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Biomedical subjects

G M Clark

Publications and source records attributed to G M Clark.

At least 217 records · Page 12Linked to original sources
PubMed1994

Tumor biologic factors and breast cancer prognosis among white, Hispanic, and black women in the United States.

BACKGROUND: In the United States, prognosis and survival after the diagnosis of breast cancer is poorer among black patients and, to a lesser extent, among Hispanic patients, compared with white patients. Patients who are black or Hispanic have been reported to present with higher stage or more advanced disease. Even after adjusting for stage, however, survival rates are lower for blacks but not for Hispanics. PURPOSE: Our purpose was to compare survival, age, tumor size, nodal status, estrogen-receptor (ER) and progesterone-receptor (PgR) status, histologic type, S-phase fraction, DNA ploidy status, HER-2/neu protein expression, and p53 protein status, along with systemic treatment, in a large group of white, black, and Hispanic U.S. women. METHODS: From 1970 to 1991, breast tumor specimens were submitted to The University of Texas Health Science Center from 31 contributing hospitals throughout the United States for ER and PgR assay. A total of 4885 white, 1016 black, and 777 Hispanic women were eligible for this study. Median follow-up was 57 months. RESULTS: Overall, white women were significantly more likely to be older and to have smaller tumors, have less lymph node involvement, have tumors with positive ER and PgR status, and have a lower S-phase fraction compared with Hispanic or black women. There were no clinically important differences in DNA ploidy, histologic type, HER-2/neu, and p53 expression among the three groups. Considering all stages, white women had the best overall survival (date of diagnosis to date of death) at 5 years--75% +/- 1% (means +/- SE), with a median survival of 166 months, but Hispanic women had an intermediate survival--70% +/- 2% (median survival, 156 months), and black women had the worst survival--65% +/- 2% (median survival, 117 months) (P < .0001). For node-negative patients, there was no significant difference in disease-free survival (date of diagnosis to date of first recurrence) or overall survival, although blacks tended to have a worse prognosis. For node-positive or locally advanced disease and for metastatic disease, blacks had significantly (P < .0001) worse disease-free and overall survival than did white or Hispanic women. Differences in the use of systemic therapy did not explain these outcomes. CONCLUSION: A number of biologic factors associated with poor prognosis are found with a significantly increased frequency in breast tumors from Hispanic and, particularly, from black women. Tumors with a more aggressive biology could lead to a higher stage at diagnosis and a poorer survival for the group as a whole.

Adult↗
PubMed1994

Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.

BACKGROUND: The creatine kinase (CK) isozymes and their substrates, creatine and creatine phosphate, are believed to play a pivotal role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, and brain. This enzyme system may also be involved in the process of cellular transformation. Inhibition of tumor cell growth by creatine analogues has been observed and may be due to the ability of these analogues to impair cellular energy generation and utilization. PURPOSE: An in vitro human tumor colony-forming assay was used to predict the clinical usefulness of creatine analogues as anticancer agents. METHODS: The ability of cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) and homocyclocreatine (1-carboxyethyl-2-iminoimidazolidine) to inhibit the growth of cells prepared from tumor samples taken directly from patients was evaluated by quantitative measurement of colony formation in a soft-agar cell culture assay system. Cyclocreatine was tested in this human tumor colony-forming assay at concentrations ranging from 0.067 to 20 mM against 128 tumor samples, 51 of which formed colonies in the assay and were considered evaluable. Homocyclocreatine was similarly tested at concentrations from 0.2 to 20 mM against 139 tumor samples; 54 were considered evaluable. The colony-forming assay was also used to compare the efficacy of the creatine analogues to representatives from the six major classes of standard chemotherapeutics (alkylating agents, antimetabolites, DNA intercalators, platinum compounds, topoisomerase inhibitors, and tubulin-interacting agents). In addition, CK levels were measured in 192 tumor samples that were taken from 166 patients. RESULTS: Cyclocreatine and homocyclocreatine, at concentrations previously achieved in animal tissues (7-20 mM), had antitumor activity against 19% and 50%, respectively, of tumor samples that formed colonies in the assay. Cyclocreatine was effective against a subset of tumors sensitive to homocyclocreatine (P = .023; Fisher's exact test), which was the more potent creatine analogue in this assay (P < .001; McNemar's test). No relationships were seen between tumor samples sensitive to the creatine analogues and those sensitive to standard chemotherapeutics. Pairwise Wilcoxon rank sum tests indicated that CK activity was significantly higher in tumors with any growth in the colony assay compared with tumors that did not grow (P < .025). CONCLUSIONS: The creatine analogues, cyclocreatine and homocyclocreatine, effectively reduced colony formation of freshly explanted human tumor cells. The mechanism of action or resistance to these compounds seems to differ from those of standard chemotherapeutics. IMPLICATIONS: Creatine analogues that may alter the energy status of the tumor cell potentially represent promising new anticancer agents that function through a unique mechanism.

