Biomedical subjects

G M Clark

Publications and source records attributed to G M Clark.

At least 19 recordsLinked to original sources

PubMed2006

Reporting recommendations for tumor marker prognostic studies (remark).

Despite years of research and hundreds of reports on tumor markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often, initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodologic problems have been cited to explain these discrepancies. Unfortunately, many tumor marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalizability of study results. The development of guidelines for the reporting of tumor marker studies was a major recommendation of the National Cancer Institute - European Organisation for Research and Treatment of Cancer (NCI - EORTC) First International Meeting on Cancer Diagnostics in 2000. As for the successful CONSORT initiative for randomized trials and for the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Biomarkers, Tumor↗

PubMed2005

REporting recommendations for tumour MARKer prognostic studies (REMARK).

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

Biomarkers, Tumor↗

PubMed2005

Hormone receptor status of a contralateral breast cancer is independent of the receptor status of the first primary in patients not receiving adjuvant tamoxifen.

PURPOSE: To determine whether the hormone receptor status of the primary breast cancer (PBC) is predictive of the hormone receptor status of the subsequent contralateral breast cancer (CBC). PATIENTS AND METHODS: We identified patients in our database with known estrogen receptor (ER; n = 193) and/or progesterone receptor (PgR; n = 178) status in their PBC and in their subsequent CBC. One hundred twenty-six of these patients had received no adjuvant therapy, 34 had received adjuvant tamoxifen, and 33 had received adjuvant chemotherapy alone. The median interval between the first diagnosis of PBC and the development of the subsequent CBC was 3 years. ER and PgR assays were assessed biochemically in two central reference laboratories using identical quality-controlled ligand-binding methods. RESULTS: Among systemically untreated patients (n = 126), 88% of patients with ER-positive PBC and 75% of patients with ER-negative PBC developed an ER-positive CBC (P = .11). Among the tamoxifen-treated patients, those with an ER-positive PBC were almost equally likely to develop an ER-positive (47%) or ER-negative (53%) CBC (P = .99). PgR status was similar. In the untreated group (n = 112), 59% of patients with a PgR-positive PBC and 66% with a PgR-negative PBC developed a PgR-positive CBC (P = .48). Among tamoxifen-treated patients (n = 33), 50% of patients with a PgR-positive PBC versus 27% of patients with a PgR-negative PBC developed a PgR-positive CBC (P = .28). CONCLUSION: ER and PgR status of the primary tumor does not predict the hormone receptor status of the subsequent CBC in the absence of selective pressure of adjuvant therapy. Thus, other reasons should be considered to clarify the failure of tamoxifen to reduce the incidence of CBC in patients with a receptor-negative PBC.

Aged↗

PubMed2004

A study of intra-cochlear electrodes and tissue interface by electrochemical impedance methods in vivo.

This paper presents methods, results and analysis for measurements of the electrochemical impedance of platinum electrodes (approximately 0.43 mm2) over a 6-month implantation in the cat cochlea. The study aimed to improve our understanding of the effects of tissue response on impedance behaviour. An increase in impedance in the post-operative period was evident with a rise of the distorted arc at high frequencies in the complex plane, correlating to anomalous charge transport at the electrode-tissue interface. The impedance at low frequencies generally showed a capacitive dispersion modelled as a constant phase element, indicating a blocking characteristic of the electrodes. The study suggests that a reduction and changes in composition of perilymph or extracellular fluid adjacent to the electrodes, as a consequence of tissue response, causes the elevated "contact impedance". This affects the efficiency and quality of neural stimulating electrodes and neural recording electrodes. The finding of the crucial role of perilymph or extracellular fluid thin layer provides a new strategy for surface materials of neural electrodes, which is discussed in the paper. The interface characteristics must be considered during interpretation of studies undertaken in vitro or in acute experiments in vivo, where physiological fluid is abundant.

Animals↗

PubMed2004

Stiffness properties for Nucleus standard straight and contour electrode arrays.

