Kenneth C. Petruk

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.

Computed tomographic angiography versus digital subtraction angiography for the diagnosis and early treatment of ruptured intracranial aneurysms.

OBJECTIVE Computed tomographic angiography (CTA) is a rapid and minimally invasive method of detecting intracranial aneurysms. We wished to determine whether CTA could replace digital subtraction angiography (DSA) in the diagnosis and operative planning of ruptured cerebral aneurysms. METHODS In a prospective study, patients with subarachnoid hemorrhage diagnosed by plain computed tomography underwent CTA, DSA, or both. Computed tomographic scans and CTA studies were first reviewed by the treating surgeon, along with a neuroradiologist, and a decision to proceed to DSA or directly to surgery was made on the basis of the type and quality of information provided by CTA. All patients underwent postoperative DSA. RESULTS A total of 173 patients were studied. In 24 patients, both CTA and DSA were negative for a source of subarachnoid hemorrhage. Twelve patients underwent DSA without prior CTA because a technologist capable of performing CTA was not available when the patient was evaluated. Nine patients in poor neurological condition underwent CTA, and all tested positive for aneurysms but died without surgical intervention. Of the 126 patients who underwent CTA and surgery, 65 (52%) also required preoperative DSA. The decision to proceed to DSA after CTA was influenced by aneurysm location; posterior communicating artery (62%) and posterior circulation locations (67-75%) more commonly proceeded to DSA than middle cerebral artery aneurysms (34%; 0.025 > P > 0.01). The sensitivity and specificity of CTA for the detection of all aneurysms, ruptured and unruptured, in the group of patients who underwent both types of angiograms preoperatively were 84 and 100%, respectively. In the group of 61 patients in whom aneurysm surgery was performed on the basis of CTA results alone, the sensitivity and specificity for the detection of all aneurysms, as compared with postoperative DSA, were 90 and 100%, respectively. Missed aneurysms (n = 24) were always small (<4 mm) and were usually found in patients with multiple aneurysms in whom the larger, ruptured aneurysm was identified by CTA. In one patient, the aneurysm missed by preoperative CTA would have resulted in a different operation if detected preoperatively. CONCLUSION It is possible to proceed to ruptured aneurysm repair entirely on the basis of good-quality CTA studies that demonstrate an aneurysm consistent with the pattern of bleeding observed on plain computed tomography (48% of the patients in this series and most common middle cerebral artery aneurysms). However, detection of small unruptured aneurysms in patients with multiple lesions remains a problem.

Glioma immunology and immunotherapy.

OBJECTIVE Despite advances in conventional therapy, the prognosis for most glioma patients remains dismal. This has prompted an intensive search for effective treatment alternatives. Immunotherapy, one such alternative, has long been recognized as a potentially potent cancer treatment but has been limited by an inadequate understanding of the immune system. Now, increased insight into immunology is suggesting more rational approaches to immunotherapy. In this article, we explore key aspects of modern immunology and discuss their implications for glioma therapy. METHODS A thorough literature review of glioma immunology and immunotherapy was undertaken to inquire into the basic immunology, central nervous system immunology, glioma immunobiology, standard glioma immunotherapy, and recent immunotherapeutic advances in glioma treatment. RESULTS Although gliomas express tumor-associated antigens and appear potentially sensitive to immune responses, many factors work together to inhibit antiglioma immunity. Not surprisingly, most clinical attempts at glioma immunotherapy have met with little success to date. However, novel immunostimulatory strategies, such as immunogene therapy, directed cytokine delivery, and dendritic cell manipulation, have recently yielded dramatic preclinical results in glioma models. This suggests that glioma-derived immunosuppression can be overcome. CONCLUSION Modern molecular biology and immunology techniques have yielded a wealth of new data about glioma immunobiology. Armed with this information, many investigators have proposed novel means to stimulate antiglioma immune responses. Although definitive clinical results remain to be seen, the current renaissance in glioma immunology and immunotherapy shows great promise for the future.

TRAIL Inhibits Tumor Growth but Is Nontoxic to Human Hepatocytes in Chimeric Mice

Tumor necrosis factor (TNF) family ligand TNF-α 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.

Neuropsychological function in patients after subarachnoid hemorrhage.

Neuropsychological testing of 48 patients who had undergone operation for subarachnoid hemorrhage (SAH) due to aneurysm was performed. Before this, the patients had their level of neurological recovery classified by neurosurgeons (37 good outcome vs. 9 poor outcome). These clinical categories correlated well with the results of neuropsychological testing. The degree of psychological impairment was related to age. The mean duration between SAH and clipping of the ruptured aneurysm was 4.6 days (range, 1-16 days), and 59% had operations on or before Day 3 post-SAH. Of the 37 patients with good neurological outcome, 26 patients had good neuropsychological outcome (no more than mild deficit). Poor neuropsychological outcome was associated with age and anterior communicating artery aneurysms. The incidence of significant neuropsychological deficit was considerably less than in previous reports, and possible explanations are discussed.

