METHODS: The cases of 84 newly diagnosed NSCLC patients presenting with a solitary brain metastasis and treated from December 1993 through June 2004 were retrospectively reviewed at The University of Texas M. D. Anderson Cancer Center. All patients had undergone either craniotomy (n = 53) or SRS (n = 31) for management of the solitary brain metastasis. Forty-four patients received treatment of their primary lung cancer using thoracic radiation therapy (median dose 45 Gy; n = 8), chemotherapy (n = 23), or both (n = 13). RESULTS: The median Karnofsky performance status score was 80 (range, 60-100). Excluding the presence of the brain metastasis, 12 patients had AJCC Stage I primary cancer, 27 had Stage II disease, and 45 had Stage III disease. The median follow-up was 9.7 months (range, 1-86 months). The 1-, 2-, 3-, and 5-year overall survival rates from time of lung cancer diagnosis were 49.8%, 16.3%, 12.7%, and 7.6%, respectively. The median survival times for patients by thoracic stage (I, II, and III) were 25.6, 9.5, and 9.9 months, respectively (P = .006). CONCLUSIONS: By applying American Joint Committee on Cancer staging to only the primary site, the thoracic Stage I patients in our study with solitary brain metastases had a more favorable outcome than would be expected and was comparable to Stage I NSCLC without brain metastases. Aggressive treatment to the lung may be justified for newly diagnosed thoracic Stage I NSCLC patients with a solitary brain metastasis, but not for locally advanced NSCLC patients with a solitary brain metastasis.

Case-control study of stereotactic radiosurgery for recurrent glioblastoma multiforme.

OBJECT: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma multiforme (GBM) was evaluated in a case-control study. METHODS: All patients who underwent SRS for recurrent GBM before March 2003 formed the case group. A control group of patients who did not undergo SRS was created from an institutional database, and each case was matched for known prognostic factors in GBM. The medical and neuroimaging records of all the patients were reviewed, and survival and treatment outcomes were recorded. The case and control groups were well matched with regard to demographics and pre-SRS interventions. In the control group, the date on which magnetic resonance imaging identified a recurrent lesion that would have been eligible for SRS was deemed the "SRS" date. The number of surgeries performed in the control group was statistically higher than that in the case group. The median duration of overall survival from diagnosis was 26 months in the case group and 23 months in the control group. From the date of SRS or "SRS", the median duration of survival was 11 months in the case group and 10 months in the control group, a difference that was not statistically significant. CONCLUSIONS: It appears that a subgroup of patients with GBMs has a higher than expected median survival duration despite the initial prognostic factors. In patients with localized recurrences, survival may be prolonged by applying aggressive local disease management by using either SRS or resection to equal advantage.

Outcome variation among "radioresistant" brain metastases treated with stereotactic radiosurgery.

OBJECTIVE: To determine the influence of histopathological diagnosis on the outcome of "radioresistant" brain metastases treated with stereotactic radiosurgery (SRS). METHODS: Patients (n = 189) with "radioresistant" brain metastases (n = 264) were consecutively treated with SRS between August 1991 and July 2002. The primary site of brain metastases was melanoma (n = 103), renal cell carcinoma (n = 77), and sarcoma (n = 9). The median age of the patients was 52 years, and the median Karnofsky Performance Scale score was 80. Initial brain metastasis presentation was single in 112 patients (59%). The median SRS dose was 18 Gy (range, 10-24 Gy). The median tumor volume was 1.6 cm3 (range, 0.06-27.5 cm3). The median follow-up of all patients was 7.4 months (range, 0.16-52 mo). RESULTS: The actuarial freedom from progression after 1 year was 64% for renal cell carcinoma patients, 47% for melanoma patients, and 0% for sarcoma patients (P < 0.001). The median survival time for all patients from time of SRS was 7.5 months. The rate of 1-year survival was 40% for renal cell carcinoma patients, 25% for melanoma patients, and 22% for sarcoma patients (P = 0.0354). The incidence of neurological death was lower among patients diagnosed with renal cell carcinoma (31%) than among patients with melanoma (66%) or sarcoma (60%) (P = 0.001). CONCLUSION: Survival after SRS is significantly worse for patients with melanoma and sarcoma brain metastases compared with patients with renal cell carcinoma. Our data show that progressive brain metastases seem to cause most of the cancer-related deaths among patients with SRS-treated melanoma and sarcoma brain metastases. Future investigations using chemotherapy or novel agents to enhance the effectiveness of SRS to melanoma and sarcoma brain metastases seem warranted.

