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Biomedical subjects

G M Clark

Publications and source records attributed to G M Clark.

At least 253 records · Page 14Linked to original sources
PubMed1993

Prognostic significance of p53 gene alterations in node-negative breast cancer.

UNLABELLED: Mutations in the p53 gene can play a role in the transformation of normal to malignant cells. Because these mutations are more frequently reported later in the course of transformation, their presence could reflect a greater malignant potential of the tumor and, thus, an increased probability of metastasis and recurrence after local therapy. In a pilot study using single-stranded conformation polymorphism analysis (SSCP), 200 node-negative breast tumors were examined for mutations in the region encompassing exons 5 through 9 of the p53 gene. Exons 5 through 9 were tested because they contain 80-90% of known p53 gene mutations. The tumors ranged in size from 1 to 3 cm. 28 tumors were found to have an abnormal band pattern on both initial and repeat analysis. 4 of these tumors were sequenced; 3 contained a p53 mutation and the 4th had a rare neutral polymorphism. Disease-free survival (DFS) at 5 years for women with tumors having an abnormal SSCP analysis was 57% (+/- 10%), compared to a 79% (+/- 3%) DFS for the group with a normal pattern. By the log rank test, this difference was highly significant, p < or = 0.01. The relative risk of recurrence for the group with an abnormal SSCP pattern was 2.2. In a multivariate analysis including ER, PgR, ploidy, S-phase, age, and tumor size, an abnormal p53 by SSCP analysis and patient age were the only factors that independently predicted DFS at 5 years. CONCLUSION: Women with node-negative breast cancer who have tumors with alterations in the p53 gene, as indicated by SSCP analysis, have a significantly poorer prognosis and a higher rate of relapse at 5 years. The prognostic significance is maintained in a multivariate analysis including many established prognostic factors.

Base Sequence↗
PubMed1993

Measurement of steroid hormone receptors in breast cancer patients on tamoxifen.

Estrogen (ER) and progesterone receptor (PgR) positive breast tumors often respond to tamoxifen, but ultimately progress as they become tamoxifen resistant. An accurate assessment of receptor status in specimens from tamoxifen-resistant patients could help to understand potential mechanisms of resistance and to predict response to second line hormonal therapies. However, since tamoxifen itself can affect ER and PgR determinations, assay results can be misleading. We measured ER and PgR by both ligand binding (LBA) and immunohistochemical (IHC) assays in 34 tumors from patients on tamoxifen, 30 of whom were displaying resistance to the drug. These tumors were classified into several receptor phenotypes. Eleven patients, 8 of whom were clearly progressing, expressed both receptors while on tamoxifen. ER was significantly less often negative when measured by IHC, suggesting that ER status by LBA was falsely negative in this group due to receptor occupancy by tamoxifen. Six patients had no detectable ER by LBA or IHC but still expressed PgR. The presence of PgR suggests that ER could still be functional, though undetectable, in these tumors, or that PgR is constitutively expressed by them. Finally, 12 patients were ER and PgR-negative by both assays, suggesting hormonal independence as the mechanism for resistance in this group. In a subset of patients with receptor assays both prior to tamoxifen and at the time of progression while taking the drug, we found that most ER-positive tumors converted to an apparent ER-negative status when assayed by LBA, while PgR status frequently remained unchanged. The continued expression of ER and/or PgR in many patients with tumor progression on tamoxifen indicates that mechanisms for resistance other than receptor loss are common in breast cancer.

Adult↗
PubMed1993

DNA ploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients.

