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Biomedical subjects

G M Clark

Publications and source records attributed to G M Clark.

At least 73 records · Page 4Linked to original sources
PubMed1999

Growth factors, auditory neurones and cochlear implants: a review.

The total number and the integrity of the auditory neurones available for stimulation govern the benefits that patients can derive from cochlear implants. Although electrical stimulation of the cochlea has been reported to promote auditory neuronal survival, this trophic effect is insufficient to regenerate de novo fibres. Hence, any agent that can maximize the number of, or regenerate functional auditory neurones would be of great benefit. Several studies have identified various growth factors crucial to the normal development of auditory neurones. In addition, in vitro studies have demonstrated that several growth factors are important for the maintenance, rescue and repair of adult auditory neurones. In vivo studies confirm the in vitro findings, reporting that specific growth factors are able to support auditory neuronal survival following injury or trauma, and in lower species growth factors have been associated with regenerating auditory neurones. In addition to their trophic actions, several growth factors have also been reported to affect ion channels thus the electrical response of neuronal fibres. Indeed, growth factors have been reported to enhance neuronal excitation and to improve the efficacy of synaptic transmission. Taken in concert, these effects suggest that exogenous growth factors delivered to the cochlea may improve the transmission of the electrical stimuli from the implanted electrode to the auditory pathway. Further studies are warranted to investigate how the adjunct delivery of growth factors with the cochlear implant may constitute a better treatment for hearing-impaired individuals.

Adult↗
PubMed1999

Patients who are receiving concomitant medications should not systematically be excluded from phase I studies.

This retrospective study was designed to evaluate possible relationships between the number and types of concomitant medications administered to patients on the first day of therapy in phase I trials and demographic characteristics, outcome measures and toxicities. Concomitant medications received by 690 patients enrolled on 28 phase I trials between August 1985 and January 1996 were grouped into 31 categories based on the American Hospital Formulary Service 1993. These patients received 1650 cycles of treatment with investigational agents (median 2 cycles per patient). Median duration on-study was 49 days (range 1-776 days). Clinical response rate (complete, partial, minor) was 3.8%. Only three toxic deaths occurred (0.4%). Nearly all patients (90.9%) received at least one concomitant medication on the first day of therapy. The number of concomitant medications directly correlated with poor performance status (rSp = 0.27, p < 0.0001) and indirectly with duration on-study (rSp = -0.18, p < 0.0001). The dose of the investigational agent administered during the first course of therapy was not related to concomitant medications on the first day of therapy. Most importantly, no relationships were observed between concomitant medications and either toxicities or clinical response to therapy. We conclude that patients who are receiving concomitant medications should not systematically be excluded from phase I studies.

Adult↗
PubMed1999

Comparison of DX-8951f and topotecan effects on tumor colony formation from freshly explanted adult and pediatric human tumor cells.

DX-8951f, which shows great therapeutic potential, was tested in the human tumor cloning system in adult and pediatric tumor types against which topotecan has been active. In 47 tumors from adults, DX-8951f had definite cytotoxic activity in a concentration-dependent manner with both 1 h and continuous exposures. Topotecan was minimally effective using a 1 h exposure and showed concentration-dependent inhibition with continuous exposure. In head-to-head comparisons at 1 h exposure against adult tumors, DX-8951f was significantly more effective at 0.1 and 1.0 microg/ml than topotecan. In head-to-head comparisons (continuous exposure), 1.0 microg/ml DX-8951f was more effective than topotecan at 1.0 microg/ml in adult tumors, including three of four head and neck, one of two kidney, two of five liver, six of 10 non-small cell lung, five of eight ovarian, four of eight prostate tumors, and in single specimens of breast, mesothelioma, colon and small cell lung tumors. With continuous exposure, DX-8951f and topotecan were equally effective at equimolar concentrations. The maximum tolerated dose for DX-8951f is 3 times that of topotecan, so higher doses of DX-8951f could be administered to patients. DX-8951f is a promising new antineoplastic agent with significant activity against tumors taken directly from patients.

Adult↗
PubMed1999

Clinical findings for a group of infants and young children with auditory neuropathy.