Antineoplastic Agents↗
PubMed1994

Activity of intoplicine (RP60475), a new DNA topoisomerase I and II inhibitor, against human tumor colony-forming units in vitro.

BACKGROUND: Intoplicine (RP60475) is the most active analogue evaluated in the 7H-benzo[e]-pyrido-[4,3-b]-indole series of antineoplastic compounds. It exerts its activity through inhibition of DNA topoisomerase I and II. PURPOSE: This study was planned to determine plasma concentrations of intoplicine necessary for optimal clinical antitumor activity, as well as to pinpoint possible responsive tumor types that can be included in phase II clinical studies. METHODS: Tumor specimens were collected from patients as part of routine clinical measures. Single-cell suspensions were prepared from freshly obtained solid tumor biopsy specimens and were exposed to intoplicine either for 1 hour or continuously. The sensitivity of these specimens to intoplicine was evaluated in a human tumor soft-agar cloning assay. Response was considered positive when the colony-forming unit count in drug-treated samples was 50% or less than the response of control tumor samples treated with saline. RESULTS: With 1-hour exposure to intoplicine at final concentrations of 2.5 micrograms/mL and 10.0 micrograms/mL, 26% and 54% of the assessable specimens showed positive in vitro responses, respectively. With continuous exposure to intoplicine at concentrations of 0.25 micrograms/mL and 2.5 micrograms/mL, 16% and 71% of the assessable specimens showed positive responses, respectively. Activity was seen against breast (71%), non-small-cell lung (69%), and ovarian (45%) cancer colony-forming units at a intoplicine concentration of 10.0 micrograms/mL after 1-hour exposure. Incomplete cross-resistance with doxorubicin, cisplatin, fluorouracil, 4-hydroperoxycyclophosphamide, vinblastine, and etoposide was also observed. CONCLUSIONS: Intoplicine appears to be active in vitro against a variety of human tumors, including a subgroup of tumors insensitive in vitro to standard antineoplastic compounds. If plasma levels of 10.0 micrograms/mL can be achieved in subjects in ongoing clinical trials, intoplicine could have significant clinical activity. IMPLICATIONS: These data indicate that further investigation of intoplicine is warranted.

Antineoplastic Agents↗
PubMed1994

Do we really need prognostic factors for breast cancer?

The role of prognostic factors in optimizing treatment for breast cancer patients has clearly changed with the trend toward general use of adjuvant therapy. Nevertheless, there are at least three situations in which prognostic factors could be helpful. The first is to identify patients whose prognosis is so good that adjuvant therapy after local surgery would not be cost-beneficial. The second is to identify patients whose prognosis is so poor that a more aggressive adjuvant approach would be warranted. The third is to identify patients likely to be responsive or resistant to particular forms of therapy. Here we will discuss all of these situations, together with the appropriate cutpoint analyses and validation of individual prognostic factors and their combination into prognostic indexes which may make the discrimination of patient subsets more reliable.

Biomarkers, Tumor↗
PubMed1994

Prognostic factors: rationale and methods of analysis and integration.

With the proliferation of potential prognostic factors for breast cancer, it is becoming increasingly more difficult for physicians and patients to integrate the information provided by these factors into a single accurate prediction of clinical outcome. Here we review Cox's proportional hazards model, recursive partitioning, correspondence analysis, and neural networks for their respective capabilities in analyzing censored survival data in the presence of multiple prognostic factors, and we present some clinical applications where these models have been used.

Breast Neoplasms↗
PubMed1994

Deoxyribonucleic acid ploidy and S-phase fraction are not significant prognostic factors for patients with cervical cancer.

