Inability of computed tomography appearance of recurrent malignant astrocytoma to predict survival following reoperation.

Computed tomographic (CT) scans of 39 patients who underwent reoperation for recurrent malignant astrocytoma at Memorial Sloan-Kettering Cancer Center from 1980 through 1987 were reviewed and correlated with the patients' clinical course. Histologic diagnosis (anaplastic astrocytoma v glioblastoma multiforme) had a statistically significant impact on survival following reoperation (P = .038). Patients with high preoperative performance status (P = .29), total resection by postoperative CT scan (P = .15), and frontal lobe tumors (P = .17) tended to survive longer following reoperation. The size of the tumor at the time of recurrence did not correlate with survival following reoperation. Patients with a small amount of peritumoral edema at the time of recurrence tended to survive longer, but the effect was small (P = .16). Prognosis following reoperation cannot be accurately predicted on the basis of tumor appearance on CT scan.

Safe and cost effective use of alteplase for the clearance of occluded central venous access devices.

PURPOSE: To determine whether cryopreserved solutions of the thrombolytic agent alteplase could be used as a safe, effective, and economically reasonable alternative to urokinase in patients presenting with occluded central venous access devices (CVADs). MATERIALS AND METHODS: Alteplase has been reported as an efficacious alternative to urokinase for treatment of occluded CVADs. However, the practicality of using alteplase as the thrombolytic of choice for this indication remained conjectural. To make this approach economically feasible, alteplase was diluted to 1 mg/mL and 2.5-mL aliquots were stored at -20 degrees C until use. A need to confirm that the cryopreserving and thawing of the reconstituted solution did not compromise the safety and efficacy reported from prior trials was recognized. A quality assessment initiative was undertaken to concurrently monitor the safety and efficacy of this approach. Patients presenting with occluded CVADs received a sufficient volume of the thawed alteplase solution to fill the occluded catheter(s). Data, including efficacy, adverse reactions, dwell time, and catheter type, were collected over a 5-month period. RESULTS: One hundred twenty-one patients accounting for 168 attempted clearances were assessable for safety and efficacy. One hundred thirty-six (81%) of the 168 catheter clearance attempts resulted in successful catheter clearance (95% confidence interval, 74% to 86%). No adverse events were reported. CONCLUSION: Cryopreserved 1-mg/mL aliquots of alteplase are safe and effective in the clearance of occluded CVADs when stored at -20 degrees C for 30 days. The ability to cryopreserve alteplase aliquots makes it an economically reasonable alternative to urokinase in the setting of CVAD occlusion.

Glucosephosphate isomerase as a CSF marker for leptomeningeal metastasis.

Glucosephosphate isomerase (GPI), also known as phosphohexoisomerase, is a glycolytic enzyme whose activity is elevated in serum and CSF of patients with primary and metastatic CNS tumors. To improve the diagnostic accuracy of leptomeningeal metastasis (LM), we measured GPI levels in CSF of 66 patients with CNS or systemic malignancies with suspected LM. We determined GPI kinetically using a coupled enzyme reaction assay. There were 31 males and 35 females, aged 1 to seventy-six. Thirty-one had primary brain tumors, and 35 had systemic cancer with suspected CNS metastasis. We analyzed 95 samples; GPI values ranged from 0.85 to 329.0 U/l (normal, less than 20 U/l). Compared with positive CSF cytology and myelography, GPI sensitivity was 53.5% and specificity 92.1% for the group as a whole. There was a highly significant association between elevated CSF GPI (greater than 20 U/l) and LM. The results were similar for both primary CNS and systemic malignancies. Although not very sensitive, an elevated CSF GPI strongly suggests LM and may aid in early diagnosis of this serious complication of cancer.

Chronic morphine therapy for cancer pain: plasma and cerebrospinal fluid morphine and morphine-6-glucuronide concentrations.

Morphine-6-glucuronide (M-6-G) is an active metabolite that may contribute to the clinical effects produced by systemic administration of morphine. To help clarify the extent to which M-6-G may cross the blood-brain barrier and exert effects, we employed high-performance liquid chromatography with electrochemical detection to measure the concentrations of M-6-G and morphine in the plasma and either ventricular (three patients) or lumbar (eight patients) CSF of cancer patients receiving chronic morphine therapy. The mean ratio of morphine in ventricular CSF:morphine in plasma was 0.71; the same ratio for M-6-G was only 0.077. The average molar ratio of M-6-G: morphine in ventricular CSF was 0.207, and the average molar ratio in plasma was 1.89. Although sampling problems render the lumbar CSF results less reliable, they were very similar. Thus, plasma contained approximately twice as much M-6-G as morphine, whereas CSF contained only one-fifth to one-third as much. These data confirm that M-6-G in plasma is distributed into CSF, but to a far lesser extent than morphine. They help explain animal data demonstrating much higher potency of M-6-G on administration into CSF than systemic administration and indicate that the degree to which M-6-G contributes to morphine effects in humans remains an unresolved question.

