Biomedical subjects

G M Clark

Publications and source records attributed to G M Clark.

At least 289 records · Page 16Linked to original sources

PubMed1992

Why do so many prognostic factors fail to pan out?

Although there can be many reasons that one study fails to confirm the results of another, the consequences of data exploration and the potential for spuriously significant results are often overlooked. A series of simulation experiments were designed to mimic the characteristics of relapse-free survival data that might be encountered in a prognostic factor study of node-negative breast cancer patients. Each simulated dataset of 500 or 250 cases was divided into a training set, used to select the "best" prognostic factor cutpoint, and a validation set, used to confirm the cutpoint. Testing multiple cutpoints markedly increased the risk of making a Type I error. The power to detect even small true differences was substantial, and increased as the number of cutpoints increased. Regardless of the number of cutpoints tested on the training sets, the Type I error rate on an independent validation data set was quite stable and the power of the validation set to detect true differences was not related to the number of cutpoints. Validation power closely approximated that predicted for a simple two group comparison. It is therefore recommended that exploratory analyses of prognostic factors formally employ some method of adjusting for increased Type I errors, such as independent validation sets, ad hoc adjustment factors, or other statistical methods of estimating the true risk.

Breast Neoplasms↗

PubMed1992

Making the most of your prognostic factors: presenting a more accurate survival model for breast cancer patients.

Determining an appropriate level of adjuvant therapy is one of the most difficult facets of treating breast cancer patients. Although the myriad of prognostic factors aid in this decision, often they give conflicting reports of a patient's prognosis. What we need is a survival model which can properly utilize the information contained in these factors and give an accurate, reliable account of the patient's probability of recurrence. We also need a method of evaluating these models' predictive ability instead of simply measuring goodness-of-fit, as is currently done. Often, prognostic factors are broken into two categories such as positive or negative. But this dichotomization may hide valuable prognostic information. We investigated whether continuous representations of factors, including standard transformations--logarithmic, square root, categorical, and smoothers--might more accurately estimate the underlying relationship between each factor and survival. We chose the logistic regression model, a special case of the commonly used Cox model, to test our hypothesis. The model containing continuous transformed factors fit the data more closely than the model containing the traditional dichotomized factors. In order to appropriately evaluate these models, we introduce three predictive validity statistics--the Calibration score, the Overall Calibration score, and the Brier score--designed to assess the model's accuracy and reliability. These standardized scores showed the transformed factors predicted three year survival accurately and reliably. The scores can also be used to assess models or compare across studies.

Breast Neoplasms↗

PubMed1992

A practical application of neural network analysis for predicting outcome of individual breast cancer patients.

It has been previously shown that Neural Networks can be trained to recognize individual breast cancer patients at high and low risk for recurrent disease and death. This paper expands on the initial investigation and shows that by coding time as one of the prognostic variables, a Neural Network can use censored survival data to predict patient outcome over time. In this demonstration a Neural Network was trained, tested, and validated using censored survival data from a group of 1373 patients with node-positive breast cancer. The Neural Network method predicted patient outcome as accurately as Cox Regression modeling. The final Neural Network model can be presented with a patient's prognostic information and make a series of predictions about probability of relapse at different times of follow-up, allowing one to draw survival probability curves for individual patients.

Adult↗

PubMed1992

Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer.

