Morphologic magnetic resonance imaging features of therapy-induced cerebral necrosis.

To describe the morphologic magnetic resonance imaging (MRI) findings in histologically proven therapy-induced cerebral necrosis. We retrospectively reviewed the morphologic MRI findings in patients with therapy-induced cerebral necrosis. Images were reviewed for size, location, and characteristics of signal intensity abnormalities and T1-contrast enhancement. Images were also assessed for mass effect, necrosis, cyst, atrophy, cortical thinning, and leukoencephalopathy. The individual imaging characteristics were correlated with clinical and treatment variables. There were 44 patients. Seventy percent had a glioma, all patients had received radiation, and 57% had received chemotherapy in close proximity to radiation. All images demonstrated contrast enhancement, predominantly in the white matter. Enhancement was present in the periventricular/subependymal region in 50% of cases and the corpus callosum in 27%. The most common pattern of lesion peripheral enhancement was "spreading wavefront" and of interior enhancement was "Swiss cheese/soap bubble." The enhancing lesion was single in 60% of cases. Mass effect was present in 93% of patients. Location and patterns of enhancement were significantly associated with the interval from brain radiation to the diagnosis of therapy-induced cerebral necrosis, tumor histology, patient age, type of radiation, and administration of systemic chemotherapy. This is the largest study of the morphologic conventional MRI findings in pathologically confirmed therapy-induced cerebral necrosis. We characterized the imaging findings in a variety of tumor types following a variety of radiation treatments and other antineoplastic therapy. These findings may be of value in identifying therapy-induced cerebral necrosis in patients treated for a brain tumor.

PRODIGE: a randomized placebo-controlled trial of dalteparin low-molecular-weight heparin thromboprophylaxis in patients with newly diagnosed malignant glioma.

BACKGROUND AND OBJECTIVES: Venous thromboembolism (VTE) occurs in 20-30% of patients with malignant glioma per year of survival. We tested the efficacy of long-term dalteparin low-molecular-weight heparin (LMWH) for prevention of VTE in these patients. PATIENTS/METHODS: Adults with newly diagnosed malignant glioma were randomized to receive dalteparin 5000 anti-Xa units or placebo, both subcutaneously once daily for 6 months starting within 4 weeks of surgery. Treatment continued for up to 12 months. The primary outcome was the cumulative risk of VTE over 6 months. The target sample size was 512 patients. Events were adjudicated by a committee unaware of treatment. RESULTS: The trial began in 2002 and closed in May 2006 because of expiration of study medication. Ninety-nine patients were randomized to LMWH and 87 to placebo. Twenty-two patients developed VTE in the first 6 months: nine in the LMWH group and 13 in the placebo group [hazard ratio (HR) = 0.51, 95% confidence interval (CI): 0.19-1.4, P = 0.29]. At 6 months, there were three major bleeds on LMWH and none on placebo; at 12 months, 5 (5.1%) major bleeds on LMWH and 1 (1.2%) on placebo occurred (HR = 4.2, 95% CI: 0.48-36, P = 0.22). All major bleeds were intracranial and occurred while on study medication. The 12-month mortality rates were 47.8% for LMWH and 45.4% for placebo (HR = 1.2, 95% CI: 0.73-2.0, P = 0.48). CONCLUSIONS: Trends suggesting reduced VTE and increased intracranial bleeding were seen in the LMWH thromboprophylaxis group. The role of long-term anticoagulant thromboprophylaxis in patients with brain tumors remains uncertain.

Therapy-related myelodysplastic syndrome (t-MDS) in a patient with anaplastic astrocytoma: successful treatment with allogeneic bone marrow transplant.

OBJECTIVE: and importance Therapy-related myelodysplastic syndrome (t-MDS) is a rare and typically fatal complication of therapy for cancer, including brain tumors. We report successful therapy of t-MDS that developed after treatment for an anaplastic astrocytoma. CLINICAL PRESENTATION: t-MDS developed four and one-half years after successful therapy (resection, radiation and chemotherapy) administered for a cerebral anaplastic astrocytoma in a 34-year-old patient. INTERVENTION: The patient was treated with allogeneic bone marrow transplant (BMT) for t-MDS. CONCLUSION: She is alive three years after BMT with no evidence of brain tumor and in complete remission from t-MDS. To our knowledge, this is the first report of allogeneic BMT administered for t-MDS in an adult brain tumor patient. Clinicians must be alert to the development of t-MDS following chemotherapy for brain tumors and initiate appropriate treatment promptly.

Response to cancer therapy in a patient with a paraneoplastic choreiform disorder.