OBJECTIVE: Our purpose was to determine the usefulness of deoxyribonucleic acid ploidy and S-phase fraction as prognostic factors in patients with cervical cancer. STUDY DESIGN: Paraffin-embedded tumor specimens were obtained from 123 patients with cervical cancer (mean age 51 years, range 21 to 87 years). The mean follow-up period was 6.4 years. Deoxyribonucleic acid ploidy and S-phase fraction were determined by flow cytometry. RESULTS: A total of 119 patients were evaluable for deoxyribonucleic acid ploidy and 92 were evaluable for S-phase fraction. The overall rate of deoxyribonucleic acid aneuploidy was 60%, and the median S-phase fraction was 12.5%. Neither factor was significantly related to stage of disease. In univariate survival analyses patients with deoxyribonucleic acid aneuploid tumors had slightly better early survival than did patients with deoxyribonucleic acid diploid tumors (median survivals 2.7 and 1.4 years, respectively, p = 0.08 [Wilcoxon]), but the overall survival was not significantly different, p = 0.37 (log-rank). In multivariate analyses deoxyribonucleic acid ploidy was not a significant predictor of survival. S-phase fraction was not statistically significant in either analysis. CONCLUSION: Deoxyribonucleic acid ploidy and S-phase fraction are not useful prognostic factors for patients with cervical cancer.

Adult↗
PubMed1994

Silastic with polyacrylic acid filler: swelling properties, biocompatibility and potential use in cochlear implants.

We present a new hygroscopic implant material which consists of high-molecular-weight polyacrylic acid (PAA) as a filler in a Silastic matrix. The mixture swells upon immersion in bodily fluids; the degree of swelling depends on the ratio of PAA to Silastic and allows the design of implants that will achieve their final shape and size only after the implantation procedure. In vivo and in vitro biocompatibility tests reveal no adverse cellular or tissue responses. In cochlear implant development the material has been experimentally incorporated into intracochlear electrode arrays which curl after insertion, and in bacteriostatic devices for electrode fixation.

Acrylic Resins↗
PubMed1994

Cochlear pathology following chronic electrical stimulation of the auditory nerve: II. Deafened kittens.

The present study examines the effects of long-term electrical stimulation of the auditory nerve on cochlear histopathology and spiral ganglion cell survival in young sensorineural deafened cats. Eight kittens were deafened using kanamycin and ethacrynic acid, and implanted with bipolar or monopolar scala tympani electrodes. Following recovery from surgery the animals were unilaterally stimulated using charge balanced biphasic current pulses for 450-1730 hours over implant periods of up to four months. Charge densities varied from 0.6-0.9 microC.cm-2 geom. per phase for monopolar electrodes to 12-26 microC.cm-2 geom. per phase for the bipolar electrodes. Electrically-evoked auditory brainstem responses (EABRs) were periodically monitored during stimulation to confirm that the stimulus levels were above threshold, and to monitor any change in the response of the auditory nerve. Following completion of the stimulation program cochleae were prepared for histological examination. EABRs exhibited relatively stable thresholds for both stimulated and implanted, unstimulated control cochleae for the stimulus duration. While the growth in response amplitude as a function of stimulus current remained stable for the bipolar control and monopolar stimulated cochleae, the five cochleae chronically stimulated using bipolar electrodes exhibited a moderate to large increase in response amplitude. These increases were associated with a more widespread fibrous tissue response which may have altered the current distribution within these cochleae. Implanted control cochleae exhibited significantly less tissue response within the scala tympani. Importantly, we observed no statistically significant difference in the spiral ganglion cell density associated with chronic electrical stimulation when compared with unstimulated control cochleae. While the present study supports the safe application of cochlear implants in young profoundly deafened children, it does not corroborate previous studies that have reported electrical stimulation providing a trophic effect on degenerating auditory nerve fibres.

Analysis of Variance↗
PubMed1994

Neural processes in the dorsal cochlear nucleus of the anaesthetised cat investigated from unit responses to electrical stimulation of the auditory nerve.

Extracellular responses of dorsal cochlear nucleus single units were recorded in response to biphasic, bipolar electrical stimulation of spiral ganglion cells and their peripheral processes using a banded electrode array in the scala tympani of the barbiturate anaesthetised cat. The DCN responses to this stimulus were the result of excitatory and suppressive (including inhibitory) processes. The excitatory responses from DCN units were usually within a range of 1.8-2.8 ms and these responses were probably the result of monosynaptic input from the auditory nerve. Latencies > 2.8 ms were most likely due to activation of di- and poly-synaptic pathways from auditory nerve fibres, except that latencies between 3.5-4.75 in hearing animals could have arisen from electrophonic mechanisms. Suppression of spontaneous activity was usually long acting, lasting > 70 ms following each pulse of the pulse train, but short acting suppression with a latency of 3.5-4.75 ms and a duration of < 10 ms was occasionally observed. These suppressive responses probably resulted from synaptic inhibitory input, but neural membrane properties may have contributed. In hearing animals, excitatory latencies within the range 1.8-5.2 ms were similar for units with different response area types or different PSTH patterns in response to acoustic CF tones or noise.

