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Biomedical subjects

P Forsyth

Publications and source records attributed to P Forsyth.

At least 19 recordsLinked to original sources
PubMed2005

Biological purging of breast cancer cell lines using a replication-competent oncolytic virus in human stem cell autografts.

Autologous hematological stem cell transplantation (ASCT) is used for the treatment of many hematological and several solid cancers. ASCT, however, has proven disappointing as a therapeutic strategy for breast cancer. Our group and others have previously shown that breast cancer micrometastases found in patients' apheresis products (APs) predict shorter progression-free and overall survival. The implications of this finding are twofold: (i) contaminating tumor cells (CTCs) in AP reflect a higher systemic disease burden and/or (ii) reinfused CTCs contribute to relapse/progressive disease. To date, purging strategies have been disappointing. We have previously demonstrated the oncolytic properties of reovirus in in vitro, in vivo and ex vivo systems. In the present study, we tested the hypothesis that reovirus purges CTCs in a breast cancer cell line purging model. Reovirus-infected human breast cancer cell lines (HTB 133, HTB 132, SKBR3 and MCF7) exhibited cell death within days. Admixtures of AP with cells from breast tumor cell lines, which were then exposed to reovirus, showed complete purging of CTCs (assessed via flow cytometry/tumor cell outgrowth analysis) without deleterious effect on CD34+ cells. Our results provide preclinical support for the ex vivo use of reovirus as a purging modality for breast cancer during ASCT.

Antigens, CD34↗
PubMed2004

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.

Adrenal Cortex Hormones↗
PubMed2003

High-dose thiotepa, busulfan, cyclophosphamide and ASCT without whole-brain radiotherapy for poor prognosis primary CNS lymphoma.

Treatment of primary central nervous system lymphoma (PCNSL) with combined high-dose methotrexate (HD-MTX)-based chemotherapy and whole-brain radiotherapy (WBRT) is associated with severe neurotoxicity, but high relapse rates are associated with the use of either modality alone. In an attempt to improve upon these dismal results, we treated seven PCNSL patients with HD-MTX-based induction therapy followed by thiotepa, busulfan, cyclophosphamide (TBC), and autologous stem cell transplant (ASCT), without WBRT. Six of these patients had at least one of the following poor prognostic features: Karnofsky performance status (KPS) 60 years, or relapsed disease. All but one patient tolerated the treatment well and experienced improvements in neurological function and overall performance status post-transplant. No treatment-induced neurotoxicity (dementia, ataxia, and incontinence) was observed although the follow-up is short. One early treatment-related death occurred in a patient with multiple comorbid medical conditions. The other six patients achieved a complete response (CR) after TBC and ASCT. Five patients are currently alive and relapse-free at 5, 8, 24, 36, and 42 months from diagnosis. One additional patient relapsed and died 33 months after diagnosis. Two of the seven patients received TBC/ASCT as the only treatment after disease progression following their initial chemotherapy and both remain relapse-free at the time of this report, 22 and 31 months post-TBC/ASCT. In conclusion, prolonged CR can be attained after chemotherapy-only treatment of poor prognosis PCNSL. Furthermore, this small series suggests that high-dose chemotherapy for PCNSL should include drugs that penetrate the CNS such as busulfan and thiotepa rather than standard lymphoma regimens such as BEAM.

Adolescent↗
PubMed2002

Possible benefits of high-dose chemotherapy and autologous stem cell transplantation for adults with recurrent medulloblastoma.

In an attempt to improve the dismal prognosis of adults with recurrent medulloblastoma, six patients were treated with aggressive salvage therapy including high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). At relapse, all patients underwent surgical debulking followed by HDCT/ASCT and then radiotherapy when possible. The treatment plan included two cycles of HDCT/ASCT; first with cyclophosphamide, etoposide and carboplatin (CECb) and then 2 months later with cyclophosphamide and thiotepa (CT). Three of the six patients received the planned therapy. One patient experienced severe toxicity requiring life-sustaining therapy. This patient developed multi-organ dysfunction including multiple enhancing lesions in both cerebral hemispheres that slowly resolved over several months. Two other patients did not mobilize sufficient stem cells for two ASCT procedures. They received one ASCT conditioned with cyclophosphamide, thiotepa and carboplatin (CTCb). Three of six patients had a complete response (CR); the other three had a partial response (PR). Following the first ASCT, median duration of response was 13.5 months (range 9-29 months) and median survival was 21.5 months (range 12-42 months). There was no treatment-related mortality. We conclude that HDCT/ASCT with CECb-CT or CTCb is active against recurrent medulloblastoma in adults and may be associated with prolonged remissions. Multiple enhancing cerebral lesions on brain MRI early post-HDCT/ASCT may be a consequence of the treatment rather than metastatic disease.

