Effect on management mortality of a deliberate policy of early operation on supratentorial aneurysms

Of 736 patients with intracranial aneurysms seen at the University of Alberta from 1968 to 1985, 437 were admitted on the day of or the day after subarachnoid hemorrhage (SAH) from a supratentorial aneurysm. Of these, 205 were managed from 1968 through 1977 and 232 were managed from 1978 through early 1985 after a policy of early aneurysm operation had been implemented. Postoperative and management mortality and morbidity rates were related to the grade of the patient at the time of admission and the time interval before operation. Overall management mortality (and postoperative mortality) rates for patients treated before 1978 were 47% (19%) for all grades, 17% (12%) for Grades 1 and 2, 51% (25%) for Grades 3 and 4, and 100% (100%) for Grade 5. Since 1978, mortality has been reduced to 38% (11%) for all grades, 10% (5%) for Grades 1 and 2, 39% (17%) for Grades 3 and 4, and 96% (60%) for Grade 5. Management mortality for patients operated on Day 0 to 3 was lower than for those operated later after SAH both before and after 1978. Postoperative mortality was lowered in all patients operated from 1978 to 1985 regardless of the interval from SAH to operation, and management mortality was reduced overall, as well as for patients operated on day 0 to 3, in those treated from 1978 to 1985. The authors conclude that a policy of early aneurysm operation has contributed to a reduction of both postoperative and management mortality.     

Nimodipine treatment in poor-grade aneurysm patients. Results of a multicenter double-blind placebo-controlled trial

A multicenter, randomized placebo-controlled double-blind trial of nimodipine in poor-grade aneurysm patients was carried out in 17 Canadian hospitals. Of 188 patients enrolled in the trial, 32 were excluded for protocol violations and two were excluded due to statistical considerations, leaving 154 patients for valid outcome analysis. Nimodipine treatment was associated with a significantly better outcome (p less than 0.001): 21 (29.2%) of 72 nimodipine-treated patients had a good outcome at 3 months after subarachnoid hemorrhage (SAH) compared to eight (9.8%) of 82 placebo-treated patients. Delayed ischemic deficits from vasospasm alone were significantly less frequent in the nimodipine group (p less than 0.05) with permanent deficits occurring in five nimodipine-treated patients (6.9%) and in 22 placebo-treated patients (26.8%). Improvement in the good outcome rate and reduction in delayed ischemic deficits from vasospasm alone occurred in both Grade 3 and 4 patients, with no difference between nimodipine- and placebo-treated patients being found in Grade 5 patients. Repeat angiography after Day 4 was carried out in 124 patients. There was no significant difference in the incidence of moderate or severe diffuse spasm, which was seen in 64.3% of nimodipine-treated patients and 66.2% of placebo-treated patients. The authors conclude that nimodipine treatment in poor-grade patients with SAH results in an increase in the number of good outcomes and a reduction in the incidence of delayed neurological deterioration due to vasospasm. This effect occurs by a mechanism other than prevention of large-vessel spasm as visualized on angiography.     

Howard H. Hepburn and the development of skull tongs for cervical spine traction

The first use of skull tongs for cervical spine traction is credited primarily to W.G. Crutchfield. In 1933, Crutchfield described his application of extension tongs to the calvaria of a 23-year-old woman with a traumatic C2-C3 fracture. Less recognized are the contributions of Howard H. Hepburn, who designed skull tongs for cervical spine traction at the University of Alberta several years before Crutchfield's first case. Hepburn was the first neurosurgeon at the University of Alberta in Edmonton. On the basis of his experience treating wounded soldiers in World War I, he developed the hypothesis that traction would promote healing in cervical spine injuries. Hepburn designed skull extension tongs that were modeled on common ice tongs, and he used an automobile inner tube as an elastic to keep the tongs firmly applied to the patient's head. These tongs were first used in the mid-1920s, and by 1930 they were applied routinely. Crutchfield's 1933 report refers to the application of "Edmonton extension tongs." This suggests that he was at least indirectly aware of Hepburn's work, although how this information reached him is not entirely clear. Hepburn attended a meeting of the British Medical Society in 1930, and he is thought to have discussed his tongs during the conference. Hepburn's work has received some attention previously; his original tongs were included in a 1973 Smithsonian Institute exhibit on cervical spine traction as an example of an early cranial traction device. However, his contributions are underappreciated in the neurosurgical community and deserve wider recognition.     

Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.

PURPOSE: To prospectively compare standard radiation therapy (RT) with an abbreviated course of RT in older patients with glioblastoma multiforme (GBM). PATIENTS AND METHODS: One hundred patients with GBM, age 60 years or older, were randomly assigned after surgery to receive either standard RT (60 Gy in 30 fractions over 6 weeks) or a shorter course of RT (40 Gy in 15 fractions over 3 weeks). The primary end point was overall survival. The secondary end points were proportionate survival at 6 months, health-related quality of life (HRQoL), and corticosteroid requirement. HRQoL was assessed using the Karnofsky performance status (KPS) and Functional Assessment of Cancer Therapy-Brain (FACT-Br). RESULTS: All patients had died at the time of analysis. Overall survival times measured from randomization were similar at 5.1 months for standard RT versus 5.6 months for the shorter course (log-rank test, P =.57). The survival probabilities at 6 months were also similar at 44.7% for standard RT versus 41.7% for the shorter course (lower-bound 95% CI, -13.7). KPS scores varied markedly but were not significantly different between the two groups (Wilcoxon test, P =.63). Low completion rates of the FACT-Br (45%) precluded meaningful comparisons between the two groups. Of patients completing RT as planned, 49% of patients (standard RT) versus 23% required an increase in posttreatment corticosteroid dosage (chi(2) test, P =.02). CONCLUSION: There is no difference in survival between patients receiving standard RT or short-course RT. In view of the similar KPS scores, decreased increment in corticosteroid requirement, and reduced treatment time, the abbreviated course of RT seems to be a reasonable treatment option for older patients with GBM.     

