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Background: The possibility of tumor sanctuary sites in the central nervous system (CNS) of patients receiving paclitaxel has been suggested by laboratory data identifying low concentrations of drug in the brain and cerebrospinal fluid (CSF) of rats., Methods: The pattern of disease progression in patients with metastatic breast cancer who had an initial response to paclitaxel treatment in five Phase II trials at the Memorial Sloan-Kettering Cancer Center was reviewed., Results: Of 152 patients, 53 had a partial or complete response, and 25 had a minor response. Of the 78 patients who responded to paclitaxel, 52 had subsequent disease progression, 22 changed treatments before progression occurred (as specified by the protocol and/or to receive high dose consolidation chemotherapy), 2 stopped receiving treatment because of toxicity, 1 continued receiving treatment, and 1 died with no evidence of disease progression. Six of the 52 patients who progressed after initially responding to paclitaxel had isolated CNS progression while maintaining their systemic response (leptomeningeal metastasis in three, brain metastases in two, brain and leptomeningeal metastases in one). One patient had CNS progression (brain metastases) associated with other systemic sites of progression. All patients with CNS disease developed neurologic symptoms, prompting neurologic evaluation; one had only a mild headache, which was not recognized until evaluation for paclitaxel-related peripheral neuropathy., Conclusions: These data suggest that the CNS, and particularly the CSF, is an important sanctuary site for patients with metastatic breast cancer receiving paclitaxel.

Background: Metastases to the meninges from prostatic cancer are rare, accounting for less than 0.5% of all solid tumor cases. Management for patients with leptomeningeal metastases of various histologic types includes intrathecal chemotherapy and radiation therapy, but the prognosis is poor. Therefore, the identification of selected patients for whom effective therapy exists is of paramount importance., Methods: A patient with adenocarcinoma of the prostate presented with leptomeningeal metastases as his first manifestation of metastatic disease., Results: Androgen blockade was initiated with flutamide and ketoconazole. After 5 days of therapy, leuprolide acetate depot was substituted for ketoconazole. The patient responded to therapy and remained asymptomatic with a normal serum prostate-specific antigen levels at 16-plus months with no further evidence of malignant cells in spinal fluid from repeated lumbar punctures., Conclusion: Patients with hormone-naive metastatic prostatic carcinoma manifested as carcinomatous meningitis should be considered for hormonal ablative therapy. This is preferred to the use of intrathecal chemotherapy, which has limited efficacy.

Background: Deep venous thrombosis (DVT) and pulmonary embolism (PE) are common in patients with brain metastases. Few data exist to help guide the clinician's choice between the two therapeutic options of anticoagulation and inferior vena cava filter placement., Methods: The authors reviewed their institutions' experience with the treatment of venous thromboembolism in 51 adult patients with known brain metastases since 1980., Results: Ten patients were initially treated with Greenfield filters; four (40%) had recurrent nonfatal thromboembolic events (two PE and two DVT), and three required anticoagulation. Thirty-nine patients were treated initially with anticoagulation; none of these patients later received filters. Two patients with DVT were untreated and both died of PE. Among 42 patients who received anticoagulation, the duration of anticoagulation ranged from 5 to 563 days (mean, 100 days). Two patients who received anticoagulation experienced devastating central nervous system hemorrhage in the setting of supratherapeutic anticoagulation by conventional laboratory criteria. A third patient experienced a minor deterioration, possibly attributable to hemorrhage, for a 7% (3 of 42) incidence of serious central nervous system complications. Three asymptomatic patients developed hyperdensity within metastases on routine follow-up noncontrast computed tomography scan, suggesting possible intratumoral hemorrhage. Three patients taking warfarin had recurrent DVT with prothrombin time between 15.1 and 17.7. Systemic bleeding complications were generally minor and occurred in only eight patients (19%)., Conclusions: Anticoagulation is more effective than Greenfield filters and acceptably safe when maintained in the therapeutic range in most patients with brain metastases and venous thromboembolism.

Background: Ocular lymphoma is an uncommon cause of chronic vitreitis or uveitis, often refractory to steroid treatment, and frequently representing another site of multifocal primary central nervous system lymphoma (PCNSL)., Methods: The authors reviewed the medical and ophthalmologic records of 24 patients with ocular lymphoma; 23 had associated PCNSL:, Results: In half, the eyes were the initial site of disease; in the others central nervous system (CNS) lymphoma developed before, or concurrent with, ocular lymphoma. Most patients had bilateral ocular symptoms; slit-lamp examination revealed asymptomatic disease in four. Vitrectomy was not always diagnostic, particularly in patients who had received steroids. Ocular ultrasound, performed on seven patients, provided an objective measure of disease and treatment response. Patients received a variety of therapeutic combinations of steroids, radiation, and chemotherapy, including high-dose cytosine arabinoside. Despite therapy, eventual ocular or CNS relapse or both was common. Thirteen patients have died, 12 with known recurrent CNS disease., Conclusions: Ocular lymphoma frequently is associated with PCNSL: The diagnosis should be considered in patients with steroid-resistant chronic vitreitis or uveitis. Patients with PCNSL should be carefully evaluated for ocular involvement, regardless of symptoms. Treatment can contribute to prolonged remission, but eventual ocular or CNS relapse is the rule.