Handheld cellular telephones and risk of acoustic neuroma.

The hypothesis that intracranial energy deposition from handheld cellular telephones causes acoustic neuroma was tested in an epidemiologic study of 90 patients and 86 control subjects. The relative risk was 0.9 (p = 0.07) and did not vary significantly by the frequency, duration, and lifetime hours of use. In patients who used cellular telephones, the tumor occurred more often on the contralateral than ipsilateral side of the head. Further efforts should focus on potentially longer induction periods.

Good performance status of long-term disease-free survivors of intracranial gliomas.

PURPOSE: To determine the long-term impact on function of treatment for primary cerebral gliomas, Karnofsky Performance Status, employment history, and memory function were used to evaluate the status of adults who are alive and disease-free more than 1 year after cranial irradiation. METHODS AND MATERIALS: Of 30 eligible adult patients, seventeen patients had anaplastic astrocytoma, seven had a glioblastoma, four had low grade astrocytoma, one had a mixed glioma, and one had an anaplastic oligodendroglioma. Sixteen patients received partial brain irradiation only, 12 had whole brain irradiation with a partial brain boost, and two had whole brain irradiation only. The total dose ranged from 54-66 Gy, with a fraction size of 1.7-2.0 Gy. Median follow-up was 3.5 years. Eighty-three percent of patients also received adjuvant chemotherapy. RESULTS: Karnofsky Performance Status generally remained stable after the completion of irradiation. Mean Performance status was 84 at the end of irradiation and was unchanged at the time of last follow-up. The actuarial freedom from performance status decline after irradiation was 93% at 5 years. The performance status increased in two patients, both within several months of completing irradiation. Most patients (68%) returned to work after irradiation. Sixty-two percent remained at work 1 year later, and 58% were working at the time of last follow-up. No patient who did not return to work within 4 months of completing irradiation was able to work at a later date. All working patients were employed in a capacity similar to their pre-morbid position. Only one patient, with an intercurrent lung cancer, eventually developed deficits that limited self care. CONCLUSIONS: Contrary to previously published reports, long-term glioma survivors maintained a relatively good performance status in the absence of recurrence and did not experience a progressive decline in neuropsychologic function after completion of cranial irradiation. A patient's function state at the completion of irradiation is a reliable predictor of long-term functional outcome in the absence of recurrence. Although the number of patients in each subgroup is small and no significant differences could be detected, patients treated with partial brain irradiation had a higher and more stable performance status, better memory function, and superior employment history.

Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma.

Recurrence patterns of glioblastoma multiforme (25) and anaplastic astrocytoma (9) were studied using CT scans of 34 patients who received all or a portion of their surgical treatment at Memorial Sloan-Kettering Cancer Center from January 1983 through February 1987. Thirty-two patients presented with unifocal tumors and two with multifocal tumors. All patients received radiation therapy following initial surgery. Eighteen patients who underwent re-operation following CT evidence of recurrence had histologic verification of recurrent tumor; sixteen patients had radiographic evidence of recurrence only. Seventy-eight percent (25/32) of unifocal tumors recurred within 2.0 cm of the pre-surgical, initial tumor margin, defined as the enhancing edge of the tumor on CT scan. Fifty-six percent (18/32) of tumors recurred within 1.0 cm of the initial tumor margin. Tumors for which a gross total resection was accomplished tended to recur closer to the initial tumor margin than did subtotally resected tumors (p greater than 0.1). Extensive pre-operative edema was associated with a decreased distance between initial and recurrent tumor margins. Large tumors were generally not more likely to recur further from the initial tumor margin than were smaller tumors. No unifocal tumor recurred as a multifocal tumor. Only one tumor (initially near the midline) recurred in the contralateral hemisphere. The findings support the use of partial brain irradiation for post-operative treatment of glioblastoma multiforme and anaplastic astrocytomas, and may help to determine the most appropriate treatment volume for interstitial irradiation.

Phase II study of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma.

