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J G Cairncross

Publications and source records attributed to J G Cairncross.

At least 19 recordsLinked to original sources
PubMed1998

Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas.

BACKGROUND/METHODS: Gliomas are common malignant neoplasms of the central nervous system. Among the major subtypes of gliomas, oligodendrogliomas are distinguished by their remarkable sensitivity to chemotherapy, with approximately two thirds of anaplastic (malignant) oligodendrogliomas responding dramatically to combination treatment with procarbazine, lomustine, and vincristine (termed PCV). Unfortunately, no clinical or pathologic feature of these tumors allows accurate prediction of their response to chemotherapy. Anaplastic oligodendrogliomas also are distinguished by a unique constellation of molecular genetic alterations, including coincident loss of chromosomal arms 1p and 19q in 50%-70% of tumors. We have hypothesized that these or other specific genetic changes might predict the response to chemotherapy and prognosis in patients with anaplastic oligodendrogliomas. Therefore, we have analyzed molecular genetic alterations involving chromosomes 1p, 10q, and 19q and the TP53 (on chromosome 17p) and CDKN2A (on chromosome 9p) genes, in addition to clinicopathologic features in 39 patients with anaplastic oligodendrogliomas for whom chemotherapeutic response and survival could be assessed. RESULTS/CONCLUSIONS: Allelic loss (or loss of heterozygosity) of chromosome 1p is a statistically significant predictor of chemosensitivity, and combined loss involving chromosomes 1p and 19q is statistically significantly associated with both chemosensitivity and longer recurrence-free survival after chemotherapy. Moreover, in both univariate and multivariate analyses, losses involving both chromosomes 1p and 19q were strongly associated with longer overall survival, whereas CDKN2A gene deletions and ring enhancement (i.e., contrast enhancement forming a rim around the tumor) on neuroimaging were associated with a significantly worse prognosis. The inverse relationship between CDKN2A gene deletions and losses of chromosomes 1p and 19q further implies that these differential clinical behaviors reflect two independent genetic subtypes of anaplastic oligodendroglioma. These results suggest that molecular genetic analysis may aid therapeutic decisions and predict outcome in patients with anaplastic oligodendrogliomas.

Adult↗
PubMed1998

Gliomas in families: chromosomal analysis by comparative genomic hybridization.

Gliomas that aggregate in otherwise unremarkable families may have a heritable genetic basis. To determine the spectrum of genetic alterations in glioma-susceptible families, we examined tumor DNA from familial cases for regions of chromosomal gain or loss using comparative genomic hybridization (CGH). We compared chromosomal alterations within and among glioma families to those found in sporadic gliomas. A specific chromosomal abnormality common to the tumors of multiple unrelated probands with glioma or a specific chromosomal abnormality common to multiple affected persons in a single glioma-prone family would support the hypothesis of an inherited predisposition to glioma and at the same time identify specific regions of the genome harboring putative glioma susceptibility genes. Tumor DNA from 11 patients from seven families with two or more individuals with glioma was analyzed, including three members of a remarkable family having 10 affected individuals. We found no chromosomal abnormality common to all tumors of all probands nor did we find family-specific abnormalities in two of three glioma-prone kindreds. There were frequent copy number aberrations (CNAs) on chromosomes 7, 10, 19, and the sex chromosomes; other CNAs included +3q(13.3-29), -4q, +5q, -9q34, +12, -13q(21-->33), -15, -16p, +17qter, -18, -21, and -22. Amplifications occurred at +2 7p(11.1-->12), +2 7q(21.2-->33), +2 12q(13.2-->14), and +2 12p(11-->12). Although there were several novel CNAs [-16p, and +2 12p(11-p12)], none could readily explain the inheritance of these tumors.

Adolescent↗
PubMed1998

Malignant glioma: who benefits from adjuvant chemotherapy?

We combined two randomized prospective Brain Tumor Study Group data sets to analyze the effects of prognostic factors on survival by treatment group. Adjuvant chemotherapy increased long-term survival regardless of prognostic factors. Pathological review revealed that oligo dendrogliomas were overrepresented among long-term survivors independent of therapy. Prognostic factors do not predict benefit from adjuvant nitrosourea in malignant gliomas, and long-term survival with chemotherapy is not explained by oligodendroglial tumors.

Adult↗
PubMed1998

Long-term glioblastoma multiforme survivors: a population-based study.

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 > or = 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 > or = 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.