Epidural and intrathecal analgesia is effective in treating refractory cancer pain.

The use of neuraxial (intrathecal and epidural) analgesia has been suggested in treatment guidelines put forth for the treatment of refractory cancer pain. We review the literature and present our algorithm for using neuraxial analgesia. We also present our outcomes using this algorithm over a 28-month period. We used neuraxial analgesia in 87 of 4,107 patients, approximately 2% of those seen for pain consultation. Evaluation of those patients at an 8-week follow-up revealed improved pain control. After institution of neuraxial analgesia, there was a significant reduction in the proportion of patients with severe pain (defined as a "pain worst" score in the severe range of 7-10), from 86% to 17%, noted to be highly statistically significant. At follow-up, numerical pain scores decreased significantly from 7.9 +/- 1.6 to 4.1 +/- 2.3. No difference was noted between the intrathecal and epidural groups. Oral opioid intake after instituting neuraxial analgesia revealed a significant decrease from 588 mg/day oral morphine equivalents to 294 mg/day. At follow-up, self-reported drowsiness and mental clouding (0-10) also significantly decreased from 6.2 +/- 3.0 and 5.4 +/- 3.4 to 3.2 +/- 3.0 and 3.1 +/- 3.0, respectively. This retrospective review shows promising efficacy of neuraxial analgesia in the context of failing medical management.

Stereotactic radiosurgical treatment in 103 patients for 153 cerebral melanoma metastases.

PURPOSE: To report on the outcome of patients with melanoma brain metastases treated with stereotactic radiosurgery (SRS). PATIENTS AND METHODS: One hundred three patients with 153 intracranial melanoma metastases consecutively underwent Linac-based SRS between November 1991 and October 2001. The Kaplan-Meier method, univariate comparisons with log-rank test, and multivariate analyses with classification and regression tree models were performed. Calculations were based on last imaging date rather than the date of the last visit. RESULTS: Median age was 51 years (range, 18-93 years). Median Karnofsky performance status was 90. Sixty-one patients (59%) had single brain metastasis at presentation. Treatment sequence was SRS alone (61 patients), SRS + whole-brain radiotherapy (WBRT) (12 patients), and salvage SRS after WBRT (30 patients). The median tumor volume was 1.9 cm(3) (range, 0.06-22.3 cm(3)). The median SRS minimum peripheral dose and isodose was 18 Gy (range, 10-24 Gy) and 85% (range, 60%-100%), respectively. The median follow-up was 6 months for all patients and 13 months (range, 2-46 months) for patients alive at the time of analysis. The 1-year local control (LC) for all patients treated with SRS was 49%. Among the patients treated with initial SRS alone, the 1-year LC was better for patients with tumors < or =2 cm(3) than with tumors >2 cm(3): 75.2% vs. 42.3% (p < 0.05). The 1-year distant brain metastasis-free survival incidence was 14.7% for the 73 patients receiving either initial SRS alone or SRS +WBRT. The initial number of brain lesions (single vs. multiple) was the only factor with a significant effect on distant brain metastasis-free survival at 1 year: 23.5% for single metastases and 0% for multiple lesions (p < 0.05). The 1-year overall survival was 25.2%. Stratification by Score Index for Radiosurgery (SIR) revealed a significant effect on survival, which was 29% at 1 year for SIR >6 and 10% for SIR <==6 (relative hazard ratio, 2.1; p < 0.05) in classification and regression-tree multivariate analysis involving age, Karnofsky performance status, primary tumor control, tumor volume, SRS dose, SIR (>6 vs. < or =6), and systemic disease status. CONCLUSIONS: Initial SRS alone was an effective treatment modality for smaller cerebral melanoma metastases, achieving a 75% incidence of 1-year LC for < or =2 cm(3) single brain metastases and should be considered in patients with SIR >6. The role of WBRT in melanoma brain metastases cannot be addressed, owing to retrospective bias toward administering this treatment to patients with more aggressive disease. A prospective study is needed to assess the role of WBRT in patients with melanoma brain metastasis.

Safety of continuous intrathecal midazolam infusion in the sheep model.