Background: Primary central nervous system lymphoma (PCNSL) still occurs mainly in patients who are immunosuppressed, but its incidence is rising dramatically among immunocompetent individuals. The Epstein-Barr virus (EBV) has been detected by in situ hybridization in PCNSL tumor tissue from patients who are immunodeficient, but not from patients who are immunocompetent. Using the more sensitive polymerase chain reaction (PCR) technique, the authors analyzed PCNSL tissue from 13 patients with acquired immune deficiency syndrome (AIDS) and 13 patients who were immunocompetent for the presence of EBV genome., Methods: DNA was extracted from paraffin-embedded biopsy or autopsy specimens. PCR was run using primers for EBV (from the first internal repeat segment of the EBV genome), and identical samples were run simultaneously with primers against actin or the p53 gene as controls to establish the presence of DNA in the sample. Reaction products were also Southern blotted to confirm EBV specificity., Results: EBV was detected in the tumor tissue of 11 of 13 patients (85%) with AIDS and of 7 of 13 patients (54%) who did not have AIDS. There was a history of illness that might suggest or predispose to immune compromise in 5 of 13 patients without AIDS; however, prior illness did not predict EBV-positive tumors., Conclusions: Although mechanisms remain to be clarified, EBV was present in a high percentage of patients with AIDS-related PCNSL and non-AIDS-related PCNSL:

Neuropathy and myopathy are common sequelae of intensive chemotherapy protocols that contain vincristine and corticosteroids. The authors prospectively monitored the evolution of neuropathy and myopathy during an intensive 12-week chemotherapy program for patients with intermediate and high-grade non-Hodgkin's lymphoma. In this study, vincristine was administered by bolus injection followed by a 3-day continuous intravenous (IV) infusion (total dose of 2.0 mg/m2 every other week); the maximum dose of vincristine was not arbitrarily limited. Cronassial, a mixture of four naturally occurring gangliosides, was administered in a randomized double-blind test to evaluate whether this agent could prevent vincristine-induced neuropathy. High doses of dexamethasone (50 mg/d for 3 days weekly or every other week) were also prescribed. Patients were monitored every 4 weeks with comprehensive physical and neurologic examinations and electrophysiologic studies of peripheral nerve function. Twenty-seven patients were fully evaluable. Weakness was a prominent adverse reaction in this study, and all patients had moderate to severe signs and symptoms of neuropathy and myopathy. Cronassial (100 mg) administered by intramuscular (IM) injection daily provided no protection against the development of neuropathic symptoms. Vincristine typically impaired fine-motor coordination initially, whereas corticosteroids were associated with delayed development of proximal muscle weakness. Results of electrodiagnostic studies did not add to the clinical examination results. The authors conclude that symptomatic weakness due to neuropathy or myopathy appears in a predictable manner during intensive vincristine/corticosteroid-based treatment protocols. Simple clinical tests can be used to rapidly distinguish between toxic effects due either to vincristine or corticosteroids, and routine implementation of these tests can prevent inappropriate dose attenuation of these agents.

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, but it is occurring with increased frequency even among apparently immunocompetent patients. Although secondary malignancies frequently involve the lymphoreticular system, PCNSL has been reported as a second neoplasm only once previously. Seven patients are discussed who developed PCNSL after successful treatment for a prior neoplasm. The original cancer was colon (one), breast (one), thyroid (one), Hodgkin's disease (two), and non-Hodgkin's lymphoma (two). Patients with systemic non-Hodgkin's lymphoma were thought to have a separate cerebral lymphoma on the basis of a prolonged disease-free interval from their systemic lymphoma, and the absence of systemic disease, when PCNSL was diagnosed and through subsequent follow-up. The PCNSL developed a median of 10 years after the diagnosis of the first tumor and 6 years after the last evidence of systemic disease. The diagnosis of PCNSL was often delayed because of confusion with brain metastases, and initial shrinkage or disappearance of the lesion after corticosteroids. Formation of PCNSL may be a consequence of treatment for the first malignancy, reflect an unidentified inherent predisposition to neoplastic transformation, or result from the changing epidemiology of PCNSL in the general population. These mechanisms are not mutually exclusive, and a single hypothesis cannot account for all these cases.