Robert E. Albright

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m2/day or 150 mg/m2/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m2/day or 125 mg/m2/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

The Brain Tumor Cooperative Group NIH Trial 87-01: A randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine

OBJECTIVE The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. METHODS The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. (125)I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the (125)I implantation plus external beam radiation and BCNU therapy. RESULTS The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of (125)I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. CONCLUSION We conclude that there is no long-term survival advantage of increased radiation dose with (125)I seeds in newly diagnosed glioma patients.

Infiltrative polyneuropathy due to acute monoblastic leukemia in hematologic remission

A 66-year-old man with acute monoblastic leukemia developed acute polyneuropathy with quadriplegia, autonomic instability, and respiratory failure while he was in hematologic remission following both systemic and intrathecal chemotherapy. Autopsy revealed dense infiltration of somatic and autonomic peripheral nerves, sparing the meninges. There was a small peripheral infiltrate in one of four dorsal root ganglia, but, otherwise, sensory and autonomic ganglia were normal. The blood-nerve barrier may allow some malignant cells to escape cytotoxic agents. The epineurium and ganglia lack a blood-tissue barrier, and malignant cells could have been eradicated at those sites.

Microcomputer-based Technique for 3-d Reconstruction and Volume Measurement of Computed Tomographic Images: Part 1: Phantom Studies

This paper presents a microcomputer-based technique that accurately quantifies volumes from computed tomographic (CT) scans of irregularly shaped objects as well as displaying 3-D reconstructions. The method uses standard CT film, allowing analysis of previous or outside CT studies. The planimetry method showed less than 5% error in measuring irregular 2-D areas larger than 6 mm2. The method is demonstrated to be significantly more accurate than spherical, ellipsoid, or rectangular geometric models in quantifying object volume by CT (P less than .001). With a single gantry angle, planimetry showed a two standard deviation error under 10% in measuring the volume of irregular objects compared with an error over 30% for ellipsoid models. The inaccuracy of the spherical model (80% error) and the rectangular prism model (192% error) renders them impractical to provide quantitative object volume. Microcomputer planimetry provides an accurate and versatile means to measure the volume and produce 3-D reconstructions of objects scanned with CT, and it has potential application in quantifying tumor response with CT and magnetic resonance imaging.

Comparative neurotoxicity of angiographic contrast media

The neurotoxic effects in cerebral angiography of three iodinated ionic contrast media, nonionic iopamidol, 25% mannitol, and saline controls were compared in 25 rabbits. Diatrizoate sodium meglumine was the most toxic agent, followed by diatrizoate meglumine, iothalamate meglumine, and mannitol in terms of blood-brain barrier (BBB) disruption and coupled perfusion decline. HIPDm distribution was more sensitive than trypan blue extravasation for monitoring brain dysfunction. Iopamidol and saline controls exhibited no visual BBB breakdown or alteration in regional uptake of 1–125 HIPDm, confirming the safety of nonionic iopamidol as compared with presently used ionic contrast media.

Microcomputer-based technique for 3-D reconstruction and volume measurement of computed tomographic images. Part 2: Anaplastic primary brain tumors.

Serial computed tomography (CT) plays an integral part in monitoring effects of therapy for primary anaplastic brain tumors. Despite advances in CT technology, clinicians often cannot obtain accurate quantitative volume information to complement the qualitative assessment of tumor change. This paper presents a microcomputer-based method that provides both quantitative volume measurements and 3-D reconstructions of primary anaplastic brain tumors based on their hard copy CT or magnetic resonance imaging studies. The findings of this study demonstrate that planimetry is feasible for routine clinical use and is superior in accuracy to the spherical geometric model, which is shown to significantly overestimate tumor volume. The findings of 62 quantitative tumor studies (17 patients) showed a direct relationship between the total tumor volume and the volume of the hypodense intratumor core. There was no evidence of a relationship between the total tumor volume and the amount of peritumor low density (edema).

Establishment of a CSF bank

A bank of well-characterized CSF has been established by collecting and storing (— 70 °C) CSF samples remaining after completion of routine clinical studies. Over 1, 700 individual patient samples were collected during a 12-month period. A database derived largely from information downloaded from existing hospital-based systems includes the results of individual CSF laboratory studies, in addition to the patient age, primary diagnoses, and details of any malignancy. CSF control material is used to verify storage conditions. The CSF bank supplies investigators with CSF handled in a standardized manner for more precise investigation of CNS disease.

Establishment of a Cerebrospinal Fluid Bank

In most clinical laboratories, cerebrospinal fluid (CSF) is discarded within several days. Such disposal is unfortunate since the study of various compounds and their metabolites in CSF can provide clinicians and researchers with an expanded view of central nervous system (CNS) function and pathophysiology. Since CSF from patients with a variety of neurologic and medical conditions is not readily available for use in these studies, a cryorepository or “Bank” of well-characterized cerebrospinal fluid (CSF) has been established by collecting and storing (-75 C) CSF samples remaining after completion of routine clinical studies. Since 1986, over 11,000 individual patient samples have been deposited in the CSF Bank and are available for retrospective research purposes. Wherever possible, corresponding plasma or serum is stored with the CSF sample. The CSF and blood are aseptically aliquoted into polypropylene or glass freezer vials. A database derived largely from information downloaded from hospital-based systems includes the results of all CSF laboratory studies, in addition to the patient age and the primary discharge diagnoses. By organizing the storage of CSF and corresponding blood within 24–48 hours of collection and following established storage techniques, uniform samples with associated patient information can be provided to investigators. The database permits rapid sample selection based on clinical or laboratory parameters as defined by the investigator.

CSF TRAP: a procedure to improve laboratory testing with myelography.

CSF TRAP (Transport and Rapid Accessioning for Additional Procedures) is a procedure that provides storage of and rapid access to cerebrospinal fluid (CSF) specimens and allows clinicians to review initial findings before ordering low-yield CSF studies. The cost-effectiveness of routinely using the CSF TRAP procedure with myelography is examined in a study group of 819 patients, 74% with disc diseases, spinal stenosis, spondylolisthesis, or pain syndromes, 10% with cancer, and 16% with neuropathies and miscellaneous conditions. Routine studies on CSF obtained during myelography provided little additional clinical information, except for patients with cancer (of 80 patients with cancer, the results of cytological examination of the CSF were positive in 12) and patients with multiple sclerosis, for whom oligoclonal band and IgG analysis provided supportive diagnostic data. The utilization of the CSF TRAP procedure with elimination of unnecessary culture and cytological studies on patients with disc diseases, spinal stenosis, spondylolisthesis, and pain syndromes, reduces myelographic CSF procedures by 20%, for a savings exceeding

Regression analysis of data with repeated measurements using the method of successive differences

14,000. The CSF TRAP procedure allows for a more cost-efficient analysis of CSF obtained using myelography, while providing fluid for analysis in patients with unexpected findings.