Several potential prognostic factors are available today for patients with breast cancer, and many more are being identified and studied. To evaluate the clinical utility of these factors, it will be necessary to measure them on a large number of patients, and then follow these patients so that multivariate survival analyses can be performed. The Oncology Research Network was established in 1986 by the University of Texas Health Science Center at San Antonio and Nichols Institute Reference Laboratories in order to evaluate the clinical utility of new prognostic factors for patients with primary breast cancer. The first generation of prognostic factors included steroid receptors, along with DNA ploidy and S-phase fraction determined by flow cytometry. Currently, laboratory results have been obtained from more than 127,000 patients, and follow-up information is available on a subset of more than 25,000 of these patients. S-phase fraction was related to the ploidy status of the tumor. An increased incidence of aneuploidy and higher S-phase fractions were found in estrogen and progesterone receptor negative tumors, tumors from patients with positive axillary lymph nodes, tumors greater than 2 cm in diameter, and patients younger than 35 years of age. Preliminary survival analyses suggest that S-phase fraction and DNA ploidy, in combination with other prognostic factors, are powerful predictors of early disease relapse. The Oncology Research Network provides an important resource for examining the clinical significance of new laboratory assays and for expediting improvements in existing laboratory techniques.

Breast Neoplasms↗
PubMed1993

William L. McGuire Memorial Symposium. The role and prognostic significance of p53 gene alterations in breast cancer.

Alterations in the p53 tumor suppressor gene are the most frequent genetic changes found in breast cancer, with an incidence reported in a range of 15 to 50%. The incidence of p53 alterations is approximately 15% for in situ carcinoma, while for invasive node-positive disease it is 2 to 3 times higher. This high rate of alteration suggests that the gene plays a central role in the development of breast cancer. The p53 gene functions as a negative regulator of cell growth. Alterations in the gene lead to loss of its usual negative growth regulation and more rapid cell proliferation. Since p53 alteration can reflect a more advanced state of progression and a higher rate of proliferation, breast tumors that have a p53 alteration could have a greater probability of having micrometastasis. p53 alterations could therefore be a prognostic factor for recurrence after primary local therapy. Consistent with this hypothesis, several independent studies using different methodologies have found that breast tumors with altered p53 have a worse prognosis and are also more likely to have other poor prognostic factors.

Amino Acid Sequence↗
PubMed1993

Multiple-marker immunohistochemical phenotypes distinguishing malignant pleural mesothelioma from pulmonary adenocarcinoma.

The diagnostic distinction between malignant pleural epithelial mesothelioma and pulmonary adenocarcinoma is often difficult and partially reliant on the use of immunohistochemistry (IHC). While there are several available IHC markers preferentially expressed in adenocarcinomas compared with mesotheliomas, there are no readily available or well-validated markers preferentially expressed in mesotheliomas and no markers are absolutely specific for either tumor. Thus, there always will be an element of doubt regarding the identity of lesions diagnosed by IHC using these markers and an undesirable reliance on negative results if the lesion is truly a mesothelioma. To help optimize the ability of currently available but imperfect markers to resolve adenocarcinoma and mesothelioma and to minimize the impact of false-negative results on their diagnosis, a systematic study was undertaken to identify multiple-marker immunostaining phenotypes that are the most specific and sensitive for each type of tumor. The study involved staining a series of malignant epithelial mesotheliomas (n = 34) and pulmonary adenocarcinomas (n = 103) with eight markers that were selected on the basis of previous reports of their relatively restricted specificities for one or the other of these lesions (and included carcinoembryonic antigen [CEA], tumor-associated glycoprotein 72 [B72.3], Leu-M1, vimentin, thrombomodulin, secretory component, carcinoma antigen-125, and periodic-acid-Schiff with diastase [for mucin]. Considering the markers one, two, and three at a time, all possible combinations of results were analyzed by computer to identify the phenotype most sensitive and specific for adenocarcinoma or mesothelioma. The best single marker was CEA (positive: 97% specific and sensitive for adenocarcinoma; negative: 97% specific and sensitive for mesothelioma). However, because examples of both tumor types expressed CEA, none of the study cases were unequivocally resolved and the risk of false-negative results was relatively high. The best two markers were CEA and B72.3 (both positive: 100% specific and 88% sensitive for adenocarcinoma; both negative: 99% specific and 97% sensitive for mesothelioma). The four possible combinations of results for these two markers resolved 68% of cases (93 of 137 cases), with less risk of false-negative results than a single marker. In general, several three-marker panels resulted in sensitivities and specificities similar to the two-marker panel of CEA and B72.3. In particular, the three-marker panel of CEA, B72.3, and Leu-M1 resulted in eight possible phenotypes that resolved 74% of cases (101 of 137 cases), with even further reduced risk of false-negative results.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1993

Profound hearing loss in the cat following the single co-administration of kanamycin and ethacrynic acid.

Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) has previously been shown to produce a rapid and profound hearing loss in guinea pigs. In the present study we describe a modified technique for developing a profound hearing loss in cats. By monitoring the animal's hearing status during the intravenous infusion of EA the technique minimizes the effects of individual variability to the drug regime. Seven cats received a subcutaneous injection of KA (300 mg/kg) followed by intravenous infusion of EA (1 mg/min). Click-evoked auditory brainstem responses (ABRs) were recorded to monitor the animal's hearing during the infusion. When the ABR thresholds rose rapidly to levels in excess of 90 dB SPL the infusion of EA was stopped. This occurred at EA doses of 10-25 mg/kg, indicating considerable individual variability to the deafening procedure. However, there was a strong negative correlation (r = -0.93) between the EA dose and body weight which accounted for much of this variability. Subsequent ABR monitoring showed that this profound hearing loss was both bilateral and permanent. Significantly, blood urea and creatinine levels, monitored for periods of up to three days after the procedure, remained within the normal range. Furthermore, there was no clinical evidence of renal dysfunction as indicated by weight loss or oliguria. Cochlear histopathology, examined after a two months to three year survival period, showed an absence of all inner and outer hair cells in the majority of cochleas. The extent of loss of spiral ganglion cells was dependent on their distance from the round window and the period of survival following the deafening procedure. Clearly, the degeneration of spiral ganglion cells continued for several years following the initial insult. Finally, we observed no evidence of renal histopathology. In conclusion, the co-administration of KA and EA produces a profound hearing loss in cats without evidence of renal impairment. Monitoring the animal's hearing status during the procedure ensures that the dose of EA can be optimised for individual animals. Moreover, it may be possible to adapt this procedure to produce animal models with controlled high frequency hearing losses.

Animals↗
PubMed1993

Hair cell mediated responses of the auditory nerve to sinusoidal electrical stimulation of the cochlea in the cat.

Electrical stimulation of the cochlea elicits discharges of auditory nerve fibres which are mediated by the electrical or mechanical stimulation of inner hair cells (electrophonic responses). In order to isolate hair-cell mediated responses from those elicited by electrical stimulation of the nerve, the compound action potential (CAP) evoked by an acoustic probe was forward-masked by sinusoidal monopolar, or localized bipolar electrical stimulation of the base of the cochlea. The degree of masking of a given probe estimated the synaptically mediated response to the masker of the population of auditory nerve fibres innervating the cochlear location tuned to the probe. There was a peak of masking for probes close to the frequency of the electrical stimulus, suggesting a spatial tuning of the hair cell mediated response along the cochlea. This is consistent with excitation of the inner hair cells by a propagating mechanical response which is generated within the electrical field at the base of the cochlea. Furthermore, tuning curves for masking of a given probe were sharply tuned to electrical stimulation close to the probe frequency. This masking was not dependent upon the presence of functional outer hair cells close to the electrodes, suggesting an alternate transduction of electrical to mechanical energy.

Action Potentials↗
PubMed1993

Electrical stimulation of the auditory nerve: the effect of electrode position on neural excitation.