OBJECTIVE: To examine the prevalence of auditory neuropathy in a group of infants at risk for hearing impairment and to present an overview of the clinical findings for affected children. DESIGN: Results for 20 subjects who showed repeatable cochlear microphonic potentials in the absence of click-evoked auditory brain stem responses are included in this study. Behavioral and steady state evoked potential thresholds were established in each case. Where possible, otoacoustic emission and speech perception results (unaided and aided) also were obtained. RESULTS: One in 433 (0.23%) of the children in our series had evidence of auditory neuropathy. The audiometric findings for these subjects varied significantly, with behavioral thresholds ranging from normal to profound levels. Discrimination skills were also variable. Approximately half of the subjects showed little understanding, or even awareness, of speech inputs in both the unaided and aided conditions. There were, however, a number of children who could score at significant levels on speech discrimination tasks and who benefited from the provision of amplification. CONCLUSION: The results suggest that auditory neuropathy is more common in the infant population than previously suspected. The effects of neuropathy on auditory function appear to be idiosyncratic, producing significant variations in both the detection and discrimination of auditory signals. As such, the management of children with this disorder must allow for individual differences.

Audiometry, Evoked Response↗
PubMed1999

A comparison of Tactaid II+ and Tactaid 7 use by adults with a profound hearing impairment.

OBJECTIVE: To evaluate and compare use of the Tactaid II+ and the Tactaid 7, in terms of speech perception, by adults with a hearing impairment. DESIGN: Eight adults used one device daily for approximately 10 wk and attended seven training sessions. Performance was measured with tests of phonetic contrast perception, closed-set vowel and consonant identification, word and phoneme recognition in monosyllabic word lists, word recognition in sentences and speechtracking rate. A questionnaire was also administered. The protocol was repeated with the alternative device. RESULTS: With each device, the group discriminated most phonetic contrasts at better-than-chance levels and demonstrated somewhat enhanced visual or auditory-visual perception when measured in terms of vowel identification, monosyllabic word recognition and speechtracking rate. An increase in speechtracking rate was also demonstrated for some individuals. Subjects generally reported little subjective improvement in speech perception and production, but were satisfied with the physical attributes of each device. Five of six subjects preferred the Tactaid 7. CONCLUSIONS: The Tactaid II+ and the Tactaid 7 provided suprasegmental and segmental information, enabling the group to discriminate phonetic contrasts and improve their perception of some speech materials. No consistent advantage was found for either device, thought most subjects preferred the Tactaid 7. Alternatives likely to provide a greater benefit to communication should be considered before a Tactaid fitting.

Acoustic Stimulation↗
PubMed1999

A stochastic model of the electrically stimulated auditory nerve: single-pulse response.

Most models of neural response to electrical stimulation, such as the Hodgkin-Huxley equations, are deterministic, despite significant physiological evidence for the existence of stochastic activity. For instance, the range of discharge probabilities measured in response to single electrical pulses cannot be explained at all by deterministic models. Furthermore, there is growing evidence that the stochastic component of auditory nerve response to electrical stimulation may be fundamental to functionally significant physiological and psychophysical phenomena. In this paper we present a simple and computationally efficient stochastic model of single-fiber response to single biphasic electrical pulses, based on a deterministic threshold model of action potential generation. Comparisons with physiological data from cat auditory nerve fibers are made, and it is shown that the stochastic model predicts discharge probabilities measured in response to single biphasic pulses more accurately than does the equivalent deterministic model. In addition, physiological data show an increase in stochastic activity with increasing pulse width of anodic/cathodic biphasic pulses, a phenomenon not present for monophasic stimuli. These and other data from the auditory nerve are then used to develop a population model of the total auditory nerve, where each fiber is described by the single-fiber model.

Action Potentials↗
PubMed1999

A stochastic model of the electrically stimulated auditory nerve: pulse-train response.

The single-pulse model of the companion paper [1] is extended to describe responses to pulse trains by introducing a phenomenological refractory mechanism. Comparisons with physiological data from cat auditory nerve fibers are made for pulse rates between 100 and 800 pulses/s. First, it is shown that both the shape and slope of mean discharge rate curves are better predicted by the stochastic model than by the deterministic model. Second, while interpulse effects such as refractory effects do indeed increase the dynamic range at higher pulse rates, both the physiological data and the model indicate that much of the dynamic range for pulse-train stimuli is due to stochastic activity. Third, it is shown that the stochastic model is able to predict the general magnitude and behavior of variance in discharge rate as a function of pulse rate, while the deterministic model predicts no variance at all.

Analysis of Variance↗
PubMed1999

The effects of stochastic neural activity in a model predicting intensity perception with cochlear implants: low-rate stimulation.