Adult↗
PubMed1998

Bihemispheric malignant glioma: one size does not fit all.

Recurrence of malignant glioma following radiotherapy most commonly occurs in close proximity to the original contrast enhancing CT/MRI tumor volume. For this reason current radiation planning favors focal radiotherapy fields designed to cover the preoperative tumor contrast enhancing volume +/- surrounding edema with a 2-4 centimetre margin. Two patients with bifrontal malignant gliomas treated with such radiotherapy fields experienced out of field tumor progression while on treatment. Posterior extension along the corpus callosum, not evident on pretreatment imaging, was hypothesized as the cause of the geographic miss. The literature documenting recurrence patterns of malignant glioma following radiotherapy support focal field radiotherapy fields for most patients with malignant glioma. Reporting bias may exist in the literature, however, due to the whole brain radiotherapy used in older series reporting recurrence patterns and exclusion of patients with bihemispheric or more locally extensive tumors in more modern series. Tumor location and pattern of growth at presentation may be important factors in predicting patterns of spread and relapse after radiotherapy.

Adult↗
PubMed1998

Low-grade gliomas in children: tumor volume response to radiation.

OBJECT: The authors conducted a retrospective review to examine and document the frequency, degree, and timing of the radiologically confirmed response to radiotherapy of low-grade gliomas in children. METHODS: Between 1963 and 1995, 80 patients 17 years of age or younger were referred to the London Regional Cancer Centre in London, Ontario after diagnosis of a low-grade glioma. All patients underwent surgical resection or biopsy procedures and 47 underwent radiotherapy (40 postoperatively and seven at the time of tumor progression). Nineteen patients with residual measurable lesions who received radiation therapy were selected for volumetric analysis of tumor response to this treatment. The extent and timing of response to radiation were determined by the process of comparing postoperative, preirradiation computerized tomography (CT) scans with postirradiation, follow-up CT scans. For one patient the comparison was made by using serial magnetic resonance images. Residual tumor was found on postoperative CT scans in all cases. The mean preradiotherapy tumor volume was 17.1 cm3, and the postradiotherapy volume was reduced to a mean of 11.5 cm3. A reduction in tumor volume was demonstrated in eight patients by the time of their first postirradiation follow-up CT scan and in two patients a slower reduction in volume over time was shown, bringing the total number of "responders" to 10. In five of these 10 patients the tumor had shown a maximum response by the time of the first postirradiation CT scan; the median time to response was 3.3 months. A 25% or greater reduction in tumor volume was seen in eight (42%) of the 19 patients. A 50% or greater reduction was noted in five (26%) of the patients. A complete response was demonstrated at 7, 12, and 15 months, and 5 years, respectively, in four patients (21%). One responder's tumor eventually increased in size after radiotherapy and he died of his disease. The magnitude of the radiographically demonstrated response to radiation did not correlate significantly with clinical outcome (that is, survival or symptom improvement). CONCLUSIONS: On the basis of this CT scan analysis of the response of low-grade gliomas in children to radiotherapy, the authors suggest that these lesions respond to radiation, as demonstrated by tumor shrinkage on serial imaging. Major or complete responses occur occasionally. However, low-grade gliomas in children mimic other benign brain tumors such as pituitary adenomas and meningiomas in that, although growth is frequently arrested after radiotherapy, residual tumor can persist for many years, illustrating that tumor shrinkage may not be a good measure of treatment efficacy. Nevertheless, radiation therapy can result in improvement of clinical symptomatology in association with or independent of visible tumor reduction. As radiation treatment techniques become increasingly conformal and because studies indicate that lower doses of radiation may be equally effective, improvement of symptoms may be an important consideration when weighing treatment options, particularly in patients with residual or unresectable disease.

Adolescent↗
PubMed1998

Genetic background influences timing, morphology and dissemination of lymphomas in p53-deficient mice.

