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Biomedical subjects

P M Brasher

Publications and source records attributed to P M Brasher.

14 recordsLinked to original sources
PubMed2001

Reovirus as an oncolytic agent against experimental human malignant gliomas.

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<.0001 for both U251N and U87 cell lines). The animals treated with live virus also appeared to be healthier and gained body weight (P =.0001). We then tested the ability of reovirus to infect and kill primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas. CONCLUSIONS: Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.

Animals↗
PubMed1999

Accuracy of Pap tests reported as CIN I.

Papanicolaou (Pap) tests reported as CIN I (cervical intraepithelial neoplasia, grade 1) may be subject to laboratory misclassification because of screening and interpretative errors. A peer-groupC consensus review was conducted to measure the misclassification rate of Pap tests reported as CIN I and to analyze the undercalled and overcalled tests for due cause. Four hundred and forty-nine Pap tests originally reported as CIN I were independently reviewed twice by a panel of four pathologists, and disagreements were resolved by consensus review. Results were based on the original screening for the first review and, following the removal of those markings, were based on a second, independent rescreening for the second review. A review result of low-grade squamous intraepithelial lesion (LSIL) and atypical squamous cells of undetermined significance (ASCUS) favoring LSIL was equated with the original CIN I result. Final classification was based on the second consensus review. Misclassified tests were categorized as screening or interpretative errors, based on a comparison of the review classifications. LSIL and ASCUS favoring LSIL were reported in 85.1% and 73.9% of the first and second reviews, respectively. In the final classification there were 362 (80.6%) LSIL and ASCUS-LSIL and 87 (19.4%) misclassifications: 31 (6.9%) undercalls and 56 (12.5%) overcalls. Screening error accounted for 35.5% of undercalled tests, and the remainder were interpretative errors, as were all those overcalled. In this study, Pap tests reported as CIN I were subject to misclassification because of a laboratory error in 19.4% of tests. Reductions in screening and interpretative errors were identified as mechanisms for improving accuracy. Diagn. Cytopathol. 1999;21:129-136.

Algorithms↗
PubMed1999

Is primary CNS lymphoma really becoming more common? A population-based study of incidence, clinicopathological features and outcomes in Alberta from 1975 to 1996.

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 (94.95-138.7610(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.

Adolescent↗
PubMed1999

Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas.

Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis.

Brain↗
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

Risk-specific follow-up for endometrial carcinoma patients.

OBJECTIVE: To propose a risk-specific follow-up protocol for endometrial carcinoma patients. METHODS: A retrospective cohort of endometrial carcinoma patients was used to identify risk factors for recurrence. Based on a profile of risk factors, women were classified at either low or high risk for recurrence (median follow-up 70 months). The classification system was validated on a subsequent cohort. RESULTS: Surgical stage, grade, and histology were found to be significant predictors (P < 0.001) of recurrence. In the original cohort, patients with stage Ia, grade 1 or 2, or stage Ib, grade 1 adenocarcinoma, had a recurrence rate of 4/98 (4.1%). The remaining high-risk patients had a recurrence rate of 37/158 (23.4%). When applied to the subsequent cohort, the rates were similar: low risk 3/113 (2.7%) and high risk 30/140 (21.4%). Seventy-five percent of recurrences occurred within 3 years of diagnosis and the majority were heralded by site-specific symptoms. CONCLUSIONS: Women with endometrial carcinoma can be successfully classified for low or high risk of recurrence. It is proposed that low-risk patients not be maintained on routine follow-up and that a tailored schedule of follow-up be used for high-risk patients. These changes would serve patients more appropriately and use health care resources more efficiently.

Adenocarcinoma↗
PubMed1994

Risks and probabilities of breast cancer: short-term versus lifetime probabilities.

OBJECTIVE: To calculate age-specific short-term and lifetime probabilities of breast cancer among a cohort of Canadian women. DESIGN: Double decrement life table. SETTING: Alberta. SUBJECTS: Women with first invasive breast cancers registered with the Alberta Cancer Registry between 1985 and 1987. MAIN OUTCOME MEASURES: Lifetime probability of breast cancer from birth and for women at various ages; short-term (up to 10 years) probability of breast cancer for women at various ages. RESULTS: The lifetime probability of breast cancer is 10.17% at birth and peaks at 10.34% at age 25 years, after which it decreases owing to a decline in the number of years over which breast cancer risk will be experienced. However, the probability of manifesting breast cancer in the next year increases steadily from the age of 30 onward, reaching 0.36% at 85 years. The probability of manifesting the disease within the next 10 years peaks at 2.97% at age 70 and decreases thereafter, again owing to declining probabilities of surviving the interval. CONCLUSIONS: Given that the incidence of breast cancer among Albertan women during the study period was similar to the national average, we conclude that currently more than 1 in 10 women in Canada can expect to have breast cancer at some point during their life. However, risk varies considerably over a woman's lifetime, with most risk concentrated after age 49. On the basis of the shorter-term age-specific risks that we present, the clinician can put breast cancer risk into perspective for younger women and heighten awareness among women aged 50 years or more.