Most models of auditory nerve response to electrical stimulation are deterministic, despite significant physiological evidence for stochastic activity. Furthermore, psychophysical models and analyses of physiological data using deterministic descriptions do not accurately predict many psychophysical phenomena. In this paper we investigate whether inclusion of stochastic activity in neural models improves such predictions. To avoid the complication of interpulse interactions and to enable the use of a simpler and faster auditory nerve model we restrict our investigation to single pulses and low-rate (< 200 pulses/s) pulse trains. We apply signal detection theory to produce direct predictions of behavioral threshold, dynamic range and intensity difference limen. Specifically, we investigate threshold versus pulse duration (the strength-duration characteristics), threshold and uncomfortable loudness (and the corresponding dynamic range) versus phase duration, the effects of electrode configuration on dynamic range and on strength-duration, threshold versus number of pulses (the temporal-integration characteristics), intensity difference limen as a function of loudness, and the effects of neural survival on these measures. For all psychophysical measures investigated, the inclusion of stochastic activity in the auditory nerve model was found to produce more accurate predictions.

Cochlear Implants↗
PubMed1999

Gap detection by early-deafened cochlear-implant subjects.

Two studies investigating gap-detection thresholds were conducted with cochlear-implant subjects whose onset of profound hearing loss was very early in life. The Cochlear Limited multiple-electrode prosthesis was used. The first study investigated the effects of pulse rate (200, 500, and 1000 pulses/s) and stimulus duration (500 and 1000 ms) on gap thresholds in 15 subjects. Average gap thresholds were 1.8 to 32.1 ms. There was essentially no effect of pulse rate and for almost all subjects, no effect of stimulus duration. For two subjects, performance was poorer for the 1000-ms stimulus duration. The second study investigated the relationships between gap thresholds, subject variables, and speech-perception scores. Data from the first study were combined with those from previous studies [Busby et al., Audiology 31, 95-111 (1992); Tong et al., J. Acoust. Soc. Am. 84, 951-962 (1988)], providing data from 27 subjects. A significant negative correlation was found between age at onset of deafness and gap thresholds and most variability in gap thresholds was for the congenitally deaf subjects. Significant negative correlations were found between gap thresholds and word scores for open-set Bamford-Kowal-Bench (BKB) sentences in the auditory-visual condition and lipreading enhancement scores for the same test.

Adolescent↗
PubMed1999

Acquisition of a tactile-alone vocabulary by normally hearing users of the Tickle Talker.

Tactile-alone word recognition training was provided to six normally hearing users of the Tickle Talker, an electrotactile speech perception device. A mean group tactile-alone vocabulary of 31 words was learned in 12 h of training. These results were comparable to, or superior to, those reported for other tactile devices and Tadoma. With increased training the group became faster at learning tactually new words, which were introduced in small training sets. However, as their tactile-alone vocabulary grew, subjects required more training time to reach the pass criterion when evaluated on their recognition of their whole vocabulary list. A maximum possible vocabulary size was not established. The application of tactile-alone training with hearing-impaired users of the device is discussed.

Adult↗
PubMed1999

Intracellular responses of onset chopper neurons in the ventral cochlear nucleus to tones: evidence for dual-component processing.

Intracellular responses of onset chopper neurons in the ventral cochlear nucleus to tones: evidence for dual-component processing. The ventral cochlear nucleus (VCN) contains a heterogeneous collection of cell types reflecting the multiple processing tasks undertaken by this nucleus. This in vivo study in the rat used intracellular recordings and dye filling to examine membrane potential changes and firing characteristics of onset chopper (OC) neurons to acoustic stimulation (50 ms pure tones, 5 ms r/f time). Stable impalements were made from 15 OC neurons, 7 identified as multipolar cells. Neurons responded to characteristic frequency (CF) tones with sustained depolarization below spike threshold. With increasing stimulus intensity, the depolarization during the initial 10 ms of the response became peaked, and with further increases in intensity the peak became narrower. Onset spikes were generated during this initial depolarization. Tones presented below CF resulted in a broadening of this initial depolarizing component with high stimulus intensities required to initiate onset spikes. This initial component was followed by a sustained depolarizing component lasting until stimulus cessation. The amplitude of the sustained depolarizing component was greatest when frequencies were presented at high intensities below CF resulting in increased action potential firing during this period when compared with comparable high intensities at CF. During the presentation of tones at or above the high-frequency edge of a cell's response area, hyperpolarization was evident during the sustained component. The presence of hyperpolarization and the differences seen in the level of sustained depolarization during CF and off CF tones suggests that changes in membrane responsiveness between the initial and sustained components may be attributed to polysynaptic inhibitory mechanisms. The dual-component processing resulting from convergent auditory nerve excitation and polysynaptic inhibition enables OC neurons to respond in a unique fashion to intensity and frequency features contained within an acoustic stimulus.