Trauma and damage during insertion of electrode arrays into the human cochlea are strongly related to the stiffness of the array. The stiffness properties of electrode arrays, which were determined by three-point flexural bending and buckling tests, are reported in this paper. To date there has been limited publication on mechanical properties of these electrode arrays. Previous studies mainly focused on characterizing the stiffness of the tip of the Nucleus straight array with little emphasis on characterizing the stiffness of its whole length. In this study, stiffnesses of the Nucleus straight and contour electrode arrays have been determined along their length. Young's modulus of elasticity of the Nucleus straight array has been found to increase from the tip (182 MPa) to the rear end (491 MPa), whereas the stiffness of the contour array is greatest near the tip (480 MPa) and is fairly uniform in the middle and rear sections of the electrode array (380-400 MPa). Buckling experiments have shown that the contour array has much higher critical buckling load (about four times) than the Nucleus straight array. The results from three-point flexural bending and buckling experiments provide significant data for the development of electrode arrays, from which new array designs with improved flexibility can be developed. The results of stiffness properties are also important input for use in finite element models to predict the trajectories during insertion and to help evaluate the effects of different electrode array designs on damage sustained during insertion.

Acoustic Stimulation↗

PubMed2003

Evaluation of trajectories and contact pressures for the straight nucleus cochlear implant electrode array - a two-dimensional application of finite element analysis.

A two-dimensional (2D) finite element analysis has been used in this study to model the insertion of the Nucleus electrode array with different stiffness properties in order to evaluate the propensity of damage by visualizing the predicted trajectories and by comparing the buckling stresses and the contact pressures at the tip (and its distribution along the length) of the electrode array. Previous temporal bone studies have shown that damage during insertion of an electrode array around the basal turn of the cochlear spiral could be related to the design and the stiffness properties of the electrode array. However, it is difficult to evaluate different designs of electrode arrays purely by experimental methods as the experimental conditions and their results are difficult to reproduce. Three electrode arrays with different mechanical properties, i.e. uniform stiffness, graded stiffness, and a soft tip have been modelled. Buckling stress and contact pressure at the tip of the electrode array were found to be highest for the arrays with uniform stiffness. The contact pressures at the tip of the electrode array appeared strongly influenced by the stiffness profile and were optimal for graded stiffness. The results indicate the importance of the electrode array design and stiffness properties in minimizing trauma. However, there are a number of limitations in the present 2D evaluation which will require further analysis using a three-dimensional model to obtain definitive results.

Cochlea↗

PubMed2003

Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer.

BACKGROUND: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. PATIENTS AND METHODS: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. RESULTS: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. CONCLUSIONS: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.

Administration, Oral↗

PubMed2003

Cyclo-oxygenase-2 (COX-2) mRNA expression correlates with progesterone receptor positivity in human breast cancer.

BACKGROUND: We previously presented evidence showing that cyclo-oxygenase 2 (COX-2) plays an important role in mammary carcinogenesis and angiogenesis in human breast cancer. The present study aims to compare COX-2 mRNA expression with hormone receptor status, S-phase fraction, telomerase activity, and DNA ploidy in human breast cancer. METHODS: Total cellular RNA was extracted from frozen breast tissue samples according to standard methodology. The mRNA copy numbers for COX-2 were determined in 18 infiltrating carcinomas using quantitative RT-PCR and TaqMan methodology. The oestrogen receptor (ER) and progesterone receptor (PgR) status was determined using the ligand-binding technique (ER+ = > 3 fmol/mg, PgR+ = > 5 fmol/mg). We also determined DNA ploidy status (diploid or aneuploid), S-phase fraction (< 6% = low, 6-10% = intermediate, > 10% = high), and telomerase activity (total protein generated by TRAP assay). RESULTS: The median COX-2 mRNA copy number per micro g of RNA was 126 713 (range = 15 717-2 022 050). COX-2 expression was significantly associated with PgR positivity (p = 0.013). The association between COX-2 and DNA diploidy failed to reach a statistical significance (p = 0.085). No significant association was detected between COX-2 and S-phase fraction, ER status, or telomerase activity. CONCLUSIONS: COX-2 mRNA expression is associated with PgR positivity in human breast cancer. This observation is consistent with the hypothesis that COX-2 upregulates aromatase activity.

Breast Neoplasms↗

PubMed2002

Short-term auditory memory in children using cochlear implants and its relevance to receptive language.