OBJECTIVE: To assess the pharmacokinetics, toxicity, and efficacy of antineoplastons A10 (NSC 648539) and AS2-1 (NSC 620261). DESIGN: We initiated a phase II trial in order to determine whether evidence of antitumor activity of A10 and AS2-1 could be documented. MATERIAL AND METHODS: Patients with anaplastic astrocytoma or glioblastoma multiforme recurring after radiation therapy were eligible for enrollment in the trial. Patients received escalating doses of A10 and AS2-1 by multiple intermittent intravenous injections with use of a portable programmable pump to the target daily dose of 1.0 g/kg for A10 and of 0.4 g/kg for AS2-1. RESULTS: Nine patients were treated, in six of whom the treatment response was assessable in accordance with protocol stipulations. No patient demonstrated tumor regression. Reversible grade 2 or 3 neurocortical toxicity, consisting of transient somnolence, confusion, and exacerbation of an underlying seizure disorder, was noted in five patients. Mean steady-state plasma concentrations of phenylacetate and phenylacetylglutamine after escalation to the target doses of A10 and AS2-1 were 177+/-101 microg/mL and 302+/-102 microg/mL, respectively. Patients who exhibited confusion tended to have higher phenylacetate levels. CONCLUSION: Although we could not confirm any tumor regression in patients in this study, the small sample size precludes definitive conclusions about treatment efficacy. Antineoplaston-related toxicity was acceptable in most patients with appropriate dose modification, although severe neurocortical toxicity may occur. Steady-state plasma concentrations of phenylacetate with use of A10 and AS2-1 were similar to those reported with use of similar doses of phenylacetate alone.

Detection of DNA abnormalities by flow cytometry in cells from cerebrospinal fluid.

To evaluate the diagnostic utility of flow cytometry (FCM) as compared to cytology, DNA and RNA content of cells were measured in 233 samples of cerebrospinal fluid (CSF) from 147 patients with solid tumors or lymphomas and 17 controls with nonmalignant disorders. All control specimens were normal. Twenty-eight samples were abnormal: 20 showed an aneuploid peak and 8 an increased number of cells with DNA content in the S and G2M phases of the cell cycle. Of these 28, cytologic results were positive in 18, suspicious in 3, and negative in 7. All but one of the suspicious and negative cases had confirmatory laboratory and/or radiographic evidence of leptomeningeal metastasis within one week of FCM examination. Cytologic results were positive in eight samples negative by FCM. Compared with cytology, the sensitivity of FCM was 69% and the specificity 95%. Abnormal DNA content by FCM can be a useful adjunct to cytologic examination.

A versatile method for planning stereotactic brain implants.

Our approach to planning stereotactic 125I brachytherapy of brain tumors has involved least-squares optimization of individual seed positions within the target contour, followed by repeated combining of seeds from nearest-neighbor catheters in order to achieve an acceptably low number of catheters and an acceptable-separation of entry points. In one option, the catheters diverge from an extra-cranial point that can be close to the skull if all catheters are to be placed through a small craniectomy to treat a larger-diameter target. In another option, catheters converge toward a point beyond the target, to facilitate perpendicularity at the skull surface if a separate opening is to be drilled for each catheter. In either case, the fact that seed orientations are known, permits including anisotropy in dose calculations. Trial seed locations are constrained to a target region defined on a 1-mm mesh, both in the initial optimization of single-seed catheters and in subsequent combinations followed by tune-up optimizations. In the optimization process, sum-of-squares contributions are weighted more heavily when the dose rate is lower than the target dose rate; the weighting imbalance falls short of keeping all target points above the target dose rate and requires targeting on a dose rate about 25% higher than the desired minimum dose rate.

The significance of morphologically viable glioma cells found at the time of operation after interstitial brachytherapy.

The significance of finding morphologically intact viable glioma cells in tumors treated with high-dose irradiation delivered by interstitial brachytherapy was examined. Freshly resected tissue was taken from 12 patients after (n = 8) or both before and after (n = 4) interstitial brachytherapy. All posttreatment tissue was taken from regions within a radius of 2.0 to 4.0 cm of the radioactive source. From each sample, monolayer cell culture was established. All untreated samples from primary tumors grew well and became established as cell lines within 1 to 3 weeks. In contrast, cells from treated tumors only formed small colonies of 50 to 100 cells each. These cells grew slowly and, within 14 to 21 days, degenerated. Neither the use of conditioned medium or cell extract from established glioma cell lines nor the application of growth factors (platelet-derived growth factor and/or epidermal growth factor) stimulated growth or lengthened survival. The only exception was tumor resected from approximately 4 cm from the nearest radioactive source and from which a viable cell line could be established (IRR). Cytogenetic analysis of tissue from one sample (IR) before source implantation and from another (IRR) after source implantation, both from the same patient, showed that cells IR and IRR were derived from the same stem cell. To establish the reason why cell IRR remained clonogenic despite high-dose irradiation, IRR cells were irradiated with gamma irradiation with a dose rate of approximately 1 Gy/min for 24 hours. This colony-forming assay showed that IRR cells were radiosensitive.(ABSTRACT TRUNCATED AT 250 WORDS)

Interstitial irradiation of malignant gliomas.