Using permanent-section immunohistochemistry, we investigated the role of HER-2/neu in the development and progression of human breast cancer by measuring its overexpression in a series of hyperplastic (n = 30), dysplastic (n = 15), and malignant neoplastic (n = 708) lesions of ductal epithelium and by evaluating the relationships between overexpression and clinicopathologic features known to have prognostic significance in these lesions. The neoplasms included pure ductal carcinoma in situ (DCIS; n = 59) and infiltrating ductal carcinoma (IDC; n = 649). The latter were all node negative and stratified into IDC combined (n = 237) or not combined (n = 412) with a "significant amount" of DCIS (defined as DCIS greater than or equal to 10% of total tumor cellularity). Overexpression of HER-2/neu was not observed in any of the hyperplastic or dysplastic lesions. In contrast, it was present in 56% of pure DCIS and in 77% of the comedo subtype of this group. Only 15% of IDC overexpressed HER-2/neu. However, the rate of overexpression was significantly higher in the subset of IDC combined with DCIS compared with the subset of IDC not combined with DCIS (22% v 11%, respectively; P less than .0001). These results are consistent with the hypothesis that HER-2/neu plays a more important role in initiation than in progression of ductal carcinomas. They also suggest that overexpression decreases within individual tumors as they evolve from in situ to increasingly invasive lesions or, alternatively, that many invasive carcinomas arise de novo (ie, without progressing through a significant in situ stage) by mechanisms not involving HER-2/neu. In addition, overexpression of HER-2/neu was associated with several poor prognostic features (younger patient age, premenopause, negative estrogen receptor status, negative progesterone receptor status, and high nuclear grade) in the subset of IDC combined with DCIS. With one exception (negative estrogen receptor status) these associations were lost in IDC not combined with DCIS, also suggesting that the role of HER-2/neu changes during the progression of human breast cancer.

Biomarkers, Tumor↗

PubMed1992

A gated differential amplifier for recording physiological responses to electrical stimulation.

Artifact from electrical stimulation imposes a problem for the recording of physiological responses to electrical stimulation. Here we describe a simple, low-cost, gated differential amplifier for the recording of physiological responses to electrical stimulation. The gain of the amplifier is set to 1 during electrical stimulation by setting the gate input to a high logic state to avoid overloading of the amplifier by the artifact. Following electrical stimulation, the gate input is set to a low logic state, resulting in a gain of 1000 for frequencies between 300 Hz and 25 kHz (-3 dB points). The gain at low frequencies (0-0.2 Hz) is held constant at 1 to avoid transients in the output signal arising from changes in gain at these frequencies. The gain of the amplifier following stimulation (gate low) was independent of the magnitude of the artifact and was therefore suitable for the measurement of neural field potentials with low impedance electrodes.

Amplifiers, Electronic↗

PubMed1992

Cochleotopic selectivity of a multichannel scala tympani electrode array using the 2-deoxyglucose technique.

The 2-deoxyglucose (2-DG) technique was used to study the cochleotopic selectivity of a multichannel scala tympani electrode array in four cats with another acting as an unstimulated control. Each animal was unilaterally deafened and a multichannel electrode array inserted 6 mm into the scala tympani. Thresholds to electrical stimulation were determined by recording electrically evoked auditory brainstem responses (EABRs). Each animal was injected with 2-DG, and electrically stimulated using bipolar electrodes located either distal or proximal to the round window. The contralateral ear was stimulated with acoustic tone pips at frequencies that matched the electrode place. Stimulation of both distal and proximal bipolar electrodes at 3 x EABR threshold, evoked localized 2-DG labelling in both ipsilateral cochlear nucleus (CN) and the contralateral inferior colliculus (IC), which was very similar in orientation and breadth to labelling evoked by the contralateral tone pips. The cochleotopic position of labelling to proximal stimulation was located in the 24-26 kHz region of each structure, whereas the distal labelling was located around 12 kHz. Distal stimulation at 10 x EABR threshold produced very broad 2-DG labelling in IC centered around the 12 kHz place. The present 2-DG results clearly illustrate cochleotopic selectivity using multichannel bipolar scala tympani electrodes. The extent of this selectivity is dependent on electrical stimulus levels. The 2-DG technique has great potential in evaluating the efficacy of new electrode array designs.

Acoustic Stimulation↗

PubMed1992

Cochlear pathology following chronic electrical stimulation of the auditory nerve. I: Normal hearing kittens.