UNLABELLED: We investigated the safety of midazolam administered by continuous intrathecal infusion in relevant animal models. Preservative-free midazolam was delivered to sheep and pigs by using implanted infusion systems (SynchroMed pumps plus silicone catheters). Sheep received midazolam 5 mg/d (n = 4) or 15 mg/d (n = 7) or saline (n = 2) for 43 days at 125 micro L/h. One sheep received 10 mg/d. Infusion concentrations ranged from 1.7 to 2.5 mg/mL (5 mg/d) and from 2.5 to 5.0 mg/mL (15 mg/d). Pigs were evaluated for toxicity only and received 15 mg/d (n = 2) or saline (n = 1) for 43 days at 125 micro L/h. Behavior, neurologic function, and vital signs were documented. Serum and cerebrospinal fluid chemistry and cytology were evaluated, and histology was performed on spinal cord tissue. Behavior and neurologic function remained normal in all subjects. Gross and microscopic evaluation of spinal tissue revealed mild inflammation surrounding the catheter tract in both the midazolam-treated and the saline-treated groups. This inflammation was likely attributable to the mechanical presence of the catheter. These data demonstrate that continuous intrathecal infusion of preservative-free midazolam at doses up to 15 mg/d were well tolerated. IMPLICATIONS: We investigated the toxicity of preservative-free intrathecal midazolam delivered continuously via implanted infusion systems in sheep and pigs. Doses of 5-15 mg/d were well tolerated. The lack of neurotoxicity observed suggests that intrathecal midazolam may be an alternative for the treatment of intractable pain that is unresponsive to opioids.

Polyanalgesic Consensus Conference 2003: an update on the management of pain by intraspinal drug delivery-- report of an expert panel.

Intraspinal drug infusion using fully implantable pump and catheter systems is a safe and effective therapy for selected patients with chronic pain. The options for this approach are increasing, as drugs that are commercially available for systemic administration are adapted to this use and other drugs that are in development specifically for intraspinal administration become available. In 2000 a Polyanalgesic Consensus Conference was organized to evaluate the existing literature and develop guidelines for drug selection. The major outcome of this effort, an algorithm for drug selection, was based on the best available evidence at the time. Rapid changes have occurred in the science and practice of intraspinal infusion and a Polyanalgesic Consensus Conference 2003 was organized to pursue the following goals: 1) to review the literature on intraspinal drug infusion since 1999, 2) to revise the 2000 drug-selection algorithm, 3) to develop guidelines for optimizing drug dosage and concentration, 4) to create a process for documenting minimum evidence supporting the use of a drug for intraspinal infusion, and 5) to clarify issues pertaining to compounding of drugs. Based on the best available evidence and expert opinion, consensus recommendations were developed in all these areas. The panel's conclusions may provide a foundation for clinical practice and a rational basis for new research.

Continuous intrathecal infusion of hydromorphone: safety in the sheep model and clinical implications.

OBJECTIVE: To determine the safety of hydromorphone delivered by continuous intrathecal infusion via implanted delivery systems in sheep. DESIGN: Sheep implanted with intrathecal infusion systems were randomly assigned to receive either 1.5, 3, or 6 mg/day hydromorphone HCl or saline control (3 sheep/dose level) at a fixed infusion rate of 1.92 mL/day for 28-31 days. Infusions were initiated approximately 5 days after surgical implantation of the delivery systems (pumps and intrathecal catheters), and investigators were blinded to doses administered. An additional group of sheep (N=3) received hydromorphone (open label) at a dose of 12 mg/day. All animals were examined daily during drug infusion for changes in behavior and neurologic function. Cerebrospinal fluid was analyzed for protein, cytology, and hydromorphone concentration in samples collected prior to and at the end of drug infusion. The spinal cord with the catheter in situ was removed en bloc and fixed in formalin for microscopic analysis. RESULTS: All sheep receiving intrathecal hydromorphone exhibited gaiting deficits and biting behavior over the caudal lumbar area above the infusion site. Animals treated with 12 mg/day were sedate and lethargic, and exhibited repeated biting behavior over the caudal lumbar area during the study. No lesions were noted in any animal upon gross evaluation of the spinal cord. Microscopic changes were comparable between hydromorphone- and saline-treated animals with one exception. Mild inflammation 5 cm cranial to the catheter tip was present in two of three sheep receiving 12 mg/day and in one of three sheep receiving 1.5 mg/day. Mild chronic inflammation hydromorphone in the vicinity of the catheter was also presented in saline-treated animals. CONCLUSIONS: Hydromorphone was not associated with inflammatory mass formation in the sheep model. Further studies are necessary to determine whether hydromorphone is a safer alternative to morphine for continuous intrathecal infusion for the treatment of chronic pain.