Acoustic Stimulation↗
PubMed1999

Biologic markers as predictors of clinical outcome from systemic therapy for primary operable breast cancer.

PURPOSE: To determine whether pretreatment clinical features and molecular markers, together with changes in these factors, can predict treatment response and survival in patients with primary operable breast cancer who receive neoadjuvant therapy. PATIENTS AND METHODS: Mitoxantrone, methotrexate (with or without mitomycin), and tamoxifen chemoendocrine therapy was administered to 158 patients before surgery. Clinical response was assessed after four cycles of treatment. Fine-needle aspiration cytology for estrogen receptor (ER), progesterone receptor (PgR), c-erbB-2, p53, bcl-2, Ki67, S-phase fraction (SPF), and ploidy were performed pretreatment and repeated on day 10 or day 21 after the first cycle of treatment. RESULTS: Good clinical response (GCR, defined as complete response or minimal residual disease) was achieved in 31% of patients (49 of 158). Tumor size, nodal disease, response, ER, PgR, c-erbB-2, p53, bcl-2, Ki67, SPF, and ploidy were analyzed as predictors of survival. By univariate analysis, node-positive disease (P =.05), lack of ER (P <.05) and PgR (P <.05), and failure to attain GCR (P =.008) were associated with a significantly increased risk of relapse. A significantly increased risk of death was associated with node-positive disease (P =.02), lack of ER expression (P =.04), and failure to attain GCR. By multivariate analysis, GCR was an independent predictor for survival (P =.05). ER expression (P =.03), absence of c-erbB-2 (P =.03), and a decrease in Ki67 on day 10 or day 21 of the first cycle (P <.05) significantly predicted for subsequent GCR. CONCLUSION: Molecular markers may be used to predict the likelihood of achieving GCR, which seems to be a valid surrogate marker for survival.

Adult↗
PubMed1999

Tumor characteristics and clinical outcome of tubular and mucinous breast carcinomas.

PURPOSE: To comprehensively characterize the clinical and biologic features of tubular and mucinous carcinomas in a large cohort of patients and to relate this to clinical outcome and management. PATIENTS AND METHODS: The clinical and biologic features of 444 patients with tubular and 1,221 patients with mucinous carcinomas were compared with those of 43,587 patients with infiltrating ductal carcinoma, not otherwise specified (NOS). Disease-free survival (DFS) and overall survival (OS) for patients with tubular and mucinous carcinomas were compared with those of patients with NOS carcinomas and with age-matched sets from the general population. RESULTS: Tubular and mucinous carcinomas were more likely to occur in older patients, be smaller in size (tubular only), have substantially less nodal involvement, be estrogen receptor- and progesterone receptor-positive, have a lower S-phase fraction, be diploid, and be c-erbB-2- and epidermal growth factor receptor-negative compared with NOS carcinomas. Axillary node involvement was a poor prognostic feature in mucinous but not tubular carcinomas. Mucinous carcinomas < or = 1 cm had a < or = 5% incidence of node involvement. The 5-year DFS and OS were 94% and 88% for tubular, 90% and 80% for mucinous, and 80% and 77% for NOS carcinoma, respectively (P < .001 for differences among all three types for both DFS and OS). The 5-year OS of females from the general population age-matched to the patients with tubular and mucinous carcinomas was 89% and 82%, respectively, which is not different from the OS of patients with tubular or mucinous carcinomas. CONCLUSION: The biologic phenotype of tubular and mucinous carcinomas is quite favorable. Consistent with this observation, the survival of patients with tubular and mucinous carcinomas is similar to that of the general population. Systemic adjuvant therapy and node dissection may be avoided in many patients with these special types of carcinoma.

Adenocarcinoma↗
PubMed1999

Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer.

PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.

Adult↗
PubMed1999

Significance of axillary lymph node metastasis in primary breast cancer.