Adult↗
PubMed2000

NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94).

PURPOSE: We conducted a phase II multicentre study of gemcitabine in patients with anaplastic astrocytoma and glioblastoma multiforme at first relapse. PATIENTS AND METHODS: Patients with anaplastic astrocytoma or glioblastoma multiforme receiving a stable dose of steroids and ECOG performance status < or = 3 were eligible for this study at the time of first relapse. One adjuvant chemotherapy regimen was permissible. Patients received gemcitabine 1000 mg/m2 i.v. weekly x 3, repeated on a four-weekly cycle. RESULTS: Of 20 patients enrolled, 15 were evaluable for response, 19 for non-hematological toxicity and 18 for hematological toxicity. Seven patients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme (GBM). Age ranged from 28-71 years (median 50). Fifteen patients discontinued therapy due to disease progression. The median number of cycles administered was 1 (range 1-11); only two patients received more than three cycles. Hematologic toxicity was acceptable and no grade 4 toxicity was seen. One patient developed Pneumocystis pneumonia and eventual pulmonary embolism; one died of gastric hemorrhage related to steroid therapy. No objective responses were seen. Nine patients had stable disease (median duration 2.7 months, range 0.9-11.2). CONCLUSIONS: Gemcitabine given in this dose and schedule seems well tolerated but is not active in patients with recurrent high-grade gliomas.

Adult↗
PubMed2000

Myeloablative chemotherapy for recurrent aggressive oligodendroglioma.

The objective of this study was to ascertain the duration of tumor control and the toxicities of dose-intense myeloablative chemotherapy for patients with recurrent oligodendrogliomas. Patients with previously irradiated oligodendrogliomas, either pure or mixed, that were contrast enhancing, measurable, and behaving aggressively at recurrence were eligible for this study. Only complete responders or major partial responders (75 % reduction in tumor size) to induction chemotherapy--either intensive-dose procarbazine, lomustine, and vincristine or cisplatin plus etoposide-could receive high-dose thiotepa (300 mg/m2/day for 3 days) followed by hematopoietic reconstitution using either bone marrow or peripheral blood stem cells. Thirty-eight patients began induction chemotherapy and 20 (10 men, 10 women; median age 46 years; median Karnofsky score 80) received high-dose thiotepa. For the high-dose group, the median event-free, progression-free, and overall survival times from recurrence were 17, 20, and 49 months, respectively. Tumor control in excess of 2 years was observed in 6 patients (30%). Four patients (20%) are alive and tumor free 27 to 77 months (median, 42 months) from the start of induction therapy; however, fatal treatment-related toxicities also occurred in 4 patients (20%). Three patients died as a result of a progressive encephalopathy which, in 2 instances, was accompanied by a wasting syndrome; 1 patient died as a consequence of an intracerebral (intratumoral) hemorrhage. Fatal toxicities occurred in patients with pretreatment Karnofsky scores of 60 or 70. High-dose thiotepa to consolidate response was a disappointing treatment strategy for patients with recurrent aggressive oligodendroglial neoplasms, although several patients had durable responses. Moreover, as prescribed, high-dose thiotepa had significant toxic effects in previously irradiated patients, especially those with poorer performance status.

Adult↗
PubMed1999

Suppression of ING1 expression in sporadic breast cancer.

Down regulation of the ING1 candidate tumour suppressor promotes growth in soft agar and focus formation in vitro and tumour formation in vivo. ING1 encodes a nuclear, cell cycle-regulated protein, overexpression of which efficiently blocks cell growth and is capable of inducing apoptosis in different experimental systems. Here we present the first report of ING1 mutation and expression analysis in a total of 452 cancer samples. One germline missense alteration and three germline silent alterations were detected in 377 primary breast cancers while marked (2 - 10-fold) decreases in ING1 mRNA expression were seen in 44% of primary breast cancers and in ten of ten breast cancer cell lines examined. Furthermore, the majority of breast cancers (58%) showing decreased ING1 expression had metastasized to regional lymph nodes whereas only 9% of cancers with elevated ING1 expression, compared to adjacent normal tissues, were metastatic. Thus, ING1 mutation is very rare in breast or ovarian cancers, however, repression of ING1 expression frequently accompanies tumour development of breast cancer.

Adult↗
PubMed1999

Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials.