The aim of this study was to assess auditory sequential, short-term-memory (SSTM) performance in young children using cochlear implants (CI group) and to examine the relationship of this performance to receptive language performance. Twenty-four children, 5 to 11 years old, using the Nucleus 22-electrode cochlear implant, were tested on a number of auditory and visual tasks of SSTM. The auditory memory tasks were designed to minimize the effect of auditory discrimination ability. Stimuli were chosen that children with cochlear implants could accurately identify with a reaction time similar to that of a control group of children with normal hearing (NH group). All children were also assessed on a receptive language test and on a nonverbal intelligence scale. As expected, children using cochlear implants demonstrated poorer auditory and visual SSTM skills than their hearing peers when the stimuli were verbal or were pictures that could be readily labeled. They did not differ from their peers with normal hearing on tasks where the stimuli were less likely to be verbally encoded. An important finding was that the CI group did not appear to have a sequential memory deficit specific to the auditory modality. The difference scores (auditory minus visual memory performance) for the CI group were not significantly different from those for the NH group. SSTM performance accounted for significant variance in the receptive language performance of the CI group. However, a forward stepwise regression analysis revealed that visual spatial memory (one of the subtests of the nonverbal IQ test) was the main predictor of variance in the language scores of the children using cochlear implants.

Acoustic Stimulation↗

PubMed2001

Optimizing flow cytometric DNA ploidy and S-phase fraction as independent prognostic markers for node-negative breast cancer specimens.

Developing a reliable and quantitative assessment of the potential virulence of a malignancy has been a long-standing goal in clinical cytometry. DNA histogram analysis provides valuable information on the cycling activity of a tumor population through S-phase estimates; it also identifies nondiploid populations, a possible indicator of genetic instability and subsequent predisposition to metastasis. Because of conflicting studies in the literature, the clinical relevance of both of these potential prognostic markers has been questioned for the management of breast cancer patients. The purposes of this study are to present a set of 10 adjustments derived from a single large study that optimizes the prognostic strength of both DNA ploidy and S-phase and to test the validity of this approach on two other large multicenter studies. Ten adjustments to both DNA ploidy and S-phase were developed from a single node-negative breast cancer database from Baylor College (n = 961 cases). Seven of the adjustments were used to reclassify histograms into low-risk and high-risk ploidy patterns based on aneuploid fraction and DNA index optimum thresholds resulting in prognostic P values changing from little (P < 0.02) or no significance to P < 0.000005. Other databases from Sweden (n = 210 cases) and France (n = 220 cases) demonstrated similar improvement of DNA ploidy prognostic significance, P < 0.02 to P < 0.0009 and P < 0.12 to P < 0.002, respectively. Three other adjustments were applied to diploid and aneuploid S-phases. These adjustments eliminated a spurious correlation between DNA ploidy and S-phase and enabled them to combine independently into a powerful prognostic model capable of stratifying patients into low, intermediate, and high-risk groups (P < 0.000005). When the Baylor prognostic model was applied to the Sweden and French databases, similar significant patient stratifications were observed (P < 0.0003 and P < 0.00001, respectively). The successful transference of the Baylor prognostic model to other studies suggests that the proposed adjustments may play an important role in standardizing this test and provide valuable prognostic information to those involved in the management of breast cancer patients.

Breast Neoplasms↗

PubMed2001

LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro.

Neurotrophic factors are known to play a crucial role in the elongation and guidance of auditory nerve fibres to their targets within the organ of Corti. Maintenance of these neural connections following deafness would clearly influence the efficacy of therapies for hearing recovery. The growth factors leukaemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 5 (TGF-beta5) were tested for their efficacy in promoting neurite outgrowth from dissociated cultures of early postnatal rat auditory neurons. Our results indicate that while BDNF enhances neurite outgrowth in a strong fashion, LIF is more potent; moreover, the combined administration of both factors has even greater neuritogenic capacities. TGF-beta5, although neurotrophic, has no neuritogenic activity on cultured auditory neurons. LIF and BDNF may therefore be potential candidates when developing pharmacological therapies for hearing recovery.

Animals↗

PubMed2001

Psychophysics of a prototype peri-modiolar cochlear implant electrode array.