The authors report a patient with chorea and multifocal neurologic abnormalities associated with a small-cell lung carcinoma. A previously unreported antibody directed at a 76-kD neuronal protein antigen was identified in both serum and CSF. Antitumor treatment resulted in dramatic and sustained clinical neurologic and serologic responses.

Synthesis of stereodefined polysubstituted olefins. 1. Sequential intermolecular reactions involving selective, stepwise insertion of Pd(0) into allylic and vinylic halide bonds. The stereoselective synthesis of disubstituted olefins.

Palladium-catalyzed allylic substitution and cross-coupling reactions have been combined into a sequential procedure to provide a range of disubstituted olefin products starting from two-, three-, and four-carbon common olefin templates. Diverse application of this template strategy is demonstrated in a variety of model studies and in a parallel synthesis (combinatorial) approach to prepare an allylic amine molecular library. An approach toward the preparation of astaxanthin beta-D-diglucoside, an interesting antioxidant whose total synthesis has yet to be reported, using the olefin-template approach is also discussed.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

Diffuse bilateral cerebral astrocytomas with atypical neuroimaging studies.

The authors describe the clinical behavior of eight patients with cerebral astrocytomas, in whom computerized tomography (CT) or magnetic resonance (MR) imaging of the brain was characterized by diffuse bilateral cerebral hemisphere tissue density abnormalities and minimal focal mass effect. Five patients were newly diagnosed, and three others had been treated for focal low-grade astrocytoma. Histological diagnoses included anaplastic astrocytoma (three patients), low-grade astrocytoma (three patients), glioblastoma (one patient), and gliosis with later development of glioblastoma (one patient). In five patients, brain tumor was not suspected from the neuroimaging studies, the findings of which were mistaken for radiation leukoencephalopathy, vasogenic edema, or multiple sclerosis. Serial CT scans or MR images undertaken over intervals of 3 to 184 weeks showed progression of abnormal tissue densities in seven patients and multifocal contrast-enhancing masses developed on CT scan in two patients. An autopsy in each of four patients showed diffuse cerebral infiltration by astrocytoma. It is concluded that neuroimaging studies in some patients with diffusely infiltrating cerebral astrocytoma are atypical for neoplasm and can be mistaken for other diseases, especially those that predominantly affect cerebral hemisphere white matter.

Cerebrovascular complications in cancer patients.

Cerebrovascular disorders often complicate the clinical course of a variety of solid tumors and hematologic/lymphoreticular malignancies. In rare instances, cerebrovascular disease is the presenting sign of cancer. Cerebral hemorrhages are more common in leukemia, and infarctions are more common in lymphoma and solid tumors. The usual causes of stroke are the direct effects of tumor in the brain or adjacent structures, coagulation disorders, infection, or toxicity of antineoplastic therapy. The type of systemic cancer, the extent of systemic and central nervous system metastasis, and the type of antineoplastic treatment are the most important clues in determining the etiology of cerebrovascular disease in cancer patients. Neuroimaging studies often assist in diagnosis and disease localization. Coagulation function tests are most useful in identifying coagulopathies associated with hemorrhage.

Modulation of proliferation and antigen expression of a cloned human glioblastoma by interleukin-4 alone and in combination with tumor necrosis factor-alpha and/or interferon-gamma.

As part of continuing studies to investigate the possible regulatory effects of cytokines on malignant astrocytes, we investigated the effects of interleukin-4 (IL-4) alone and in combination with tumor necrosis factor-alpha (TNF alpha) and/or interferon-gamma (IFN gamma) on the cell growth and major histocompatibility complex (MHC) antigen expression of a cloned human glioblastoma cell line (9C). The 9C cells were treated with IL-4 alone or in combination with TNF alpha and/or IFN gamma and were examined for proliferation by crystal violet assay and for Class II MHC antigen by flow cytometry. Results indicated that IL-4 alone did not affect 9C proliferation. In combination with TNF alpha or IFN gamma, however, IL-4 significantly and dose-dependently inhibited cell growth. As previous reports have shown, TNF alpha combined with IFN gamma exerted an additive growth suppressive effect on glioblastoma cells, probably by enhancing TNF receptor expression. This additive effect of TNF alpha and IFN gamma was further enhanced by IL-4. In contrast, IL-4 did not modulate expression of Class II MHC antigen on 9C cells, even in combination with IFN gamma, which predictably enhanced this antigen. These results suggest that IL-4 is capable of modulating glioblastoma growth only in the presence of other cytokines, such as TNF alpha and/or IFN gamma. Further, the effect of IL-4 on glioblastoma proliferation is selective and independent of the mechanisms involved in regulating MHC antigen expression.