The present study examines the histopathological effects of long-term intracochlear electrical stimulation in young normal hearing animals. Eight-week old kittens were implanted with scala tympani electrode arrays and stimulated for periods of up to 1500 h using charge balanced biphasic current pulses at charge densities in the range 21-52 microC cm-2 geom. per phase. Both click and electrically evoked auditory brainstem responses were periodically recorded to monitor the status of the hair cell and spiral ganglion cell populations. In addition, the impedance of the stimulating electrodes was measured daily to monitor their electrical characteristics during chronic implantation. Histopathological examination of the cochleas showed no evidence of stimulus induced damage to cochlear structures when compared with implanted, unstimulated control cochleas. Indeed, there was no statistically significant difference in the ganglion cell density adjacent to the stimulating electrodes when compared with a similar population in implanted control cochleas. In addition, hair cell loss, which was restricted to regions adjacent to the electrode array, was not influenced by the degree of electrical stimulation. These histopathological findings were consistent with the evoked potential recordings. Finally, electrode impedance data correlated well with the degree of tissue growth observed within the scala tympani. The present findings indicate that the young mammalian cochlea is no more susceptible to cochlear pathology following chronic implantation and electrical stimulation than is the adult.

Animals↗

PubMed1992

Cochlear implants in children, adolescents, and prelinguistically deafened adults: speech perception.

A group of 10 children, adolescents, and prelinguistically deafened adults were implanted with the 22-electrode cochlear implant (Cochlear Pty Ltd) at the University of Melbourne Cochlear Implant Clinic and have used the prosthesis for periods from 12 to 65 months. Postoperative performance on the majority of closed-set speech perception tests was significantly greater than chance, and significantly better than preoperative performance for all of the patients. Five of the children have achieved substantial scores on open-set speech tests using hearing without lipreading. Phoneme scores in monosyllabic words ranged from 30% to 72%; word scores in sentences ranged from 26% to 74%. Four of these 5 children were implanted during preadolescence (aged 5:5 to 10:2 years) and the fifth, who had a progressive loss, was implanted during adolescence (aged 14:8 years). The duration of profound deafness before implantation varied from 2 to 8 years. Improvements were also noted over postoperative data collection times for the younger children. The remaining 5 patients who did not demonstrate open-set recognition were implanted after a longer duration of profound deafness (aged 13:11 to 20:1 years). The results are discussed with reference to variables that may affect implant performance, such as age at onset of loss, duration of profound loss, age at implantation, and duration of implantation. They are compared with results for similar groups of children using hearing aids and cochlear implants.

Adolescent↗

PubMed1992

The impact of phase I clinical trials on the quality of life of patients with cancer.

This prospective, non-randomized study was designed to evaluate the quality of life (QOL) of cancer patients receiving new cytotoxic therapy. QOL was measured using a linear analog self assessment scale (LASA). Cancer patients who received a phase I agent (n = 45) had no significant changes in any of the individual QOL variables, overall QOL (p = 0.77) or performance status (p = 0.08) following one course of phase I therapy. However, patients who were not eligible for entry on a phase I protocol and who received supportive care (n = 10) experienced significant decreases in overall QOL (p = 0.02) and performance status (p = 0.003) after 1 month of follow-up. This pilot study suggests that participation in phase I trials does not adversely affect one's QOL.

Adult↗

PubMed1992

Factors predicting postoperative sentence scores in postlinguistically deaf adult cochlear implant patients.

A sample of 64 postlinguistically profoundly to totally deaf adult cochlear implant patients were tested without lipreading by means of the Central Institute for the Deaf (CID) sentence test 3 months postoperatively. Preoperative promontory stimulation results (thresholds, gap detection, and frequency discrimination), age, duration of profound deafness, cause of deafness, lipreading ability, postoperative intracochlear thresholds and dynamic ranges for electrical stimulation, depth of insertion of the electrode array into the scala tympani, and number of electrodes in use were considered as possible factors that might be related to the postoperative sentence scores. A multiple regression analysis with stepwise inclusion of independent variables indicated that good gap detection and frequency discrimination during preoperative promontory testing, larger numbers of electrodes in use, and greater dynamic ranges for intracochlear electrical stimulation were associated with better CID scores. The CID scores tended to decrease with longer periods of profound deafness.