Histological studies have shown that the Melbourne/Cochlear electrode array lies along the outer wall of the scala tympani and is therefore some distance from the residual VIIIth nerve elements. In order to investigate the influence of electrode position on neural excitation we systematically varied the position of the electrode array within the cat scala tympani while recording electrically evoked auditory brainstem responses (EABRs). Using both normal hearing and long-term deafened animals, we observed significant reductions in EABR thresholds as the electrode array was moved from the outer wall towards the modiolus. Further threshold reductions were observed when the array was placed underneath the osseous spiral lamina (OSL) close to the peripheral dendrites. These changes were independent of the bipolar inter-electrode separation, and were observed over a wide range of cochlear pathologies varying from normal to a moderate spiral ganglion cell loss. Interestingly, the one animal exhibiting extensive neural loss showed no correlation between EABR threshold and electrode position. There was also a general decrease in the gradient of the EABR input-output function as the electrode array was moved closer to the neural elements. This was, however, only statistically significant when the electrode was positioned adjacent to the peripheral dendrites. Significant reductions in EABR threshold were also observed as the inter-electrode spacing of the bipolar electrodes was increased. The gradient of the EABR input-output function also increased with increasing inter-electrode spacing, although again, this was only significant when the electrode array was positioned close to the neural elements. The present results indicate that the optimum placement of a Melbourne/Cochlear electrode array is adjacent to the peripheral dendrites. However, such a site would be difficult to achieve in practice while minimizing insertion trauma. An array lying adjacent to the modiolus would be a safe alternative while ensuring a significant reduction in threshold compared with the existing site (outer wall). This placement should result in more localized neural excitation patterns, an increase in the number of bipolar electrodes available, together with an increase in their dynamic range. These changes may lead to further improvements in speech perception among cochlear implant patients.

Animals↗
PubMed1993

In vitro evaluation of the antineoplastic activity of combretastatin A-4, a natural product from Combretum caffrum (arid shrub).

Combretastatin A-4 is a natural product which was isolated from the South African tree Combretum caffrum. In this study, the cytotoxic activity of combretastatin A-4 was tested in radiometric and human tumor cloning assays against eight different tumor cell lines and against 15 patient tumors in the human tumor cloning assay. To test the preferential cytotoxicity of combretastatin A-4 against tumor cells versus non-tumor cells, it was also tested in the radiometric assay against both normal human diploid fibroblasts and human bone marrow cells. Of the eight cell lines used, combretastatin A-4 showed preferential cytotoxicity for six of them. In addition, combretastatin A-4 showed a concentration-dependent cytotoxicity against a variety of human tumors. Based on the data generated in this study, combretastatin A-4 should be further tested in in vivo preclinical models.

Antineoplastic Agents, Phytogenic↗
PubMed1993

Factors in the development of a training program for use with tactile devices.

A review of the literature suggests that, in order to maximize the benefits available through a tactile device, it must be accompanied by an effective and adaptive training program. There are a number of factors to consider in the design of such a training program, including the type of tasks and response formats to include, the amount of training, subject motivation and device use, the characteristics of the potential user population, the specific device to be used and the type of information it provides, and the evaluation procedures to be followed. The type and saliency of the information provided by a particular tactile device are highlighted as the most important yet neglected consideration in designing a training program. The training program used with the University of Melbourne's multiple-channel electrotactile device is presented to show how these important factors may be addressed, to indicate the flexibility required in a training program, and to provide a general framework on which researchers may base the development of programs for other tactile devices.

Adolescent↗
PubMed1993

The effects of auditory feedback from the nucleus cochlear implant on the vowel formant frequencies produced by children and adults.

Cochlear implants provide an auditory signal with which profoundly deaf users may monitor their own speech production. The vowel production of two adults and three children who used the Nucleus multiple-electrode cochlear implant was examined to assess the effect of altered auditory feedback. Productions of words were recorded under conditions where the talkers received auditory feedback (speech processor turned on) and where no auditory feedback was provided (speech processor turned off). Data were collected over 3 days at weekly intervals. First and second formant frequencies were measured and the data were analysed to assess significant differences between auditory feedback conditions, vowel context, and data collection points. Overall, the results varied across talkers, across the data collection days, and depended on the consonant environment of the vowel. However, two effects of auditory feedback were noted. First, there was a generalized shift in first formant frequencies between the processor on and processor off conditions across three of the five subjects, but the shift differed in direction for each subject. Second, for three of the five talkers, the two front vowels /epsilon/ and /i/ were more neutralised in the absence of auditory feedback. However, this effect was less pronounced than that noted by previous studies.

Aged↗
PubMed1993

Electrode position, repetition rate, and speech perception by early- and late-deafened cochlear implant patients.