Obturator mononeuropathy caused by pelvic cancer: six cases.

OBJECTIVE: To report the clinical and pelvic CT findings in six patients with obturator mononeuropathy caused by cancer. DESIGN: A clinical case series of six patients followed for 2 months to 10 years (one patient lost to follow-up). SETTING: Three referral centers. PATIENTS: Three men and three women, ages 52 to 81 years. Three patients had transitional cell carcinoma of the bladder, and one patient each had pelvic papillary carcinoma, carcinoma of unknown origin, and lymphoma. MAIN RESULTS: In each patient, symptoms of obturator mononeuropathy were the sole presenting sign of new or recurrent pelvic cancer. Three patients had ipsilateral leg edema in addition to the typical sensory and motor findings of obturator mononeuropathy. Tumor sites detected on pelvic CT that correlated with obturator nerve compression or infiltration, singly or in combination, included the posterolateral wall of the upper pelvis or midpelvis, the anterior wall of the lower pelvis, and the external obturator and pectineus muscles extrinsic to the bony pelvis. Antineoplastic treatment provided symptomatic relief in four patients. CONCLUSIONS: Pelvic CT or MRI should be performed to exclude pelvic tumor in patients with obturator mononeuropathy if there is no temporal association with pelvic trauma or intra-abdominal, pelvic, or hip surgery.

Effect of cranial irradiation on seizure frequency in adults with low-grade astrocytoma and medically intractable epilepsy.

We report the effect of cranial irradiation on seizure frequency in five adults with unresected (biopsy-proven) cerebral hemisphere low-grade astrocytoma and medically intractable epilepsy. Seizures were refractory to standard antiepileptic drugs for 7 months to 27 years. Treatment with 5,400 cGy to 6,120 cGy focal radiation reduced seizure frequency by more than 90% in three patients (one of whom became seizure-free) and by more than 75% (but less than 90%) in one patient. One patient had no response. Brain CT or MRI showed a partial tumor response to radiation in three of the four patients with reduced seizure frequency. In three patients, the reduced seizure frequency continued to the most recent follow-up of 1 to 1.5 years. In the patient who became seizure-free, seizures recurred at 8.2 years and were associated with tumor progression. Irradiation can reduce seizure frequency in some patients with unresected cerebral hemisphere low-grade astrocytoma and medically intractable epilepsy.

Effect of recombinant tumor necrosis factor-alpha on three-dimensional growth, morphology, and invasiveness of human glioblastoma cells in vitro.

In order to investigate the antiproliferative and anti-invasive effects of tumor necrosis factor (TNF)-alpha on human glioblastoma cells, an in vitro three-dimensional (anchorage-independent) assay was performed using Matrigel, a mixture of extracellular matrix proteins. Four glioblastoma-derived cell lines, including one cloned line, were cultured in Matrigel with or without TNF-alpha. In the Matrigel containing TNF-alpha, three of the four cell lines, including the cloned line, showed significant growth inhibition in a dose-dependent manner. Dramatic three-dimensional morphological differences were observed between TNF-treated and untreated glioblastoma cells cultured in Matrigel. Untreated cells formed large and highly branched colonies throughout the gel. In contrast, the majority of TNF-treated cells demonstrated truncated branching processes and, at a high TNF-alpha dose, an increasing number of cells remained in relatively small spherical aggregates, their cell processes being significantly reduced. Quantitative invasion assay using a micro-Boyden chamber system confirmed that TNF-treated cells lost invasiveness in a dose-dependent manner. These results suggest that TNF-alpha exerts not only antiproliferative but also anti-invasive effects on human glioblastoma cells in vitro. It is believed that this is the first report showing the anti-invasive effect of TNF-alpha on tumor cells.

Comparison of cisternal and lumbar CSF examination in leptomeningeal metastasis.

We compared cisternal and lumbar CSF examination in 14 patients suspected of having leptomeningeal metastasis from cancer. Malignant cells were present in 12 patients--in both cisternal and lumbar CSF in nine patients and only in cisternal CSF in three. Cisternal CSF cytologic examination should be considered in patients suspected of having leptomeningeal metastasis if lumbar CSF is nondiagnostic.

Cerebrovascular complications in cancer patients.

The clinician should be alert to the possibility of cerebrovascular disease in cancer patients who develop signs of diffuse or focal cerebral dysfunction. The cause of cerebrovascular disease can usually be determined by knowing the primary tumor type, extent of metastatic disease, and type of antineoplastic treatment. Symptomatic infarctions are more common than hemorrhages in patients with carcinoma, and NBTE and cerebral intravascular coagulation are the most common causes of infarction. Brain hemorrhages in patients with carcinoma are usually from hemorrhage into metastatic tumor. Symptomatic hemorrhages are much more common than infarction in patients with leukemia, and hemorrhages may be caused by coagulopathy or central nervous system infiltration. Infarction in leukemia is usually due to septic embolism or intravascular coagulation. By determining the cause of cerebrovascular disease in the cancer patient, the clinician can often recommend appropriate treatment and predict the clinical outcome.