To examine the influence of genetic background on tumorigenesis in p53-deficient mice, we used selective breeding to produce congenic mice with a null p53 gene mutation introduced into the VM inbred strain. Cohorts of homozygous p53 null (-/-) mice from the original C57B6/129Sv mixed strain and the VM congenic strain were monitored for spontaneous tumor development, as were control cohorts of wild-type (+/+) and heterozygous (+/-) animals. Twenty-six of 28 C57B6/129Sv (-/-) mice died by the study end date (median survival =184.5 days). Twenty-three of 26 VM (-/-) mice died and their survival was significantly shorter (111 days, P<0.0001). Of 26 C57B6/129Sv (-/-) mice that died, 21 were autopsied: all 21 had lymphomas. Of 26 VM mice that died (23 -/-, 3 +/-), 21 were autopsied: 19 developed lymphoma and two had sarcomas. Several mice had additional neoplasms. Lymphomas in VM mice were distinct from those in C57B6/129Sv mice in that they i) arose on average more than two months earlier, ii) involved thymus more often than spleen or lymph nodes and iii) were more often poorly differentiated, high grade tumors. These results demonstrate that genetic background alone influences the onset, morphology and dissemination of lymphomas in p53-deficient mice and suggest the presence of genes which modify the timing and biological nature of lymphomas in these mice.

Animals↗
PubMed1998

Chemotherapy for brain tumors.

Traditionally, cytotoxic drugs have played a limited role in the treatment of brain tumors, but important advances in chemotherapy have occurred during the past decade. Certain central nervous system (CNS) malignancies are remarkably chemosensitive. These include primary CNS lymphoma, medulloblastoma, oligodendroglioma, and intracranial germ-cell tumors. This review focuses on advances in the chemotherapy of these chemosensitive tumors and also discusses the potential use of chemotherapeutic agents, both cytotoxic and cytostatic, in other brain tumors, such as glioblastomas and anaplastic astrocytomas. In addition, a brief description of future directions that may hold promise, including high-dose chemotherapy with stem-cell rescue, blood-brain barrier disruption, and regional treatment using controlled-release biodegradable polymers, is included.

Antineoplastic Agents↗
PubMed1997

Measuring bias in uncontrolled brain tumor trials--to randomize or not to randomize?

PURPOSE: To help investigators decide if new therapies for glioma warrant definitive evaluation in randomized studies we have been developing a method for assessing the degree to which patient selection may have enhanced the results of uncontrolled treatment trials. In this study, we analyzed the impact of case selection on the survival of patients with malignant glioma receiving adjuvant stereotactic radiosurgery, a promising therapy reserved for those with small tumors and good performance status. METHODS: Following published eligibility criteria we simulated the patient selection process for stereotactic radiosurgery given as a boost at the conclusion of conventional radiotherapy. Eligible patients were culled from a pre-existing clinical/imaging database of 101 consecutive conventionally-treated patients with biopsy-proven malignant glioma and known survival times. Median durations of survival and 2- and 3-year survival rates were determined for those judged eligible or ineligible for stereotactic radiosurgery. RESULTS: Twenty-seven percent of patients were deemed eligible for stereotactic radiosurgery, eligible patients had more favorable prognostic factors and significantly longer median survival than ineligible patients (23.4 vs. 8.6 months; 2-year rate, 48% vs. 15%; 3-year rate, 30% vs. 7%); eligible patients also had a longer median survival than the entire group of unselected patients (23.4 vs. 11.4 months). Radiosurgery-eligible, conventionally-treated patients with glioblastoma multiforme and a group of radiosurgery-treated patients at a special referral center had similar median survival times (16.4 vs. 19.7 months). CONCLUSION: We provide additional evidence for selection bias in uncontrolled trials of stereotactic radiosurgery and by simulating the selection process accurately have detected a larger bias effect than noted previously. Judging from experience with interstitial radiation and intraarterial chemotherapy where substantial selection bias also occurred and randomized controlled trials proved disappointing, we conclude that a phase III study of stereotactic radiosurgery for malignant glioma is unlikely to yield a positive result and may not be necessary.

Adolescent↗
PubMed1997

Prospective study of postoperative magnetic resonance imaging in patients with malignant gliomas.