Psychophysical and speech perception studies were conducted on eight patients using the 22-electrode cochlear implant manufactured by Cochlear Pty. Ltd. Four early-deafened patients became deafened at 1-3 years of age and were implanted at 5-14 years of age. Four late-deafened (postlingual adult) patients became deafened at 38-47 years of age and were implanted at 42-68 years of age. Psychophysical studies measured the discrimination of trajectories with time-varying electrode positions and repetition rates. Speech perception studies measured performance using two speech coding strategies: a multi-electrode strategy which coded the first and second formant frequencies, the amplitudes of the two formants, and the fundamental frequency; and a single-electrode strategy which coded the amplitudes of the first and second formants, and the fundamental frequency. In general, the four late-deafened patients and one early-deafened patient were more successful than the other three early-deafened patients in the discrimination of electrode position trajectories and in speech perception using the multi-electrode strategy. Three of the four late-deafened patients were more successful than the early-deafened patients in the discrimination of repetition rate trajectories. Speech perception performance in the single-electrode strategy was closely related to performance in repetition rate discrimination. The improvement in speech perception performance from the single-electrode to multi-electrode strategy was consistent with successful performance in electrode discrimination.

Acoustic Stimulation↗
PubMed1993

Psychophysical and speech perception studies: a case report on a binaural cochlear implant subject.

Further improvements in speech perception for cochlear implant patients in quiet and in noise should be possible with speech processing strategies using binaural implants. For this reason, presented here is a series of initial psychophysical and speech perception studies on the authors' first binaural cochlear implant patient. For an approximate matching of the places of stimulation on the two sides, the patient usually reported a single percept when the two sides were simultaneously stimulated. Lateralization was strongly influenced by amplitude differences between the electrical stimuli on the two sides, but only weakly by interaural time delays. Speech testing, comparing monaural with binaural electrical stimulation, showed a binaural advantage particularly in noise.

Adult↗
PubMed1993

The perception of temporal modulations by cochlear implant patients.

The perception of temporal modulations of pulsatile electric stimuli was measured in seven cochlear implant patients using the Cochlear Pty. Limited prosthesis. Four patients were postlingually deafened adults and three patients were young adults who were deafened very early in life. The first study measured detection thresholds for modulated pulse duration for a series of modulation frequencies and pulse rates. The shape of the detection thresholds as a function of modulation frequency, the temporal modulation transfer function, often resembled a low-pass filter with a 50-100-Hz cut-off frequency. Thresholds did not markedly vary across the different pulse rates for most patients. Thresholds were less than 10%-20% of the range of usable hearing for most patients. The second study compared detection thresholds for modulated pulse durations around different reference pulse durations: 50, 100, and 300 microseconds. Detection thresholds were generally proportional to the different reference pulse durations. The third study measured difference limens for the discrimination of modulation depth. The difference limens were similar to the detection thresholds for the same reference pulse duration and pulse rate. The three patients deafened very early in life showed more within-group variation in performance, and their overall levels of performance were poorer than those of the postlingually deafened adults.

Acoustic Stimulation↗
PubMed1993

Glutathione transferase GST pi in breast tumors evaluated by three techniques.

The glutathione transferases are involved in intracellular detoxification reactions. One of these, GST pi, is elevated in some breast cancer cells, particularly cells selected for resistance to anticancer agents. We evaluated GST pi expression in 60 human breast tumors by three techniques, immunohistochemistry. Northern hybridization, and Western blot analysis. There was a significant positive correlation between the three methods, with complete concordance seen in 64% of the tumors. There was strong, inverse relationship between GST pi expression and steroid receptor status with all of the techniques utilized. In addition, there was a trend toward higher GST pi expression in poorly differentiated tumors, but no correlation was found between tumor GST pi content and DNA ploidy or %S-phase. GST pi expression was also detected in adjacent benign breast tissue as well as infiltrating lymphocytes; this expression may contribute to GST pi measurements using either Northern hybridization or Western blot analysis. These results suggest that immunohistochemistry is the method of choice for measuring GST pi in breast tumors.

Blotting, Northern↗