Alternating sequential intracarotid BCNU and cisplatin in recurrent malignant glioma.

The authors entered 43 patients with recurrent malignant glioma in a trial of alternating sequential intracarotid BCNU and cisplatin. Protocol design was alternating courses of BCNU (2 doses, 300 to 400 mg each) and cisplatin (2 doses, 150 to 200 mg each) each at 4-week to 6-week intervals. Eight of 40 patients (20%) evaluable after the first course of BCNU showed partial or minor response. Only 18 patients were evaluable after the first course of cisplatin, and 5 were evaluable after the second course of BCNU. Median survival was 9 months (range, 2 weeks to 6 years). Cerebral or ocular toxicity unique to this method of chemotherapy administration and failure to show clinical improvement were the most common reasons for removal from study. Because of the high attrition rate, the authors were unable to determine a meaningful response to alternating sequential BCNU and cisplatin or to test the clinical degree of cross-resistance to these agents in human malignant glioma.

Percutaneous aspiration of brain tumor cysts via the Ommaya reservoir system.

We performed percutaneous aspiration of 21 brain tumor cysts in 20 patients using the Ommaya reservoir system. Ages ranged from 3 to 70 years, median 48. Sixteen were primary tumors (12 anaplastic glioma, 2 craniopharyngioma, 1 oligodendroglioma, 1 brainstem glioma) and 4 were metastatic. Fourteen had the CT appearance of a true cyst and 7 a pseudocyst. We placed 18 catheters through twist drill holes via CT stereotactic guidance and 3 through burr holes via CT guidance and effectively aspirated 3 to 50 ml cyst fluid from 1 to 18 times in each patient. Postaspiration CT showed complete or significant reduction in cyst size in all patients in whom it was performed (18 after initial aspiration and 9 after subsequent aspirations). Asymptomatic intracyst hemorrhage occurred in 2 patients after cyst wall biopsy and catheter placement. There have been no other complications at follow-up of 4 to 114 weeks. In our experience, tumor cyst aspiration by the Ommaya reservoir system is as effective as percutaneous needle aspiration, but after catheter placement aspiration can be performed with minimal technical skill, avoiding repeated CT guidance required for needle aspiration of recurrent deep-seated cysts.

Monocyte tumoricidal activity and tumor necrosis factor production in patients with malignant brain tumors.

Monocyte-mediated tumoricidal activity, tumor necrosis factor alpha (TNF alpha) secretion and gene expression were examined in astrocytoma patients, patients with other types of brain tumors (primary or metastatic), and normal individuals. The spontaneous monocyte-mediated tumoricidal activity of either patient group against an astrocytoma cell line was significantly greater than normal. There was no difference between patient groups. When monocytes were stimulated with lipopolysaccharide in vitro, tumoricidal activity increased in all patient groups. Patient monocyte activity tested shortly (48 h) after surgery was not different from that before surgery. Both spontaneous and stimulated monocyte cytocidal activities were tumor-cell-restricted: melanoma and astrocytoma cells were equally susceptible but non-neoplastic glial cells were not affected. Examination of monocyte TNF alpha secretion and mRNA expression indicated that patient activity was comparable to or greater than normal. These results demonstrate that, despite steroid therapy, circulating monocytes in astrocytoma and other brain tumor patients retain intact functional activity.

Cerebral infarction from non-bacterial thrombotic endocarditis. Clinical and pathological study including the effects of anticoagulation.

The clinical and pathologic findings in 42 autopsy proved cases of cerebral infarction from cancer-associated non-bacterial thrombotic endocarditis were reviewed. Carcinoma of the lung was the most common malignancy. Most patients had disseminated cancer, but in six patients, the condition was stable or in remission, and six patients had localized cancer; two patients were not known to have cancer until neurologic symptoms developed. Neurologic symptoms were focal, suggesting stroke in 18; diffuse, suggesting metabolic encephalopathy in nine; and mixed in five. Neurologic signs were often the only evidence of thromboembolism. The definitive diagnostic test was cerebral angiography showing multiple arterial occlusions. Anticoagulation with heparin appeared to help some patients and did not promote brain hemorrhage. Early diagnosis and vigorous treatment of non-bacterial endocarditis may prevent severe neurologic disability.