Adolescent↗

PubMed1992

Prognostic significance of S-phase fraction in good-risk, node-negative breast cancer patients.

PURPOSE: Formalin-fixed, paraffin-embedded tissues from axillary node-negative breast cancer patients were analyzed by flow cytometry to determine the prognostic significance of DNA ploidy and S-phase fraction (SPF). PATIENTS AND METHODS: All patients were registered on a good-risk control arm of an intergroup clinical trial. They had small- to intermediate-sized (less than 3 cm), estrogen receptor (ER)-positive tumors and received no adjuvant therapy after modified radical mastectomy or total mastectomy with low axillary-node sampling. The median follow-up was 4.8 years. RESULTS: Assessable ploidy results were obtained from 92% of the 298 specimens studied (51% diploid, 49% aneuploid), and SPFs were assessable for 83% of the tumors. SPFs for diploid tumors ranged from 0.7% to 11.9% (median, 3.6%), compared with a range of 1.2% to 26.7% (median, 7.6%) for aneuploid tumors (P less than .0001). No significant differences in disease-free or overall survival were observed between patients with diploid and aneuploid tumors. Using different SPF cutoffs by ploidy status (4.4% for diploid, 7.0% for aneuploid), patients with low SPFs had significantly longer disease-free survival rates than patients with high SPFs (P = .0008). The actuarial 5-year relapse rates were 15% and 32% for patients with low (n = 142) and high SPFs (n = 105), respectively. Similar relationships between SPF and clinical outcome were observed for patients with diploid tumors (P = .053) and for patients with aneuploid tumors (P = .0012). CONCLUSION: S-phase fraction provides additional prognostic information for predicting disease-free survival for axillary node-negative breast cancer patients with small, ER-positive tumors.

Actuarial Analysis↗

PubMed1992

HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma.

PURPOSE: Amplification and/or overexpression of the HER-2/neu oncogene have been shown to correlate with poor clinical outcome in patients with axillary node-positive breast cancer. In contrast, the prognostic significance of HER-2/neu in node-negative disease is controversial. This study was undertaken to evaluate further the relationship between HER-2/neu and clinical outcome in node-negative disease. PATIENTS AND METHODS: Overexpression of HER-2/neu was evaluated by permanent-section immunohistochemistry in tumors from 613 patients with long-term clinical follow-up enrolled in the Intergroup Study 0011. Patients were stratified into low-risk (n = 307) and high-risk (n = 306) groups on the basis of tumor size and estrogen-receptor (ER) status. Low-risk patients were defined as having small (less than 3 cm), ER-positive tumors and were observed without additional treatment after initial surgery. High-risk patients had either ER-negative or large (greater than or equal to 3 cm), ER-positive tumors and were randomized to be observed (n = 146) or to receive adjuvant chemotherapy (n = 160) after surgery. RESULTS: The rate of HER-2/neu overexpression was 14.3% in all tumors combined and was higher in invasive carcinomas with (21.5%) than without (11.2%) a significant noninvasive or in situ histologic component (P less than .0001). There was no relationship between overexpression and clinical outcome in the natural history setting of combined low-risk and high-risk patients not receiving adjuvant therapy (n = 453). Based on the reasoning that the influence of HER-2/neu may have been obscured by high-risk features and/or the presence of noninvasive carcinoma, we also analyzed the subset of patients with low-risk lesions not containing a significant in situ component (n = 179). Patients of this group with HER-2/neu-positive tumors showed only 40% disease-free survival (DFS) at 5 years, compared with over 80% in patients with HER-2/neu-negative tumors (P less than .0001). A similar inverse correlation was observed between overexpression and overall survival in the same group of patients (P = .0001). In a separate analysis involving patients receiving adjuvant chemotherapy, those with HER-2/neu-negative tumors showed significantly improved DFS in response to therapy compared with patients with HER-2/neu-positive tumors. CONCLUSION: Overexpression of HER-2/neu is associated with poor clinical outcome in a subset of node-negative patients with small, ER-positive, predominantly invasive tumors and may play a role in resistance to adjuvant chemotherapy.

