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We conducted a feasibility study of sublingual methadone for breakthrough cancer pain, to determine whether a larger, randomized trial was warranted, and to identify a study design that would be likely to succeed. From approximately 1930 patients in the initial pool, nine patients were enrolled. Five patients completed the study, generating data on 83 discrete episodes of breakthrough cancer pain at optimal dose. Mean pain intensity dropped by 1.7 points (on a 10 point numerical scale) within 10 min of sublingual methadone administration, and by 3.2 points after 15 min. No serious or severe toxicity was encountered. Based on the results of this feasibility study, a larger randomized clinical trial of sublingual methadone for breakthrough cancer pain using this trial model would not be successful. Extensive information obtained from small numbers of carefully studied patients provides proof of concept that sublingual methadone is effective, safe, and well tolerated.

Purpose: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates. Experimental Design: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys. Results: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus’ antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates. Conclusions: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Brain and leptomeningeal metastases are common in breast cancer patients and our current treatments are ineffective. Reovirus type 3 is a replication competent, naturally occurring virus that usurps the activated Ras-signaling pathway (or an element thereof) of tumor cells and lyses them but leaves normal cells relatively unaffected. In this study we evaluated reovirus as an experimental therapeutic in models of central nervous system (CNS) metastasis from breast cancer. We found all breast cancer cell lines tested were susceptible to reovirus, with > 50% of these cells lysed within 72 h of infection. In vivo neurotoxicity studies showed only mild local inflammation at the injection site and mild communicating hydrocephalus with neither diffuse encephalitis nor behavioral abnormalities at the therapeutically effective dose of reovirus (intracranial) (ie 10(7) plaque-forming units) or one dose level higher. In vivo, a single intratumoral administration of reovirus significantly reduced the size of tumors established from two human breast cancer cell lines and significantly prolonged survival. Intrathecal administration of reovirus also remarkably prolonged survival in an immunocompetent racine model of leptomeningeal metastases. These data suggest that the evaluation of reovirus as an experimental therapeutic for CNS metastases from breast cancer is warranted.

Background:Long-term glioblastoma multiforme survivors (LTGBMS) are uncommon. The frequency which these occur in an unselected population and factors which produce these unusually long survivors are unknown.Objectives:To determine in a population- based study 1) the frequency of LTGBMS in a population and 2) identify which patient, treatment or tumor characteristics would predict which glioblastoma (GBM) patient would become a LTGBMS.Methods:The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in southern Alberta between 1/1/75 - 12/31/91. Patient charts were reviewed and histology re-examined by a blinded neuropathologist. LTGBMS were defined as GBM patients surviving ≥ 3 years after diagnosis. Each LTGBMS was compared to three age-, gender-, and year of diagnosis-matched controls to compare patient, treatment, and tumor factors to GBM patients without long-term survival.Results:There were 279 GBMs diagnosed in the study period. Five (1.8%) survived ≥ three years (range, 3.2-15.8 years). Seven additional long-term survivors, who carried a diagnosis of GBM, were excluded after neuropathologic review; the most common revised diagnosis was malignant oligodendroglioma. LTGBMS (avg. age = 45 years) were significantly younger when compared to all GBM patients (avg. age = 59 years, p - 0.0001) diagnosed in the study period. LTGBMS had a higher KPS at diagnosis (p = 0.001) compared to controls. Tumors from LTGBMS tended to have fewer mitoses and a lower Ki-67 cellular proliferative index compared to controls. Radiation-induced dementia was common and disabling in LTGBMS.Conclusions:These data highlight the dismal prognosis for GBM patients who have both a short median survival and very small chance (1.8%) of long-term survival. The LTGBMS were younger, had a higher performance status, and their tumors tended to proliferate less rapidly than control GBM patients. When long-term survival does occur it is often accompanied by severe treatment-induced dementia.

After a baseline symptom and laboratory assessment, 24 patients with metastatic bone disease and pain were randomized to receive either a 4-hr intravenous infusion of 2-dichloromethylene bisphosphonate (Cl2MDP), 600 mg in 500 mL of normal saline, or a 4-hr placebo infusion, 500 mL of normal saline. The administration was double blind. After 1 wk, the assessment was repeated and the patients were crossed over to the alternate treatment. After 1 more wk, a final assessment and blinded choice by the patient and investigator took place. Of the 21 evaluable patients, 12 (57%) chose the Cl2MDP and 4 (19%) chose the placebo; 5 (24%) patients did not have a specific preference (p = NS). The investigator chose the Cl2MDP in 14 (67%) cases, placebo in 6 (29%) cases and was unable to discern a difference in 1 (5%) case (p less than 0.05). The patients and investigator made similar selections in 16 (76%) instances. On the visual analogue scale assessments, a significant decrease in pain scores was observed following the Cl2MDP infusion (p less than 0.01) and an increase in activity scores was also demonstrated (p less than 0.01). No significant difference in the daily oral morphine equivalent analgesic requirement was demonstrated for either arm. No difference in clinical and laboratory parameters of toxicity was evident between the placebo and Cl2MDP arms of the trial. Our preliminary findings suggest that Cl2MDP is safe, and has analgesic properties that may prove to be useful in the management of metastatic bone pain.