Acoustic Stimulation↗
PubMed1994

Partial hearing loss in the macaque following the co-administration of kanamycin and ethacrynic acid.

Co-administration of kanamycin (KA) with the loop diuretic ethacrynic acid (EA) rapidly produces a profound hearing loss in the cat while maintaining normal renal function [Xu et al., Hear. Res. 70, 205-215 (1993)]. In the present paper we have applied this deafening procedure to the old world monkey Macaca fascicularis (macaque). Following the co-administration of KA and EA, the hearing loss in the macaque developed far slower than we observed in the cat. Moreover, unlike the cat, there was evidence of a partial recovery in the animal's hearing, resulting in a bilaterally symmetrical high frequency hearing loss. The extent of this hearing loss was dependent on the dose of the EA administered. Finally, the most unexpected result of the present study was the degree of acute nephrotoxicity experienced by these animals following the drug administration. The sensitivity of this species to renal failure restricted the dose of EA that could be safely administered. In conclusion, the co-administration of KA and EA cannot reliably produce a profound hearing loss in the macaque. While it can produce a dose dependent high frequency hearing loss the animal will also experience acute renal failure that requires careful management.

Animals↗
PubMed1994

Phase I clinical trial of ormaplatin (tetraplatin, NSC 363812).

Ormaplatin is a platinum analog that was developed because of an altered toxicity profile and non-cross resistance to cisplatin in both in vitro and in vivo models. To determine the toxicities and maximum tolerated dose of ormaplatin on a daily times five schedule, patients with refractory solid tumors received ormaplatin on five consecutive days at nine dose levels ranging from 1.0 to 15.0 mg/m2/day. A total of 35 patients received 70 cycles of therapy. Nausea and vomiting and myelosuppression were moderate and not dose-limiting. Dose-limiting neurotoxicity, consisting of a sensory peripheral neuropathy, was seen in all five patients who received cumulative doses greater than or equal to 165 mg/m2. This neurotoxicity was symptomatic in all patients and caused significant functional impairment in four patients with inability to walk in two patients. A sensitive atomic absorption spectroscopy analysis performed for one patient at the 13.0 mg/m2/day dose level showed a Cpmax of 163 ng/ml and a t1/2 of 10.9 min for free platinum. A phase II dose could not be determined due to the onset of peripheral neuropathy at low cumulative doses and not at absolute dose levels.

Adult↗
PubMed1994

Cochlear implants for congenitally deaf adolescents: is open-set speech perception a realistic expectation?

The prognosis for benefit from use of cochlear implants in congenitally deaf adolescents, who have a long duration of profound deafness prior to implantation, has typically been low. Speech perception results for two congenitally deaf patients implanted as adolescents at the University of Melbourne/Royal Victorian Eye and Ear Hospital Clinic show that, after 12 months of experience, both patients had significant open-set speech discrimination scores without lipreading. These results suggest that although benefits may in general be low for congenitally deaf adolescents, individuals may attain significant benefits to speech perception after a short period of experience. Prospective patients from this group should therefore be considered on an individual basis with regard to prognosis for benefit from cochlear implantation.

Adolescent↗
PubMed1994

Pitch perception for different modes of stimulation using the cochlear multiple-electrode prosthesis.

Numerical estimations of pitch were obtained from nine postlinguistically deafened adults using the 22-electrode cochlear implant manufactured by Cochlear Pty. Limited. A series of electrodes on the array were stimulated using three modes of stimulation: Bipolar (BP), common ground (CG), and monopolar (MONO). In BP stimulation, an electric current was passed between two electrodes separated by one electrode for eight patients and two electrodes for one patient. In CG stimulation, a single electrode was activated and the other electrodes on the array were connected together to serve as the return path for the current. In MONO stimulation, an electric current was passed between a single electrode and the most basal electrode on the array. Pitch estimations were generally consistent with the tonotopic organization of the cochlea. There was a marked reversal in pitch for electrodes in the middle of the array using CG stimulation for three patients. A reduced range of pitch using MONO stimulation was recorded for patients where the most basal electrode was internal to the cochlea. There were also individual differences in pitch estimations between the three modes of stimulation for most patients. The current levels required to elicit threshold (T) and comfortable listening (C) levels were, in general, higher for BP stimulation than for CG stimulation and were lowest for MONO stimulation. For CG stimulation, there was a tendency for T and C levels to be higher for electrodes in the middle of the array than at the basal or apical ends. For MONO stimulation, T and C levels uniformly increased in an apical to basal direction for the majority of patients. There was no consistent pattern in T and C levels for BP stimulation. The size of the range of usable hearing using CG stimulation tended to be similar to that using BP stimulation and was usually higher than that using MONO stimulation.