PURPOSE: Axillary lymph node status is the single most important prognostic variable in the management of patients with primary breast cancer. Yet, it is not known whether metastasis to the axillary nodes is simply a time-dependent variable or also a marker for a more aggressive tumor phenotype. The purpose of this study was to determine whether nodal status at initial diagnosis predicts outcome after relapse and therefore also serves as a marker of breast cancer phenotype. PATIENTS AND METHODS: Survival experience after first relapse in 1,696 primary breast cancer cases was analyzed using Cox proportional hazards regression. The following explanatory variables and their first-order interactions were considered: number of axillary lymph nodes involved (zero v one to three v four or more), hormone receptor status (any estrogen receptor [ER] negativity v ER negativity/progesterone receptor positivity v other ER positivity), primary tumor size (< 2 cm v 2 to 5 cm v > 5 cm), site of relapse (locoregional v distant), disease-free interval (< 1.5 years v 1.5 to 3 years v > 3 years), adjuvant endocrine therapy (none v any), adjuvant chemotherapy (none v any), and menopausal status (pre-, peri-, or postmenopausal). RESULTS: Axillary lymph node status, site of relapse, and hormone receptor status were all highly significant as main effects in the model. After adjustment for other variables, disease-free interval alone was only modestly significant but interacted with nodal status. After disease-free interval, hormone receptor status, and site of relapse were accounted for, survival after relapse was poorer in node-positive cases, when compared with node-negative cases. The hazard ratios for patients with one to three and four or more involved nodes were 1.2 (95% confidence interval [CI], 0.8 to 1.9) and 2.5 (95% CI, 1.8 to 3.4), respectively. CONCLUSION: Patients with four or more involved nodes at initial diagnosis have a significantly worse outcome after relapse than node-negative cases, regardless of the duration of the disease-free interval. We conclude that nodal metastasis is not only a marker of diagnosis at a later point in the natural history of breast cancer but also a marker of an aggressive phenotype.

Axilla↗
PubMed1999

A prognostic model that makes quantitative estimates of probability of relapse for breast cancer patients.

Tumor-node-metastasis (TNM) staging is the standard system for the estimation of prognosis of breast cancer patients. However, this system does not exploit information yielded by markers of the biological aggressiveness of breast cancer and is clearly unsatisfactory for optimal-treatment decision-making and for patient counseling. We have developed a prognostic model, based on a few routinely evaluated prognostic variables, that produces quantitative estimates for risk of relapse of individual breast cancer patients. We used data concerning 2441 of 2990 consecutive breast cancer patients to develop an artificial neural network (ANN) for the prediction of the probability of relapse over 5 years. The prognostic variables used were: patient age, tumor size, number of axillary metastases, estrogen and progesterone receptor levels, S-phase fraction, and tumor ploidy. Performances of the model were evaluated in terms of discrimination ability and quantitative precision. Predictions were validated on an independent series of 310 patients from an institution in another country. The ANN discriminated patients according to their risk of relapse better than the TNM classification (P = 0.0015). The quantitative precision of the model's estimates was accurate and was confirmed on the series from the second institution. The 5-year relapse risk yielded by the model varied greatly within the same TNM class, particularly for patients with four or more nodal metastases. The model discriminates prognosis better than the TNM classification and is able to identify patients with strikingly different risks of relapse within each TNM class.

Adult↗
PubMed1998

Heterogeneous expression of the lipocalin NGAL in primary breast cancers.

We have previously shown that neu oncogene-initiated rat mammary carcinomas uniquely over-express neu-related lipocalin (NRL), a member of the calycin protein superfamily. Here, we characterize the putative human homolog of NRL, neutrophil gelatinase-associated lipocalin (NGAL). ngal gene expression was found at moderate levels in only 2 of 17 human tissues examined, breast and lung. When breast cancers were examined for NGAL mRNA and protein levels, they were found to exhibit heterogeneous expression. NGAL levels varied in these tumors from undetectable to exceeding those in normal breast parenchyma. Immuno-histochemical analysis confirmed the presence of NGAL within breast carcinoma cells but detected only low levels of this protein in normal ductal epithelium. In contrast, large amounts of the protein were localized to the lumen of normal breast ducts in the vicinity of NGAL-expressing tumors. Interestingly, unlike NRL in rat mammary carcinomas, no significant association between NGAL expression and HER-2/neu activation was found in human breast tumors. In contrast, a significant correlation between NGAL expression in breast cancer was found with several other markers of poor prognosis, including estrogen and progesterone receptor-negative status and high proliferation (S-phase fraction). NGAL levels were stratified as high or low in breast cancers from a cohort of node-positive patients with known outcome. No significant association between NGAL expression and disease-free or overall survival was observed.

Acute-Phase Proteins↗