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D E Thrall

Publications and source records attributed to D E Thrall.

At least 19 recordsLinked to original sources
PubMed1997

Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays.

PURPOSE: To characterize the distribution of hypoxia and proliferation in human squamous cell carcinoma of the cervix via an immunohistochemical approach prior to initiation of therapy. METHODS AND MATERIALS: Patients with primary squamous cell carcinoma of the cervix uteri received a single infusion of the 2-nitroimidazole, pimonidazole (0.5 g/m2 i.v.), and 24 h later punch biopsies of the primary tumor were taken. Tissue was formalin fixed, paraffin embedded, and sectioned for immunohistochemistry. Hypoxia was detected by monoclonal antibody binding to adducts of reductively activated pimonidazole in malignant cells. Staining for endogenous MIB-1 and PCNA was detected in tumor cells via commercially available monoclonal antibodies. Point counting was used to quantitate the fraction of tumor cells immunostained for MIB-1, PCNA, and hypoxia marker binding. RESULTS: Immunostaining for pimonidazole binding was distant from blood vessels. There was no staining in necrotic regions, and only minimal nonspecific staining, mostly in keratin. In general, cells immunostaining for MIB-1 and PCNA did not immunostain for pimonidazole binding. Cells immunostaining for MIB-1 and PCNA showed no obvious geographic predilection such as proximity to vasculature. Quantitative comparison showed an inverse relationship between hypoxia marker binding and proliferation. CONCLUSIONS: Immunohistochemical staining for pimonidazole binding is consistent with the presence of hypoxic cells in human tumors and may be useful for estimating tumor hypoxia prior to radiation therapy. Immunostaining for pimonidazole binding is an ideal complement to immunohistochemical assays for endogenous proliferation markers allowing for comparisons of tumor hypoxia with other physiological parameters. These parameters might be used to select patients for radiation protocols specifically designed to offset the negative impact of hypoxia and/or proliferation on therapy. The inverse relationship between pimonidazole binding and proliferation markers is a preliminary result requiring verification.

Adult↗
PubMed1997

Quantification of CCI-103F labeling heterogeneity in canine solid tumors.

PURPOSE: The purposes of this study were to assess sources of variation in the distribution of nitroimidazole-labeled hypoxic cells in canine tumors and to quantify the reliability of estimating overall nitroimidazole-labeled area fraction from biopsies. METHODS AND MATERIALS: Hypoxic cells were labeled in 24 canine tumors by immunostaining of the nitroimidazole hypoxia marker CCI-103F. In tumors with a volume < 100 cm3, each cubic centimeter of tumor was examined; in larger tumors 100 randomly selected 1 cm3 samples were examined. These data were used to estimate the overall CCI-103F-labeled area fraction in the tumor. A variance components model was used to quantify intertumoral, intratumoral, and within slide (residual) sources of variation. The ability to estimate intratumoral CCI-103F-labeled area fraction based on information obtained from biopsies was assessed by randomly selecting two or four samples from the dataset for each tumor and comparing the mean CCI-103F-labeled area fraction from this limited sample to the labeled area fraction based on each cubic centimeter; this simulation process was repeated 1000 times. RESULTS: Intratumoral (27% of total) and intertumoral (30% of total) variation in CCI-103F-labeled area fraction were similar. Residual variation (variation at the microscopic level) accounted for 43% of total variation in CCI-103F labeling. Intratumoral variation in labeling decreased as the intratumoral CCI-103F mean labeled area fraction decreased. The accuracy of estimating the intratumoral CCI-103F-labeled area fraction in a tumor from limited sampling increased as the number of samples increased or the intratumoral labeled area fraction decreased. When four random samples were used to estimate overall CCI-103F-labeled area fraction in the tumor, estimates from approximately 90% of the 1000 simulations were within 0.10 of the intratumoral CCI-103F-labeled area fraction. Classifying a minimally labeled tumor as unlabeled based on limited sampling was unlikely. CONCLUSION: Despite intratumor variation, acceptable estimates of nitroimidazole-labeled cells in a tumor may be obtained from a clinically feasible number of biopsies.

Analysis of Variance↗
PubMed1997

Hypoxia marker labeling in tumor biopsies: quantification of labeling variation and criteria for biopsy sectioning.

BACKGROUND AND PURPOSE: The error associated with using biopsy-based methods for assessing parameters reflective of the tumor microenvironment depends on the variability in distribution of the parameter throughout the tumor and the biopsy sample. Some attention has been given to intratumoral distribution of parameters, but little attention has been given to their intrabiopsy distribution. We evaluated the intrabiopsy distribution of CCI-103F, a 2-nitroimidazole hypoxia marker. MATERIALS AND METHODS: The hypoxia marker CCI-103F was studied in dogs bearing spontaneous solid tumors. Two biopsies were taken from each of seven tumors, for a total of 14 biopsies. Biopsies were serially sectioned and four to six contiguous slides from each 100-150 microm of the biopsy were used to formulate the best estimate of CCI-103F labeled area throughout the biopsy sample. One, two or four slides were then randomly selected from each biopsy and the labeled area, based on this limited sample, was compared to the estimate obtained from counting all available slides. Random sampling of slides was repeated 1000 times for each biopsy sample. RESULTS: CCI-103F labeling variance throughout the biopsy decreased as the estimated overall labeled area in the biopsy decreased. The error associated with estimating the overall labeled area in a biopsy from a randomly selected subset of slides decreased as the number of slides increased, and as the overall labeled area in the biopsy decreased. No minimally labeled biopsy was classified as unlabeled based on limited sampling. CONCLUSION: With regard to CCI-103F labeling, quantification of the labeled area in four randomly selected slides from a biopsy can provide, in most biopsies, an estimate of the labeled area in the biopsy within an absolute range of +/-0.05.