PURPOSE: We studied the natural history of postoperative enhancement on magnetic resonance (MR) scans in patients with malignant glioma to determine the following: (1) when a postoperative MR scan most accurately shows residual enhancing tumor; and (2) whether repeated doses of the contrast agent gadopentetate dimeglumine (Gd-DTPA) were well tolerated. PATIENTS AND METHODS: Seventeen patients with malignant glioma underwent tumor resection; four (24%) had nonenhancing tumors preoperatively. Serial MR scans were performed on postoperative days 1, 3, 5, 7, 14, and 21 and were analyzed qualitatively and quantitatively. The evolution of enhancement and subacute hemorrhage were described and measured. A uniform schedule of postoperative dexamethasone administration was used in all but four patients (24%) (each required higher doses to maintain neurologic function). RESULTS: Nontumoral, marginal (i.e., postsurgical) enhancement, potentially mimicking residual tumor, developed in eight patients (53%), including tumors that were nonenhancing preoperatively, and was maximal from days 5 to 14. Tumor enhancement was optimally visualized on postoperative days 3 to 5. Nine of 10 patients (90%) with gross residual enhancing tumor showed an increase of enhancing tumor size during the study. Methemoglobin was detected at some time in all patients (100%) and was usually minor, but in six (35%) it interfered with residual tumor assessment. The 97 doses of Gd-DTPA, administered in 17 patients, were well tolerated. CONCLUSION: When accurate assessment of residual enhancing tumor is needed in patients with malignant glioma, an MR scan performed on postoperative days 3 to 5 should minimize the confounding effects of postsurgical enhancement and methemoglobin. The repeated administration of Gd-DTPA over several weeks is well tolerated.

Adolescent↗
PubMed1996

Wild-type p53 renders mouse astrocytes resistant to 1,3-Bis(2-chloroethyl)-1-nitrosourea despite the absence of a p53-dependent cell cycle arrest [corrected].

We examined the response of normal and p53-deficient mouse astrocytes to the alkylating agent 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU), a clinically useful DNA-damaging drug to which some human astrocytomas are resistant and some are sensitive. Astrocyte cultures were isolated from the cerebrums of wild-type, heterozygous, and knockout p53 neonatal mice and treated with various concentrations of BCNU. Wild-type p53 astrocytes were significantly more resistant to BCNU than were knockout p53 astrocytes, with heterozygous astrocytes exhibiting an intermediate level of resistance, Cell cycle analysis showed that wild-type p53 astrocytes treated with BCNU demonstrated a decline in the percentage of cells in G1 and an increase in the percentage of cells in G2. Similar cell cycle responses to BCNU occurred in knockout p53 astrocytes, suggesting that this effect was p53 independent. In contrast, G1 arrest was observed in wild-type astrocytes exposed to ionizing radiation and was not observed in knockout astrocytes, indicating a p53-dependent response. Our findings point to an as yet uncharacterized p53-associated mechanism of resistance to BCNU in mouse astrocytes.

Animals↗
PubMed1996

A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium.

PURPOSE: This study was designed to evaluate strategies to overcome the resistance of anaplastic gliomas of the brain to external beam radiotherapy (ERT) plus carmustine (BCNU). Patients were > or = 15 years of age, had a histologic diagnosis of malignant glioma, and a Karnofsky performance status (KPS) > or = 60%. METHODS AND MATERIALS: In Randomization 1, patients were assigned to receive either ERT alone (61.2 Gy) or ERT plus mitomycin C (Mito, IV 12.5 mg/m(2)) during the first and fourth week of ERT. After this treatment, patients went on to Randomization 2, where they were assigned to receive either BCNU (i.v. 200 mg/m(2)) given at 6-week intervals or 6-mercaptopurine (6- MP, 750 mg/m(2) IV daily for 3 days every six weeks), with BCNU given on the third day of the 6-MP treatment. Three hundred twenty-seven patients underwent Randomization 1. One hundred sixty-four received ERT alone, and 163 received ERT + Mito [average 52.7 years; 63% male; 69% glioblastoma multiforme (GBM); 66% had a resection; 56% KPS > or = 90%]. Step-wise analysis of survival from Randomization 1 or 2 indicates that survival was significantly diminished by: (a) age > or = 45 years (b) KPS < 90%; (c) GBM/gliosarcoma histology; (d) stereotactic biopsy as opposed to open biopsy or resection. Median survival from Randomization 1 in both arms (ERT + Mito) was 10.8 months. Median survival from Randomization 2 was 9.3 months for BCNU/6MP vs. 11.4 months for the BCNU group (p = 0.35). Carmustine/6-MP showed a possible survival benefit for histologies other than GBM/GS. Two hundred and thirty-three patients underwent Randomization 2. The proportion of patients in the ERT group who terminated study prior to Randomization 2 was significantly less in the ERT group than in the ERT + Mito group (20 vs. 37%, p < 0.001). CONCLUSIONS: (a) The addition of Mito to ERT had no impact on survival; (b) patients treated with ERT + Mito were at greater risk of terminating therapy prior to Randomization 2; (c) there was not a significant survival benefit to the addition of 6-MP to BCNU.

Adult↗