Breast Neoplasms↗

PubMed1992

Safety studies with the University of Melbourne multichannel electrotactile speech processor.

Results of safety investigations conducted as an integral part of the development of a multichannel electrotactile speech processor (Tickle Talker) are reported. Electrical parameters of the stimulus waveform, design of the electrode handset and cabling, and the electrical circuitry of the speech processor/stimulator and programming interface have been analyzed for potential risks. Constant current biphasic square pulses delivered to electrodes positioned on the skin surface over the digital nerve bundles were chosen to optimize the safety, comfort, and function of the electrotactile stimulus. The device was battery-powered, and the user circuit was isolated from earth-referenced sources. Each electrode was isolated by capacitive coupling, preventing DC leakage of current to the user circuit. Studies of finger temperature showed slight cooling of the skin on the fingers of both stimulated and unstimulated hands for individual subjects following electrotactile stimulation through the Tickle Talker. Subsequent analysis of finger and hand vascular circulation in five subjects showed slight reductions in hand blood flow in some individuals. The results did not demonstrate a significant mean decrease in hand or finger blood flow following electrotactile stimulation. No evidence of sympathetic involvement was found, nor were any changes in vascular structure of the hand such as those associated with Raynaud's disease found. Evidence suggests that the decrease in temperature found in the initial study may be due to a change in the ratio of blood flow between arteriovenous anastomoses and nutritive capillary beds. Studies of: 1) changes in mean threshold and comfortable pulse widths over time; and, 2) changes in tactual sensitivity as measured by hot/cold, sharp/dull, and two-point difference limen discrimination, did not detect any systematic change in peripheral nervous system function following electrotactile stimulation. Analysis of electroencephalogram (EEG) recordings taken during electrotactile stimulation, and after relatively long periods of experience with the device did not show any pathological changes which might be associated with epileptic foci. In summary, no contraindications to long-term use of the Tickle Talker were detected in the studies performed.

Adult↗

PubMed1992

Steady-state evoked potentials to amplitude modulated tones in the monkey.

A frequency-specific, objective assessment of hearing thresholds is required for use in subjects unable to perform behavioural audiometry. One such method using steady-state evoked potentials (SSEPs) in response to amplitude-modulated tones was evaluated in an experimental animal, the macaque monkey. An amplitude-modulation frequency of 165 Hz was found to produce optimum response detection in the anaesthetised animal. Auditory thresholds determined by a computerised automatic response detection system accurately reflected behavioural thresholds previously described in this species.

Animals↗

PubMed1992

A comparison of speech perception of cochlear implantees using the Spectral Maxima Sound Processor (SMSP) and the MSP (MULTIPEAK) processor.

The Spectral Maxima Sound Processor (SMSP) is a portable speech processor which has recently been developed at the University of Melbourne for use with multiple-electrode cochlear implants. In this processor, the six largest outputs (maxima) of 16 bandpass filters are used to stimulate the cochlea on a place basis at a constant rate. This speech processing strategy has been compared with the MSP(MULTIPEAK) strategy, in which four electrodes are selected for stimulation in every glottal pulse period. The study was undertaken on four postlinguistically deaf adults. The results show that, for this group of subjects, the performance of the SMSP processor was significantly better than that of the MSP(MULTIPEAK) processor for the recognition of closed-set vowels and consonants, open-set monosyllabic words, and open-set sentences in noise, when using electrical stimulation alone. The SMSP mean scores were: vowels 91.3%, consonants 74.9%, words 57.4%, and sentences in noise 78.7%. The MSP(MULTIPEAK) mean scores were: vowels 76.3%, consonants 59.4%, words 39.9%, and sentences in noise 50.0%.