Beginning in 1986, using software to optimize radiation dosimetry, we have stereotactically placed removable catheters containing high activity I-125 sources into malignant gliomas in 56 patients. There were 32 men and 24 women, age 7 to 73. Forty-four had glioblastoma multiforme, and 12 anaplastic astrocytoma. Mean Karnofsky performance score was 75, range 50-100. Twenty patients (all with glioblastoma) were implanted after resection before further therapy, and 36 were implanted at recurrence following resection, external irradiation and chemotherapy. Six thousand cGy was delivered to the enhancing tumor contour on CT scan. Mean dose rate was 37 cGy/hr. Mean tumor volume was 41 cc, range 5-187 cc. Mean volume of brain that received 60 cGy was 67 cc, range 11-184 cc. Of 20 patients treated after resection alone, 8 are alive, 3-43 months after implantation; median survival is 22 months. Of 36 patients treated at recurrence, 14 are alive, 0-19 months after implantation; median survival is 10 months. The most common side effect of the procedure, which occurred in five patients, was catheter misplacement. Twenty-four patients (43%) required 27 reoperations, 1-25 months after implantation. In 25 pathologic specimens available for review, microscopic tumor foci with substantial radiation necrosis were found in 18, radiation necrosis only was noted in 5, and glioma alone was seen in 2.

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.

Vinorelbine combined with a protracted course of temozolomide for recurrent brain metastases: a phase I trial.

Temozolomide (TMZ) has shown modest efficacy in the treatment of recurrent brain metastasis (BM). We designed a new regimen utilizing dose-intensified, protracted course of TMZ in combination with vinorelbine, a lipophilic large-spectrum agent, in an attempt to improve the efficacy of TMZ. This phase I study was conducted to establish the maximum tolerated dose (MTD) of vinorelbine for this combination. Patients with recurrent or progressive BM were eligible. Chemotherapy consisted of 28-day cycles with TMZ (150 mg/m2, days 1-7 and 15-21) and vinorelbine (days one and eight at escalating doses). The starting dose was 15 mg/m2, with increments of 5 mg/m2 for each cohort of 3-6 patients, until MTD was reached (30 mg/m2). A total of 21 patients were enrolled; the median age was 59 (41-77). The primary tumor was lung cancer in 13 patients (NSCLC in 10, SCLC in 3), breast in 6, renal in 1 and endometrial in 1. Vinorelbine dose was 15 mg/m2 in seven patients, 20 mg/m2 in five, 25 mg/m2 in four and 30 mg/m2 in six. Grades 3 and 4 neutropenia developed in six patients, lymphopenia in nine, and thrombocytopenia in six; other toxicities were rare. No dose-limiting toxicity was seen. Out of 18 evaluable patients 2 had a radiographic response (one partial and one minor). Disease was stable in 6 of 18 patients and the median survival was 27 weeks. This regimen was well tolerated and a phase II trial using a dose of 30 mg/m2 of vinorelbine is warranted.

Ethical issues in neuro-oncology.

Ethical issues and dilemmas are common in patients with brain tumors and other neuro-oncologic diseases. Basic knowledge of ethical principles and theory is essential for the day-to-day care of these patients, which often involves life and death decisions. The most important ethical principles include respect for autonomy, justice, beneficience, and nonmaleficence. The application of these principles is important for resolving ethical questions related to neuro-oncology patients such as discussing diagnosis and prognosis, whether or not to initiate therapy (including clinical trials), quality of life during and after treatment, when it is appropriate to stop treatment, if hospice care should be implemented, and pain control. Frequent consideration of these basic ethical principles will assist physicians during the decision-making process and improve their ability to make sound choices.

Turcot's syndrome. Flow cytometric analysis.

Turcot's syndrome is a rare, genetically transmittable disease in which patients with colonic polyposis (possibly complicated by the progression to adenocarcinoma) have malignant central nervous system neoplasms. Dominant, recessive, and sporadic cases have been described. A 26-year-old man is reported with no relevant family history who had intermittent abdominal discomfort in 1986. Sigmoidoscopy revealed numerous polyps, several of which showed carcinomatous change. Dukes' Stage C colorectal carcinoma was diagnosed. Treatment consisted of total colectomy with construction of a Koch's pouch. He remained well for 3 years until onset of headache, nausea, and vomiting. Computed tomographic scan disclosed a large, circumscribed, enhancing, right frontoparietal mass. After craniotomy and partial resection, histologic review disclosed anaplastic astrocytoma. He received cranial radiation therapy, 6000 cGy, by parallel opposed ports to the tumor bed, and carmustine 200 mg/m2 intravenously every 8 weeks. Flow cytometric DNA analysis was done on the paraffin-embedded archival material from the patient's normal colon, colonic adenocarcinoma, and anaplastic astrocytoma. DNA histograms revealed diploid distributions in all three samples. The G2/M fraction of the astrocytoma was elevated at 16%, and the S-phase fraction of the colonic adenocarcinoma was 19.4%.