Spinal cord stimulation relieves chemotherapy-induced pain: a clinical case report.

We present two patients with chemotherapy-induced painful neuropathy that had been poorly controlled with medications but successfully treated with spinal cord stimulation (SCS). A trial period of SCS provided effective pain relief in both patients who subsequently underwent permanent stimulator implantation. Psychophysical tests were performed before and after the implantation of trial and permanent stimulators. SCS improved pain scores and facilitated a reduction of medications. Both patients reported improved gait and one of them also reported an increase in leg flexibility. Psychophysical tests demonstrated an improvement in touch and sharpness detection thresholds. In summary, SCS offers a therapeutic option for patients with chemotherapy-induced peripheral neuropathy who have poor pain relief with standard medical treatment.

Refractory insomnia in a patient with spinal cord stimulator lead migration.

This report outlines a case of refractory insomnia temporally related to migration of cervical spinal cord stimulator leads. To our knowledge this association is previously unreported. The patient had an intractable sleep disturbance until replacement of the leads. A brief review of insomnia and its complex relationship to chronic pain is presented. We hope that this case will stimulate further discussion and possibly bring to light new insights into spinal cord stimulation and insomnia and alert others to this possible clinical association of symptoms.

Complex regional pain syndrome (CRPS): survey of current practices.

BACKGROUND AND OBJECTIVES: There are numerous treatments for complex regional pain syndrome (CRPS). These treatments are varied in scope and include pain management therapies, psychological therapies, and physiotherapy. Treatment guidelines have been published in the past, but little information exists as to how clinicians utilize these guidelines. Moreover, there has been a paradigm shift from the older "reflex sympathetic dystrophy" (RSD) nomenclature, with largely sympathetic block driven diagnosis and therapy to more recent trends towards more inclusive "CRPS" diagnostic criteria and multidisciplinary treatment. There remains controversy regarding the selection of various techniques, and the timing of advancement through the treatment algorithm to the more aggressive, interventional techniques. We set out to determine current CRPS treatment practices of interventional pain specialists. METHODS: The authors developed a 36-item, 15-20-minute questionnaire. This questionnaire was sent to 453 interventional pain specialists. RESULTS: One-hundred-five surveys were returned, with 100 being complete. Eighty-three percent of our respondents were practicing anesthesiology pain specialists who on average treat 14.9 (SD = 16.8) CRPS patients per month. CONCLUSIONS: Our survey results revealed the use of a treatment algorithm for CRPS that consists of treatment using medical therapies (pharmacologic, blocks, catheters, and implantable devices), psychological therapies, and physiotherapy in a coordinated fashion. The trend among our survey respondents is to utilize increasingly interventional techniques after a failed 2- to 4-week trial of any one particular therapy.

Fusobacterial brain abscess: a review of five cases and an analysis of possible pathogenesis.

OBJECT: The cases of five patients with fusobacterial brain abscess are presented. The authors discuss their attempt to determine the pathogenesis. METHODS: The clinical and microbiological features of five cases of fusobacterial brain abscess are reviewed. Isolates of 2031 Fusobacterium spp. and other anaerobes collected (1989-2002) at our institution were analyzed and compared for incidences and isolation sources. The findings were correlated with extensive literature on the subject. The five patients were men between 45 and 74 years of age. All experienced an insidious onset of the disease and probable hematogenous seeding of the organism(s). One patient had a monomicrobic Fusobacterium necrophorum abscess, whereas the others had polymicrobic F. nucleatum abscesses. Despite surgery and a regimen of antibiotic medications and dexamethasone, three patients experienced a paradoxical deterioration 3 days postoperatively that necessitated reevacuation of the lesion. The evacuants observed at that time contained numerous leukocytes but no microorganisms, suggesting intensified inflammation as the likely cause of deterioration. This explanation is supported by literature that fusobacteria strongly activate neutrophils. An analysis of the 2031 anaerobes from blood, wounds, and abscesses showed the considerable virulence of Fusobacterium spp., which were able to enter and/or sustain themselves in the blood circulation. This pattern was similar to that of Clostridium spp., but different from those of Peptostreptococcus spp., Bacteroides spp., and Prevotella spp., which were less invasive but more abundant. CONCLUSIONS: Some fusobacterial brain abscesses may be associated with a paradoxical postoperative deterioration, which is probably due to intensified inflammation following treatment. The blood-borne dissemination and invasive behavior of fusobacteria likely initiate such a brain abscess, and further seeding of other synergic bacteria leads to a polymicrobic abscess.