Adult↗

PubMed1992

Psychophysical studies using a multiple-electrode cochlear implant in patients who were deafened early in life.

Psychophysical studies were conducted on 10 cochlear implant patients, between 5 and 23 years of age at the time of surgery, who were deafened prior to 4 years of age. The multiple-electrode prosthesis manufactured by Cochlear Ltd. was used. Identification studies, the recognition of 2-4 stimuli after some training, were conducted on 3 of the 10 patients. For current level and repetition rate identification, performance was comparable to that observed for postlingual adult patients. For electrode position identification, however, performance was much poorer than that observed for postlingual adults. In general, the difference limens for current level, repetition rate and duration, and the gap detection thresholds were similar to those observed for postlingual adults. For 3 patients whose etiology was Usher's syndrome, the repetition rate limens at higher rates were larger than those of the other patients. The limens for electrode position, measured in a discrimination task, were 1-3 electrodes for most patients. However, for 3 patients, limens of 6-10 electrodes were recorded. For numerosity judgements, the counting of stimuli in a temporal series as a function of the rate of presentation, the patients were less successful at counting for rates of 3-8/s than for lower rates (1-2/s).

Adolescent↗

PubMed1992

The biology of breast cancer in older women.

The incidence of breast cancer among women older than 65 years of age is 1.7 times higher than the rate for women 45 to 64 years of age, and 10 times higher than for women younger than 45. In addition, the relative survival from breast cancer is decreased among elderly women. Although elderly women more frequently present with advanced breast cancer, the incidence of other poor prognostic factors generally associated with early disease recurrence and short survival is not increased among the elderly compared to younger women. Most breast tumors from elderly patients contain estrogen receptors and progesterone receptors and would be expected to respond to hormonal therapies, and most tumors have low proliferative rates which would be indicative of slow-growing, indolent tumors. Several studies have documented that elderly women often do not receive complete workups for definitive staging of their breast cancer, and that even after adjustment for comorbid conditions, elderly patients are less likely to receive optimal standard therapy for their disease.

Aged↗

PubMed1992

Prognostic potential of DNA flow cytometry measurements in node-negative breast cancer patients: preliminary analysis of an intergroup study (INT 0076).

An ancillary study (INT 0076) to the Intergroup clinical trial of node-negative breast cancer patients (INT 0011) was performed to retrospectively evaluate DNA flow cytometry measurements of ploidy (DNA content) and proliferative capacity (S-phase fraction) for their ability to predict time to recurrence. Of the 915 patients eligible for the clinical trial, 788 were registered for the ancillary flow cytometry study (INT 0076). Four hundred and three of these patients [estrogen receptor (ER)-positive, tumor size less than 3 cm] had been registered to the observation arm of the clinical trial and 385 (ER-negative and/or tumor size greater than or equal to 3 cm) had been randomly assigned to adjuvant chemotherapy (cyclophosphamide, methotrexate, fluorouracil, and prednisone for six cycles) or to observation. Paraffin blocks from 95% (748 of 788) of these patients were obtained, 712 of which had sufficient cancer tissue to be evaluable for the flow cytometric assay. DNA ploidy status (DNA diploid vs DNA aneuploid) was evaluable for 565 (79%) specimens, 64% of which were aneuploid. Proliferative capacity was estimated by the percentage of cells having an S-phase DNA content, using a trapezoidal modeling algorithm(s) as previously described. The median S-phase value for the entire group (both registered and randomly assigned patients) was 6.97%, which defined the cutoff for interpretation of high or low S-phase values. With a median follow-up time of 4.55 years, S-phase fraction, but not ploidy status, is a significant predictor for time to recurrence in both the randomly assigned and the untreated population (observed registered group and observed randomly assigned group).(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