Acoustic Stimulation↗
PubMed1994

Pitch percepts associated with amplitude-modulated current pulse trains in cochlear implantees.

The percepts elicited by electrical stimulation of auditory neurons by trains of amplitude-modulated current pulses were studied in a group of six cochlear implant users. Modulation frequencies of 100, 150, and 200 Hz were studied, with a range of carrier rates up to 1200 Hz. It was found that all but one subject could consistently rank 150- and 200-Hz modulated stimuli by modulation frequency when the carrier rate was more than 800 Hz, but for lower carrier rates the ranking was greatly affected by the harmonic relationship between carrier and modulation frequency. Pitch matching experiments showed that the subjects generally considered the modulated stimuli to be equal in pitch to unmodulated stimuli with rates the same as, or somewhat higher than, the modulation frequency. The results showed that the "pitch" of pulsatile electrical stimulation resulting from periodicities in the time structure of the electrical stimulus has similarities to the "pitch" observed for temporal patterns in acoustic stimulation such as amplitude-modulated noise. There were some differences, however, which may be attributable at least in part to the physiological response differences for electric and acoustic stimulation.

Adult↗
PubMed1994

Cathepsin D by western blotting and immunohistochemistry: failure to confirm correlations with prognosis in node-negative breast cancer.

PURPOSE: We attempted to replicate and improve on our previous study (N Engl J Med 322:297-302, 1990) that showed that 34-kd cathepsin D levels as determined by Western blotting strongly correlated with disease-free survival (DFS) and overall survival (OS) of axillary node-negative (N-) breast cancer patients. We also examined the prognostic significance of cathepsin D measured by immunohistochemistry (IHC) in these patients. PATIENTS AND METHODS: Western blotting was performed on cytosols from frozen tumor specimens of 927 N- breast cancer patients in the San Antonio Breast Tumor Bank. The monoclonal antibody M1G8 was used to detect cathepsin D (in previous study, a polyclonal antiserum had been used). The same monoclonal antibody was also used for frozen-section IHC staining of tumor specimens from 562 N- patients from the same tumor bank. Levels of cathepsin D expression were then correlated with DFS and OS. RESULTS: Although the levels of cathepsin D expression as measured by Western blotting and IHC correlated with each other and with levels of cathepsin D measured in previous work using Western blotting with the polyclonal antiserum, in this present study, using the monoclonal antibody M1G8, we were unable to demonstrate that cathepsin D expression (measured by either Western blotting or by IHC) correlates with DFS or OS. CONCLUSION: In this study, cathepsin D expression as determined by either Western blotting or IHC using the monoclonal antibody M1G8 failed to improve the prognostic evaluation of N- breast cancer patients. The role of cathepsin D expression as a prognostic factor is still not precisely defined, raising questions about its use in the routine evaluation of N- breast cancer patients.

Analysis of Variance↗
PubMed1994

Cochlear implantation in young children: histological studies on head growth, leadwire design, and electrode fixation in the monkey model.

For safe cochlear implantation in children under 2 years of age, the implant assembly must not adversely affect adjacent tissues or compromise head growth. Furthermore, growth changes and tissue responses should not impair the function of the device. Dummy receiver-stimulators, interconnect plugs, and leadwire-lengthening systems were implanted for periods of 36 months in the young monkey to effectively model the implantation of the young child. The results show that implanting a receiver-stimulator package has no adverse effects on skull growth or the underlying central nervous system. The system for fixing the electrode at the fossa incudis proved effective. There was marked osteoneogenesis in the mastoid cavity, resulting in the fixation of the leadwire outside the cochlea. This study provides evidence for the safety of cochlear implantation in young subjects.

Animals↗
PubMed1994

Evaluation of a training program intended to calibrate examiners of temporomandibular disorders.

The adequacy of a training program intended to calibrate examiners of temporomandibular disorders (TMD) was evaluated. Eight examiners blindly rated 12 subjects with various TMD signs and symptoms after participating in a 5-h intense training procedure. Some examiners had earlier experience of TMD examinations, and some were newly trained. The Craniomandibular Index was used as the assessment instrument. Agreement within the whole group of examiners was low. Training tended to increase the probability of correctly registering signs. It is concluded that the program was not sufficient to create reliability among multiple examiners. More extensive training, not only to a standard but also between the different examiners, appears necessary. Revision of the examination technique is suggested, and recommendations for strengthening the calibration procedures are made.

Adult↗