Background:The purpose of this study was to determine incidence, survival rate, and prognostic factors as well as the frequency of Collins’ Law Violators (CLVs) in an unselected population of medulloblastoma patients. Collins’ Law dictates that ’cure’ of a child with a tumor occurs after a period that includes the child’s age at diagnosis plus 9 months.Methods:Using the Alberta Cancer Registry a population-based review identified 49 patients with medulloblastoma (19 adults, 30 children) diagnosed from 1975-96. Pathology was reviewed in all cases. All patients had surgical resection, followed by radiotherapy in 47 patients and chemotherapy in 17.Results:The overall 5-year survival was 50%. There was a trend for the extent of resection to be associated with a longer survival (Long rank test, p< 0.06) but this was not significant. Tumor recurrence occurred a median of 22.4 months (range, 6.4-192.3) after diagnosis and median survival after recurrence was 9.3 months (range, 0.4-64.9). The survival curve did not appear to plateau but was affected by tumor-related deaths in 3 (21.4%) of the 21 long-term survivors diagnosed in childhood. These three patients had recurrences a mean of 11.7 years after diagnosis and are designated as CLVs.Conclusions:The survival rate in an unselected population of patients with medulloblastoma is poor. Aggressive resection of the tumors prolongs survival. The Collins’ Law Violators were relatively common and we suggest this concept be abandoned in medulloblastoma.

Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates.Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys.Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates.These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Clinical and experimental evidence suggest that the p33ING1b candidate tumor suppressor functionally cooperates with p53 in controlling biochemical and biological functions. Because p53 is frequently mutated in brain tumors and the ING1 locus maps to a site of which the loss is associated with gliomas, we analyzed the mutation and expression profiles of ING1B in human brain tumors. Here we present the first report of ING1 expression and mutation analyses in human brain tumor samples and malignant glioma cell lines.Expression and mutation analyses of ING1B together with subcellular localization studies of ING1 proteins were performed on 29 brain tumor specimens and 6 human glioma cell lines.A single point mutation (3.5%) was detected in the 29 brain tumor specimens analyzed. This missense mutation occurred in a sequence reported previously to confer nuclear translocation properties to p33ING1b. Interestingly, overexpression and subcellular mislocalization of p33ING1b were observed in all 29 of the brain tumor specimens and some glioma cell lines. In tumor samples, ING1 proteins aberrantly localized to the cytoplasm, and to a lesser extent, to the nucleus of glioma cells.Our data indicate that although mutations of ING1 seem to be infrequent in human brain tumors, deregulated expression and mislocalization of ING1 proteins, particularly the p33ING1b isoform, are common events in gliomas and glioblastomas.

Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.

Background: Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas. Methods: We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided. Results: Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression in vivo in two subcutaneous (P = .0002 for both U251N and U87) and in two intracerebral (P = .0004 for U251N and P = .0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolongation of survival (compared with control mice treated with dead virus; log-rank test, P

Summary Background: The incidence of primary CNS lymphoma (PCNSL) is believed to be increasing in immunocompetent patients but this may not be universally true. The objective of this study was to determine in a population if the incidence of PCNSL is increasing, if the histologic subtypes are changing, and to describe the clinicopathologic and outcome characteristics of PCNSL. Patients and methods: We identified all Alberta residents with a histologic diagnosis of PCNSL from 1 January 1975 to 31 December 1996 using the Alberta Cancer Registry. Annual age-standardized incidence rates (ASIR), clinicopathologic and outcome characteristics were determined. Results: There were 50 immunocompetent PCNSL patients; the median age was 64 and 30 were male. Their median survival was 10.15 months. Histology was available for review in 37 (74%) patients: 19 (51%) were diffuse large cell, 16 (43%) were immunoblastic and 2 (5%) were unclassifiable malignant lymphomas. The ASIR ranged from 0.178-1.631/10 6 and no change in ASIR was found (test for trend, P = 0.26) for gender or age. The ASIR of malignant gliomas did not change either but increased for all other non-Hodgkin's lymphoma (94.95138.7610 6 ; test for trend, P = 0.0001) The number of brain biopsies increased from 1979-1985 (test for trend, P < 0.0001) but remained stable from 1986-1996 (test for trend, P - 0.99). Conclusions: Unlike several other populations, PCNSL is not becoming significantly more common in Alberta. If this difference is real (i.e., not due to differences in cancer registry coding practices etc.) comparisons between Albertans and other populations in whom the incidence is rising may provide clues regarding the etiology of PCNSL.

To evaluate the effectiveness of intravenous clodronate in ameliorating refractory bone pain in patients with metastatic bone disease, 60 patients with established osseous metastases and persistent bone pain were randomized to receive either clodronate (600 mg or 1500 mg in 500 mL of normal saline) or 500 mL of saline as placebo. After 2 weeks, the patients were crossed over to receive the alternate treatment. After another 2 weeks, each patient and investigator made a blinded choice. Daily visual analogue scales (VAS) and analgesic diaries were recorded throughout the study period. Forty-six patients were evaluable (77%). A treatment x period interaction was identified in the VAS and daily morphine equivalent dose (DMED) scores. First period analysis of the VAS scores for general pain, pain at rest, and pain upon movement demonstrated an average reduction of 13, 14, and 24 mm, respectively, from baseline, but were not significantly different from changes following placebo. The average change in DMED was -6.4 (SE = 2.9) following clodronate and was +24.6 (SE = 14.9) following placebo (p = 0.03). In the blinded choice of which agent resulted in improvement in pain, 26 (57%) patients chose clodronate, 12 (26%) chose placebo, and eight (17%) had no preference (p = 0.0021). For the investigators who also made a blinded selection, clodronate was chosen in 30 (65%) patients, placebo in ten (22%) patients, and no difference was apparent in six (13%) (p0.0001). Intravenous clodronate appeared to have analgesic effect in patients with refractory bone pain due to metastatic bone disease. The optimal dose and duration of effect require further evaluation, particularly in patients with stable disease and persistent bone pain.