We studied AG3340, a potent metalloproteinase (MMP) inhibitor with pM affinities for inhibiting gelatinases (MMP-2 and -9), MT-MMP-1 (MMP-14), and collagenase-3 (MMP-13) in many tumor models. AG3340 produced dose-dependent pharmacokinetics and was well tolerated after intraperitoneal (i.p.) and oral dosing in mice. Across human tumor models, AG3340 produced profound tumor growth delays when dosing began early or late after tumor implantation, although all established tumor types did not respond to AG3340. A dose-response relationship was explored in three models: COLO-320DM colon, MV522 lung, and MDA-MB-435 breast. Dose-dependent inhibitions of tumor growth (over 12.5-200 mg/kg given twice daily, b.i.d.) were observed in the colon and lung models; and in a third (breast), maximal inhibitions were produced by the lowest dose of AG3340 (50 mg/kg, b.i.d.) that was tested. In another model, AG3340 (100 mg/kg, once daily, i.p.) markedly inhibited U87 glioma growth and increased animal survival. AG3340 also inhibited tumor growth and increased the survival of nude mice bearing androgen-independent PC-3 prostatic tumors. In a sixth model, KKLS gastric, AG3340 did not inhibit tumor growth but potentiated the efficacy of Taxol. Importantly, AG3340 markedly decreased tumor angiogenesis (as assessed by CD-31 staining) and cell proliferation (as assessed by bromodeoxyuridine incorporation), and increased tumor necrosis and apoptosis (as assessed by hematoxylin and eosin and TUNEL staining). These effects were model dependent, but angiogenesis was commonly inhibited. AG3340 had a superior therapeutic index to the cytotoxic agents, carboplatin and Taxol, in the MV522 lung cancer model. In combination, AG3340 enhanced the efficacy of these cytotoxic agents without altering drug tolerance. Additionally, AG3340 decreased the number of murine melanoma (B16-F10) lesions arising in the lung in an intravenous metastasis model when given in combination with carboplatin or Taxol. These studies directly support the use of AG3340 in front-line combination chemotherapy in ongoing clinical trials in patients with advanced malignancies of the lung and prostate.

Animals↗
PubMed1999

Expression and modulation of matrix metalloproteinase-2 and tissue inhibitors of metalloproteinases in human embryonic CNS stem cells.

The expression and regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in neuroectodermal precursor cells is undocumented. We report the presence of MMP-2, but no MMP-9, and of all the four known TIMPs in neuroepithelial stem cells isolated from the human CNS. The expression of TIMP-1, TIMP-2 and TIMP-3 was unchanged following stem cells differentiation into neurons and glia. In contrast, while MMP-2 and TIMP-4 were localized to both stem and mature CNS cells, their levels of expression were substantially reduced in the latter. TIMP-4 showed a 23-fold reduction in media conditioned by differentiated cells compared with stem cell-conditioned media, reflecting a 6-fold decrease in mRNA expression. Interestingly, TIMP-4 also differed from the other TIMPs in that it was cell-associated in the stem cells, where this fraction remained unchanged upon differentiation. Hence, regulation of selective MMPs and TIMPs occurs during differentiation of human neural precursors suggesting that MMP-2 and TIMP-4 in particular may perform regulatory roles in the developing CNS.

Cells, Cultured↗
PubMed1999

Alternative therapy use in neurologic diseases: use in brain tumor patients.

BACKGROUND: The extent of alternative therapy use in brain tumor patients is unknown, but it may be frequent and seems important to those who use it. OBJECTIVE: To characterize alternative therapy use in brain tumor patients. METHODS: Prospective questionnaire-based survey of 167 brain tumor patients who attended a cancer center in Southern Alberta. Physicians completed forms describing clinical information such as disease status. RESULTS: The response rate was 91% (167/184). Twenty-four percent of patients used alternative therapies and often more than one therapy at the same time. Motivation to use these therapies was influenced by the desire for patient-focused treatment and a perceived need to take charge. Alternative therapy users were younger (p = 0.04) and more likely to be on sick or disability leave (p = 0.02), to come in for repeat visits (p = 0.05), and to have received conventional treatments (p = 0.01). Users tended to have lower quality of life with respect to physical well-being, functional well-being, and a specific brain tumor subscale. Clinical variables, such as disease status, tumor type, and Karnofsky Performance Score, were not related to alternative therapy use. Major changes in number and types of alternative therapy use occurred during the study period. No major side effects or tumor responses were seen with alternative therapies. CONCLUSIONS: Alternative therapy use in brain tumor patients is common and may reflect unmet patient needs with respect to their cancer care within the current model of health care delivery.

Adult↗
PubMed1999

Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340.

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.