Adolescent↗
PubMed1994

An evaluation of routine follow-up of patients treated for endometrial carcinoma.

This retrospective review evaluates the outcome benefit of a standard follow-up protocol for 435 patients treated for endometrial carcinoma between 1981 and 1986. Routine follow-ups consisting of physical examinations and vaginal cytologies were done every 3 months for the first year, 4 months for the second year, and 6 months thereafter. Chest X rays were done biannually. Demographic, histopathologic, therapeutic, and follow-up data were studied. Exclusions due to incomplete follow-up (70), persistent disease (40), or other primary malignancies (8) left 317 patients with a disease-free state assigned to follow-up. Recurrences developed in 53 patients being followed, 40 (75%) of whom were symptomatic. Family physicians primarily diagnosed recurrences in 34 patients while recurrences in only 11 of the 53 patients (21%) were detected on routine follow-up at the cancer center (5 by examination and 6 by chest X ray). Therefore, only one recurrence was detected for every 206 routine follow-up visits. Vaginal vault cytology was not diagnostic in any patient. Seventy percent of recurrences occurred within 3 years. There was no statistical difference in survival between the group detected on routine follow-up and those who were symptomatic (P = 0.55). Routine follow-up of patients treated for endometrial cancer did not improve detection of recurrences or survival.

Endometrial Neoplasms↗
PubMed1987

Making the most of multiple measurements in estimating carrier probability in Duchenne muscular dystrophy: the Bayesian incorporation of repeated measurements using logistic discrimination.

In carrier detection studies, females-at-risk are usually tested several times if the results are ambiguous, whereas subjects in the control and obligate carrier reference groups may not be tested as often. The question is how to incorporate the multiple measurements most effectively with information in the family pedigree into combined carrier risks. Sets of measurements on individuals are not independent, but are related with the correlation coefficient 0 less than rho less than 1. We have developed a procedure for incorporating repeated measurements on individuals and their a priori chance of having the disease into logistic models. This procedure utilizes the set of measurements and an estimate of rho. We describe application of this procedure to carrier detection in Duchenne muscular dystrophy (DMD) using serum creatine kinase (CK) measurements as the biochemical indicator of carrier status. Estimates of rho for controls and obligate DMD carriers did not differ significantly from 0.5. Repeated testing with use of rho = 0.5 significantly decreased the median logistic carrier probability for controls and increased it for carriers. In some cases four to six rather than the three CK tests conventionally used in genetic counseling were necessary to obtain a stable logistic carrier probability for a subject.

Creatine Kinase↗
PubMed1986

DUCHEN: an interactive computer program for calculating heterozygosity (carrier) risks in X-linked recessive lethal diseases, and its application in Duchenne muscular dystrophy.

The program DUCHEN calculates the probability that a woman is a carrier of an X-linked, lethal recessive disease on the basis of information in the woman's family and any available biochemical data. It is easily used by persons without computer knowledge or experience. The present version can accommodate families consisting of up to 100 people in seven generations. Risks may be estimated on the basis of pedigree information only, or with the inclusion of one or more types of biochemical test results. Biochemical data are incorporated with pedigree information into final risks using the powerful statistical technique of logistic discrimination, a procedure particularly suited for the separation of non-normal populations on the basis of overlapping quantitative characteristics. Mutation rates are specified separately for males and females. DUCHEN is available in FORTRAN 77, IBM BASIC, and Applesoft BASIC, and may be used on a variety of mainframe or microcomputers. The model was used to calculate risks for 375 girls and women in 46 families with Duchenne muscular dystrophy (DMD); serum creatine kinase tests had been carried out on 167 of these subjects who were of reproductive age. Carrier probabilities equal to or lower than the population risk (0.0004) were obtained for 21% of the aunts and 43% of the cousins of affected boys from families with an isolated case of DMD and for 14% of the cousins of affected boys from families with a known DMD history. DUCHEN should assist counsellors in determining which members of large families should be further examined using either standard biochemical carrier detection methods or DNA marker studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Creatine Kinase↗
PubMedDate not supplied

A randomized controlled trial of a brief psychoeducational support group for partners of early stage breast cancer patients.

Partners of breast cancer patients are relied upon for support at a time when their own coping abilities are taxed by the challenge of cancer, yet few studies have investigated psychosocial interventions that include or target the patient's 'significant other'. Of the 118 consecutive patients approached, 36 patients and their partners participated in a randomized controlled trial of a brief psychoeducational group program for partners only. Psychometric instruments (including the Profile of Mood States (POMS), the Index of Marital Satisfaction (IMS) and DUKE-UNC Functional Social Support Scale (FSSS)) were administered pre-test, post-test and at 3 months follow-up. The Mental Adjustment to Cancer Scale (MAC) was also completed by patients. Three months after the intervention, partners had less mood disturbance than did controls. Patients whose partners received the intervention reported less mood disturbance, greater confidant support (CS) and greater marital satisfaction.

Adaptation, Psychological↗