Psychophysical measurements were performed in three hearing-impaired adult subjects implanted with a CI22 cochlear prosthesis (Cochlear Ltd.) fitted with a developmental peri-modiolar electrode array. The array was manufactured with a curvature approximating that of the inner wall of the scala tympani but, after straightening and insertion, lay on average about half way between the inner and outer walls of the scala. All subjects were tested with bipolar stimulation; two were also tested with monopolar, employing the most basal electrode as the return. Maximum comfortable level and threshold reduced with decreasing distance of electrode from the modiolus, whereas dynamic range increased. The linearity of the loudness growth function did not vary significantly with electrode position but the function was more non-linear for lower maximum comfortable levels. Current level discrimination, normalized with respect to dynamic range, improved with decreasing distance of electrode from the modiolus in two subjects. Pitch varied regularly with insertion depth of the stimulated electrode for bipolar stimulation in two subjects and also for monopolar stimulation in one subject. Electrode discrimination was enhanced by closeness to the modiolus. Whereas the forward masking patterns for bipolar stimulation of electrodes close to the modiolus had a sharp double-peaked structure, those for monopolar stimulation were flatter and had a single peak.

Adult↗

PubMed2001

Delay analysis in the auditory brainstem of the rat: comparison with click latency.

Many cells in the auditory brainstem 'phase lock' to tone stimuli. From the changing phase relationship between the stimulus and the neural response in phase-locking cells, the delay between them can be estimated. This delay, however, is consistently greater than the latency measured in response to click stimuli, an important discrepancy. In this paper the different measures of delay, namely phase delay, group delay and signal-front delay are re-examined. An improved method for computing the average group delay is presented, which accounts for the cyclical nature of the phase data. Data were collected from units in successive processing sites of auditory pathway: the auditory nerve, the cochlear nucleus, the trapezoid body and the medial nucleus of the trapezoid body. Low-characteristic frequency (CF) units gave multimodal post-stimulus-time histograms in response to clicks, and showed stepwise decreases in latency with increasing intensity, with the appearance of earlier peaks in the response, rather than shifts in the timing of the peaks. The separation of peaks corresponded to the inverse of the unit's CF. High-CF units also showed a decline in click latency with intensity, but to a lesser degree than low CF units. We present an analysis which explains the difference between click latency and delay, and which in contrast to previous accounts is experimentally testable. We demonstrate that this new framework accounts for the discrepancy between the two measures of delay, and in addition accounts for the observed stepwise shifts in click latency for low-CF units.

Acoustic Stimulation↗

PubMed2001

Temporal processing from the auditory nerve to the medial nucleus of the trapezoid body in the rat.

This investigation examines temporal processing through successive sites in the rat auditory pathway: auditory nerve (AN), anteroventral cochlear nucleus (AVCN) and the medial nucleus of the trapezoid body (MNTB). The degree of phase-locking, measured as vector strength, varied with intensity relative to the cell's threshold, and saturated at a value that depended upon stimulus frequency. A typical pattern showed decline in the saturated vector strength from approximately 0.8 at 400 Hz to about 0.3 at 2000 Hz, with similar profiles in units with a range of characteristic frequencies (480-32,000 Hz). A new expression for temporal dispersion indicates that this variation corresponds to a limiting degree of temporal imprecision, which is relatively consistent between different cells. From AN to AVCN, an increase in vector strength was seen for frequencies below 1000 Hz. At higher frequencies, a decrease in vector strength was observed. From AVCN to MNTB a tendency for temporal coding to be improved below 800 Hz and degraded further above 1500 Hz was seen. This change in temporal processing ability could be attributed to units classified as primary-like with notch (PL(N)). PL(N) MNTB units showed a similar vector strength distribution to PL(N) AVCN units. Our results suggest that AVCN PL(N) units, representing globular bushy cells, are specialised for enhancing the temporal code at low frequencies and relaying this information to principal cells of the MNTB.

Acoustic Stimulation↗

PubMed2001

The potential role of estrogen in aromatase regulation in the breast.

Aromatase is expressed in both normal and malignant breast tissues. Aromatase activity in the breast varies over a wide range. Our previous studies have demonstrated that in situ aromatization contributes to the estrogen content of breast tumors to a major extent. Consequently, alterations of aromatase activity could serve as a major determinant of tissue estradiol content. However, the mechanisms and extent of aromatase regulation in breast tissues have not been fully established. We have observed an inverse correlation between tumor aromatase activity and estrogen content in nude mice bearing xenografts of MCF-7 cells transfected with the aromatase gene. To investigate the potential role of estrogen in aromatase regulation in the breast, studies were carried out in an in vitro model. In this model, MCF-7 cells were cultured long term in estrogen-deprived medium and called by the acronym, LTED cells. We found that long-term estrogen deprivation enhanced aromatase activity by 3-4-fold when compared to the wild-type MCF-7 cells. Re-exposure of LTED cells to estrogen reduced aromatase activity to the levels of the wild-type MCF-7 cells. We also measured aromatase activity in 101 frozen breast carcinoma specimens and compared tumor aromatase activities in pre-menopausal patients versus post-menopausal patients and in post-menopausal patients with or without hormone replacement therapy (HRT). Although statistically not significant, there was a trend paralleling that observed in the in vitro studies. Aromatase activity was higher in breast cancer tissues from the patients with lower circulating estrogen levels. Our data suggest that estrogen may be involved in the regulation of aromatase activity in breast tissues.