Animals↗
PubMed1999

Which glioblastoma multiforme patient will become a long-term survivor? A population-based study.

In this clinical and histopathological study, the frequency of long-term glioblastoma multiforme (GBM) survivors (LTGBMSs) was determined in a population-based study. The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in Alberta between January 1, 1975, and December 31, 1991. Patient charts were reviewed and histology reexamined. LTGBMSs were defined as GBM patients surviving 3 years after diagnosis. Each LTGBMS was compared with 3 age-, sex-, and year of diagnosis-matched controls, and patient/treatment or tumor characteristics that predicted long-term survival were determined. There were 689 GBMs diagnosed in the study period; 15 (2.2%) of these patients survived 3 years. LTGBMSs (average age, 43.5 +/- 3.3 years) were significantly younger when compared with all GBM patients (average age, 53.0 +/- 0.56 years). LTGBMSs had a higher Karnofsky Performance Status score at diagnosis compared with controls. LTGBMSs were much more likely to have had a gross total resection and adjuvant chemotherapy than control GBM patients. Tumors from LTGBMSs tended to have fewer mitoses and a significantly lower Ki-67 cellular proliferation index compared with controls. Radiation-induced dementia was common and disabling in LTG-BMSs. In conclusion, conventionally treated GBM patients in an unselected population have a very small chance of long-term survival. The use of aggressive surgical resection and adjuvant chemotherapy may make long-term survival more likely in GBM patients if their performance status is high at diagnosis.

Adolescent↗
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↗
PubMed1997

Lack of germ-line mutations of CDK4, p16(INK4A), and p15(INK4B) in families with glioma.

Gliomas are tumors of the central nervous system that may be inherited in some patients. The gene(s) responsible for the clustering of gliomas in families have not yet been identified. Molecular studies of sporadic high-grade gliomas have revealed mutations or deletions of the genes encoding the protein kinase inhibitors p16(INK4A) and p15(INK4B) in a large proportion of tumors. Moreover, those tumors without deletions frequently display gene amplification and/or over-expression of mRNA encoding the protein kinase cdk4. We hypothesized that germ-line mutations in the p16(INK4A), p15(INK4B), or CDK4 genes might contribute to some cases of familial gliomas. To address this issue, we analyzed 36 kindreds with a predisposition to glial tumors. Genomic DNA from index members of these families was screened by PCR-single-strand conformational polymorphism analysis. We did not detect any functional mutations in the p16(INK4A), p15(INK4B), or CDK4 genes, although two individuals did have a previously described A140T polymorphism in p16(INK4A). Thus, despite the association between the sporadic forms of high-grade glioma and abnormalities of p16(INK4A), p15(INK4B), or CDK4, we found no evidence that germ-line mutations in the coding region of these three genes predispose to inherited glial tumors.

Adult↗
PubMed1996

Phase II study of prolonged oral therapy with etoposide (VP16) for patients with recurrent malignant glioma.

Because the percentage of dividing cells in malignant gliomas is small, cell cycle specific drugs such as VP16 are most effective if given continuously over prolonged periods. In this study, we chose a dose of 50 mg/day to minimize therapy interruptions for myelosuppression. VP16 was given until the neutrophil count dropped to < 1.0 x 10(9)/L or the platelets fell to < 75 x 10(9)/L and resumed when the counts rose to normal levels. We treated 46 patients with supratentorial malignant glioma (15 anaplastic astrocytoma, 21 glioblastoma multiforme, 9 anaplastic oligodendroglioma, 1 undifferentiated primary malignant brain tumor) at the time of tumor progression. All had KPS > or = 70 at study entry. All patients had prior RT, 13 with adjuvant nitrosourea. Twenty-four had prior nitrosourea chemotherapy for tumor progression, 7 had no prior chemotherapy. We treated 20 patients with VP16 at first progression and 26 at second or later progression. All patients had CT or MR scans and clinical evaluation every 8 weeks. Median time to tumor progression (TTP) was 8.8 weeks for all evaluable patients, 8.6 weeks for those treated at first progression and 8.4 weeks for those treated at second progression, 9.1 weeks for anaplastic astrocytoma, 7.5 weeks for glioblastoma multiforme and 17.1 weeks for anaplastic oligodendroglioma. There were 8 responses and 11 patients with stable disease for at least 8 weeks (R + SD = 42%). Prolonged low-dose oral VP15 is well tolerated, with minimal myelosuppression. Prolonged low-dose oral VP16 is modestly effective treatment for patients with recurrent malignant glioma and is more effective for anaplastic astrocytoma and anaplastic oligodendroglioma than glioblastoma multiforme.

Administration, Oral↗