The role of tumor size in the radiosurgical management of patients with ambiguous brain metastases.

OBJECTIVE: To identify a size cutoff below which it is safe to observe obscure brain lesions suspected of being metastases so that treatment of nonmetastases can be avoided. METHODS: Medical records from patients who underwent linear accelerator-based radiosurgery from August 1991 to October 2001 were reviewed. Inclusion criteria were defined as brain metastasis tumor volume less than 5 cm(3) (diameter, thick similar 2.1 cm) treated with a dose of 20 Gy or more. One hundred thirty-five patients had 153 evaluable brain metastases with follow-up imaging that met inclusion criteria. Median age was 54 years (range, 18-79 yr). Lesion primaries were non-small-cell lung (n = 39), melanoma (n = 44), renal (n = 37), breast (n = 18), colon (n = 3), sarcoma (n = 5), other (n = 5), and unknown primary (n = 2). Median tumor volume was 0.67 cm(3) (range, 0.06-4.58 cm(3)). The minimum peripheral dose was 20 Gy (n = 132) or 21 to 24 Gy (n = 21). At the time of analysis, the median follow-up for all patients was 10 months (range, 0.2-99 mo). RESULTS: The 1- and 2-year actuarial local control rates for all of the lesions were 69 and 46%, respectively. For lesions of 1 cm (0.5 cm(3)) or less, the corresponding local control rates were 86 and 78%, respectively, which was significantly higher than the corresponding rates of 56 and 24%, respectively, for lesions larger than 1 cm (0.5 cm(3)) (P = 0.0016). CONCLUSION: A convincing brain metastasis measuring less than 1 cm should be pursued aggressively. If the suspected brain metastasis is ambiguous, observation is proposed up to a diameter of 1 cm. This is the first study in the literature to identify a 1-cm cutoff for radiosurgical control of small brain metastases, and validation by additional studies is required.

Safety of chronic intrathecal morphine infusion in a sheep model.

BACKGROUND: The safety of chronically administered intrathecal morphine has been questioned. Therefore, the authors examined the behavioral and neurologic effects and neurotoxicity of continuous intrathecal morphine administration in sheep. METHODS: Groups of three sheep were implanted with intrathecal infusion systems for the continuous administration of morphine (3, 6, 9, 12, or 18 mg/day) or saline at a fixed infusion rate of 1.92 ml/day beginning approximately 7 days after implantation. Sheep were examined daily for any changes in behavior or neurologic function. After 28-30 days, the animals were humanely killed. Cerebrospinal fluid samples were collected and analyzed for protein, erythrocytes and leukocytes, and morphine content. The spinal cord and meninges with the catheter in situ was removed en bloc and fixed in formalin for histologic analysis. RESULTS: Unilateral hind-leg gait deficits were observed in two of three animals in each of the 12- and 18-mg/day dose groups. Gross and microscopic evaluation of spinal cord tissue from these animals revealed intradural-extramedullary inflammatory masses that compressed the spinal cord at the catheter-tip and mid-catheter areas. This inflammation was ipsilateral to extremities that exhibited gait deficits and had acute and chronic cellular components. CONCLUSIONS: The toxicity of intrathecal morphine seems to be dependent on the amount of morphine infused, although the effects of dose versus concentration cannot be clearly distinguished in this study. Intrathecal morphine doses of 12- 18 mg/day produced inflammatory masses extending from the catheter tip down the length of the catheter within the subarachnoid space. Doses of 6-9 mg/day produced mild-to-moderate inflammation 5 cm cranial to the catheter tip. A dose of 3 mg/day produced no neurotoxicity and spinal histopathologic changes that were equivalent to those observed in the saline-treated animals.