Human glioma immunobiology in vitro : implications for immunogene therapy

OBJECTIVE Human gliomas are known to be immunosuppressive. Recent reports have suggested novel strategies to overcome this immunosuppression, including immunogene therapy. We examined expression of 10 immunologically important molecules by human gliomas in vitro, and we discuss the implications for immunogene therapy. METHODS Early passage human glioma cultures and established human glioma cell lines were analyzed by flow cytometry for expression of Class I and II major histocompatibility complex (MHC), B7-2 (CD86), and Fas (CD95). Culture supernatants were assayed by enzyme-linked immunosorbent assay for interleukin (IL)-6, IL-10, IL-12, transforming growth factor beta2, prostaglandin E2, and granulocyte-macrophage colony-stimulating factor levels. RESULTS All cultures (16 of 16 samples) expressed Class I MHC and Fas, but few expressed Class II MHC (1 of 16 samples) or B7-2 (0 of 16 samples). Nearly all expressed high levels of IL-6 (19 of 21 samples; mean, 36.5 +/- 10.8 ng/10(6) cells/d) and prostaglandin E2 (21 of 21 samples; mean, 15.6 +/- 4.5 ng/10(6) cells/d) levels, and many expressed transforming growth factor beta2 (13 of 21 samples; mean, 8.6 +/- 3.7 ng/10(6) cells/d). Although several cultures (6 of 14 samples) expressed granulocyte-macrophage colony-stimulating factor, expression levels were very low (mean, 0.2 +/- 0.1 ng/10(6) cells/d). Few cultures (4 of 21 samples) expressed measurable IL-10, and none (0 of 22 samples) expressed IL-12. CONCLUSION Class I MHC and Fas expression suggests that human glioma cells may be susceptible to Class I MHC-dependent cytotoxic T cell recognition and Fas-mediated killing. Unfortunately, transforming growth factor beta2 and prostaglandin E2 probably impair T cell activation, and IL-6 may shift immunity to less effective humoral (T helper 2) responses. Proinflammatory gene expression (B7-2, granulocyte-macrophage colony-stimulating factor, and/or IL-12) is lacking. Together, these results suggest that modifying glioma cells via proinflammatory gene transfer or immunoinhibitory gene suppression might stimulate immune responses that are effective against unmodified tumors.

TRAIL Triggers Apoptosis in Human Malignant Glioma Cells Through Extrinsic and Intrinsic Pathways

Many malignant glioma cells express death receptors for tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL‐induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase‐8‐initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild‐type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to down regulate caspase‐8 inhibitor c‐FLIPS (the short form of cellular Fasassociated death domain‐like interleukin‐1‐converting enzyme‐inhibitory protein) and up‐regulate Bak, a pro‐apoptotic Bcl‐2 family member, independently of cells TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.

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.

Anatomic details of intradural channels in the parasagittal dura: a possible pathway for flow of cerebrospinal fluid.

OBJECTIVE The absorption of cerebrospinal fluid occurs primarily by means of arachnoid granulations (AG) in the superior sagittal sinus (SSS) and the lacunae laterales (LL) in the parasagittal dura. Previous descriptions of this region suggest a network of intradural channels, but finer details of extent and relationship between channels and AG were not addressed. Therefore, we undertook an anatomic study of cadaveric parasagittal dura. METHODS The SSS and parasagittal dura of 20 formalin-fixed adult cadavers and 15 autopsy specimens from patients ranging in age from 18 weeks of gestation to 80 years were studied by use of a light microscope, a scanning electron microscope, and corrosion casting. Intradural injections into the parasagittal region were performed in two formalin-fixed and four autopsy specimens from adults by use of normal saline and corrosion casting. RESULTS Extensive networks of intradural channels from 0.02 to 2.0 mm in diameter were noted in all of the specimens. Channels either were connected to the SSS at intervals along the side wall or drained directly into the LL, which extended up to 3 cm from midline. Channels lined with endothelium stained positive for Factor VIII, as did the endothelium of the LL and SSS. In some places, the network of channels seemed to coalesce to form LL. The underside of the dura was coarse and trabeculated where the channels were abundant, and AG were interdigitated between these trabeculae. In regions of the dura where channels were sparse or absent, the dural underside was smooth and lacked AG. Underlying cortical veins opened directly into the SSS and were unrelated to intradural channels. Intradural parasagittal injections from the epidural side accessed the SSS by way of channels using pressures between 0 and 20 cm H2O at 1.5 ml/min. CONCLUSION These channels may represent a pathway for the flow of cerebrospinal fluid from AG to the SSS.

Technical hurdles in a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas

SummaryObjectiveMalignant glioblastomas and melanomas continue to have a dismal prognosis despite advances in conventional therapy. This has led to investigations of novel treatment strategies including immunogene therapy. We report a pilot clinical trial of combined B7-2 and GM-CSF immunogene therapy for gliomas and melanomas and discuss technical hurdles encountered.MethodsPatients with recurrent malignant gliomas or medically refractory melanomas were vaccinated with irradiated autologous tumor cells transduced with B7-2 and GM-CSF genes using a retroviral vector. Patients were monitored for toxicity, inflammatory/immune reactions, and clinical status.ResultsVaccine preparation was attempted from 116 malignant glioma and 32 melanoma specimens. Adequate vaccines could only be prepared for five glioblastoma and three melanoma patients. Six patients (three recurrent glioblastomas and three melanomas) were actually vaccinated. Minor toxicities included flu-like symptoms (3/6), injection site erythema (4/6), and asymptomatic elevations in liver enzymes (3/6). Most patients showed evidence of an inflammatory response but specific anti-tumor immunity was not demonstrated. All six patients have died, although three patients with minimal residual disease at treatment had prolonged recurrence-free intervals after vaccination.ConclusionsCombined B7-2 and GM-CSF immunogene therapy for glioblastomas and melanomas using autologous tumor cells has many technical pitfalls hindering large scale application and evaluation. As a result, this pilot study was too limited to draw meaningful conclusions regarding safety or anti-tumor immunity. While immunotherapy has been promising in pre-clinical studies, alternate strategies will be required to bring these benefits to patients.