Cisplatin down-regulation of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-like inhibitory proteins to restore tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in human melanoma cells.

PURPOSE: Many melanoma cell lines and primary cultures are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. In this study, we investigated the molecular mechanisms that control melanoma cell resistance and searched for chemotherapeutic drugs that could overcome the TRAIL resistance in melanoma cells. EXPERIMENTAL DESIGN: We examined 21 melanoma cell lines and 3 primary melanoma cultures for their sensitivity to TRAIL-induced apoptosis, and then tested cisplatin, chemptothecin, and etoposide for their synergistic effects on TRAIL sensitivity in resistant melanoma cells. RESULTS: Of 21 melanoma cell lines, 11 showed various degrees of sensitivity to TRAIL-induced apoptosis through caspase-8-initiated cleavage of caspase-3 and DNA fragmentation factor 45. The remaining cell lines and primary cultures were resistant to TRAIL, but cisplatin, chemptothecin, and etoposide sensitized the resistant cell lines and primary cultures to TRAIL-induced apoptosis, which also occurred through the caspase-8-initiated caspase cascade. Of the two TRAIL death receptors (DR4 and DR5), melanoma cells primarily expressed DR5 on cell surface. Cisplatin treatment had no effects on cell surface DR5 expression or intracellular expression of Fas-associated death domain and caspase-8. Instead, cisplatin treatment down-regulated intracellular expression of the short form of cellular Fas-associated death domain-like interleukin-1beta-converting enzyme-like inhibitory protein (c-FLIP) and inhibited phosphorylation of the long form of c-FLIP. CONCLUSIONS: The results presented here indicate that cisplatin inhibits c-FLIP protein expression and phosphorylation to restore TRAIL-induced caspase-8-initiated apoptosis in melanoma cells, thus providing a new combined therapeutic strategy for melanomas.     

TRAIL inhibits tumor growth but is nontoxic to human hepatocytes in chimeric mice

Tumor necrosis factor (TNF) family ligand TNF-alpha and Fas ligand (FasL) can trigger apoptosis in solid tumors, but their clinical usage has been limited by hepatotoxicity. TNF-related apoptosis-inducing ligand (TRAIL) is a newly identified member of the TNF family, and its clinical application currently is under a similar debate. Here, we report a recombinant soluble form of human TRAIL (114 to 281 amino acids) that induces apoptosis in tumor cells but not human hepatocytes. We first isolated human hepatocytes from patients and showed that the human hepatocytes expressed Fas but no TRAIL death receptor DR4 and little DR5 on the cell surface. Antibody cross-linked FasL, but not TRAIL, triggered apoptosis of the human hepatocytes through cleavage of caspases. We then examined TRAIL hepatotoxicity in severe combined immunodeficient/Alb-uPA chimeric mice harboring human hepatocytes. Intravenous injection of FasL, but not TRAIL, caused apoptotic death of human hepatocytes within the chimeric liver, thus killing the mice. Finally, we showed that repeated intraperitoneal injections of TRAIL inhibited intraperitoneal and subcutaneous tumor growth without inducing apoptosis in human hepatocytes in these chimeric mice. The results indicate that the recombinant soluble human TRAIL has a profound apoptotic effect on tumor cells but is nontoxic to human hepatocytes in vitro and in vivo.     

Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apotosis in human malignant glioma cells

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially triggers apoptosis in tumor cells versus normal cells, thus providing a therapeutic potential. In this study, we examined a large panel of human malignant glioma cell lines and primary cultures of normal human astrocytes for their sensitivity to TRAIL. Of 13 glioma cell lines, 3 were sensitive (80-100% death), 4 were partially resistant (30-79% death), and 6 were resistant (< 30% death). Normal astrocytes were also resistant. TRAIL-induced cell death was characterized by activation of caspase-8 and -3, poly(ADP-ribose) polymerase cleavage, and DNA fragmentation. Decoy receptor (DcR1 and DcR2) expression was limited in the glioma cell lines and did not correlate with TRAIL sensitivity. Both sensitive and resistant cell lines expressed TRAIL death receptor (DR5), adapter protein Fas-associated death domain (FADD), and caspase-8; but resistant cell lines expressed 2-fold higher levels of the apoptosis inhibitor phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes-15 kDa (PED/PEA-15). In contrast, cellular FADD-like IL-1beta-converting enzyme-like inhibitory protein (cFLIP) expression was similar in sensitive and resistant cells. Transfection of sense PED/PEA-15 cDNA in sensitive cells resulted in cell resistance, whereas transfection of antisense in resistant cells rendered them sensitive. Inhibition of protein kinase C (PKC) activity restored TRAIL sensitivity in resistant cells, suggesting that PED/ PEA-15 function might be dependent on PKC-mediated phosphorylation. In summary, TRAIL induces apoptosis in > 50% of glioma cell lines, and this killing occurs through activation of the DR pathway. This caspase-8-induced apoptotic cascade is regulated by intracellular PED/PEA-15, but not by cFLIP or decoy receptors. This pathway may be exploitable for glioma and possibly for other cancer therapies.