Animals↗

PubMed2001

Interpreting and integrating risk factors for patients with primary breast cancer.

The term risk factor has different meanings in different contexts. Some factors may be patient specific (e.g., race, age, socioeconomic status, and environment), while others may be disease specific (e.g., biomarkers measured on tumor specimens, serum, and bone marrow). These factors have several potential clinical uses, including diagnosing a disease or assessing the risk of developing a disease, estimating prognosis for patients diagnosed with a specific disease who receive no therapy, predicting response to a particular therapy, monitoring response to therapy during a treatment course, and identifying targets of opportunity for new therapies. This article focuses on prognostic and predictive biomarkers and provides guidelines for interpreting published reports about these biomarkers. Application of these guidelines to the assessment of micrometastases in bone marrow of patients with breast cancer yields the conclusion that standardized techniques that are sensitive and reproducible for detecting micrometastases are needed before we can evaluate their prognostic significance.

Biomarkers↗

PubMed2001

Variation in speech perception scores among children with cochlear implants.

OBJECTIVE: The objective of this study was to identify common factors affecting speech perception scores in children with cochlear implants. DESIGN: Speech perception data for 167 implanted children were collected at two cochlear implant centres in Melbourne and Sydney. The data comprised audition-alone scores on open-set word and sentence tests. Children were selected on the basis that they had a Nucleus 22-electrode cochlear implant. The average age of the children was 5 yr. Information was also collected about 12 factors that may have influenced speech perception scores for each child. Analysis of covariance was used to identify factors that significantly affected speech perception scores. Pearson pairwise correlation coefficients were also calculated for all factors analyzed. RESULTS: The analyses in this study identified factors that accounted for 51%, 34%, and 45% of the variance in phoneme, word and sentence perception scores. Scores decreased by 1.4 to 2.4% per year of profound deafness prior to implantation. Children who normally use oral communication scored significantly higher than children normally using sign or simultaneous oral and sign communication. Children implanted in Sydney scored higher on average than children implanted in Melbourne. CONCLUSIONS: The results show that a significant part of the variation in speech perception scores is systematically related to audiological and environmental factors for each child. The reasons for significant differences between children using different communication modes or from different clinics were not identified.

Adolescent↗

PubMed2001

The contour electrode array: safety study and initial patient trials of a new perimodiolar design.

OBJECTIVE: The aim of these studies was to investigate the insertion properties and safety of a new intracochlear perimodiolar electrode array design (Contour). BACKGROUND: An electrode array positioned close to the neural elements could be expected to reduce stimulation thresholds and might potentially reduce channel interaction. METHODS: Two sequential studies were conducted. In study 1, the Contour electrode array was inserted in 12 human temporal bones. After cochlear surface preparation, the position of the array was noted and the basilar membrane was examined for insertion damage. On the basis of the outcome of this temporal bone study, study 2 investigated the Contour array, mounted on a Nucleus CI-24 M device and implanted in three adult patients. RESULTS: Study I showed that in 10 temporal bones, the Contour array was positioned close to the modiolus, and the basilar membrane was intact. In the two remaining bones, the arrays had pierced the basilar membrane and were positioned in the scala vestibuli apical to the penetration. Statistical analysis showed an equivalent probability of insertion-induced damage of the two array designs. In study 2, image analysis indicated that the Contour electrodes were positioned closer to the modiolus than the standard Nucleus straight array. Lower T and C levels, but higher impedance values, were recorded from electrodes close to the modiolus. Initial speech perception data showed that all patients gained useful open-set speech perception, two patients achieving scores of 100% on sentence material 3 months postoperatively. CONCLUSIONS: The temporal bone studies showed the Contour electrode array to be generally positioned closer to the modiolus than the standard Nucleus straight array, and to have an equivalent probability of causing insertion-induced damage.

Acoustic Impedance Tests↗