Animals↗
PubMed1997

Biologic basis of radiation therapy.

The biologic effects of ionizing radiation are well understood. The limitations of radiation therapy time-dose schemes typically used in veterinary medicine are also well understood. Before expensive and potentially toxic combinations of treatment, such as radiation combined with chemotherapy or radiation combined with hyperthermia, can be fully understood, the effect of optimizing the manner in which radiation itself is administered must first be defined. This will only occur after a sufficient period of observation after improvement of the radiation time-dose schemes in use today. Also, when evaluating historic data regarding the response of canine and feline tumors to irradiation, the time-dose scheme used must be considered. Many papers were published based on coarsely fractionated schemes using large doses per fraction and relatively low total doses. Thus, the response rates published must be tempered by the fact that it may be possible to obtain better tumor control rates using smaller doses per fraction and a larger total dose.

Animals↗
PubMed1997

Longevity of pimonidazole adducts in spontaneous canine tumors as an estimate of hypoxic cell lifetime.

The longevity of pimonidazole adducts in tumors was quantified as an estimate of the lifetime of hypoxic cells. Pimonidazole was given before irradiation to 12 dogs bearing spontaneous tumors, and tumors were biopsied 24, 48 and 72 h later. Pimonidazole antigen was quantified in the biopsies using ELISA and immunohistochemistry. Pimonidazole antigen was detectable in the initial biopsy in all dogs. In 5 dogs the amount of detectable antigen decreased to less than 50% of the initial amount, in 5 other dogs the amount of detectable antigen decreased to an amount between 50 and 100% of the initial amount, and in 2 dogs the amount of antigen appeared to increase relative to the initial amount. Tumors with high initial adduct concentration were characterized by greater decreases in adduct concentration than tumors with low initial adduct concentration. Immunohistochemically, labeled cells were present in 11 of 12 tumors. The geographic area in tumor biopsies labeled immunohistochemically with pimonidazole adducts (labeled area fraction) tended to decrease over time in 6 dogs, remain stable in 4 dogs and seemingly increase in 1 dog. There was no relationship in individual tumors between the relative change in antigen concentration and the relative change in labeled area fraction. Hypoxic cells which bind pimonidazole may persist for days during fractionated radiation therapy, and the potential exists for them to exert a negative effect on the host.

Animals↗
PubMed1996

Radiation plus local hyperthermia versus radiation plus the combination of local and whole-body hyperthermia in canine sarcomas.

PURPOSE: The purpose of this study was to assess the effect of increasing intratumoral temperatures by the combination of local hyperthermia (LH) and whole body hyperthermia (WBH) on the radiation response of canine sarcomas. METHODS AND MATERIALS: Dogs with spontaneous soft tissue sarcomas and no evidence of metastasis were randomized to be treated with radiation combined with either LH alone or LH + WBH. Dogs were accessioned for treatment at two institutions. The radiation dose was 56.25 Gy, given in 25 2.25 Gy daily fractions. Two hyperthermia treatments were given; one during the first and one during the last week of treatment. Dogs were evaluated after treatment for local recurrence, metastasis, and complications. RESULTS: Sixty-four dogs were treated between 1989 and 1993. The use of LH+WBH resulted in statistically significant increases in the low and middle regions of the temperature distributions. The largest increase was in the low temperatures with median CEM 43 T90 values of 4 vs. 49 min for LH vs. LH + WBH, respectively (p<0.001). There was no difference in duration of local tumor control between hyperthermia groups (p = 0.59). The time to metastasis was shorter for dogs receiving LH + WBH (p = 0.02); the hazard ratio for metastatic disease for dogs in the LH + WBH group was 2.4 (95% confidence interval, 1.2-5.4) with respect to dogs in the LH group. Complications were greater in larger tumors and in tumors treated with LH + WBH, CONCLUSION: The combination of LH + WBH with radiation therapy, as described herein, was not associated with an increase in local tumor control in comparison to use of LH with radiation therapy. The combination of LH + WBH also appeared to alter the biology of the metastatic process and was associated with more complications than LH. We identified no rationale for further study of LH + WBH in combination with radiation for treatment of solid tumors.

Animals↗
PubMed1996

Pharmacokinetics and toxicity of oral and intravenous lonidamine in dogs.

Plasma lonidamine concentration and toxicity were investigated in dogs receiving 100, 200, 400, 800, 1200 mg/m2 orally twice daily for 30 days and in dogs receiving single intravenous doses of 200, 400, 800, 1200 mg/m2. Physical or laboratory signs of toxicity were not observed in dogs receiving oral lonidamine, but severe vomiting and signs of acute hepatic and pancreatic toxicity were observed in dogs receiving intravenous doses that exceeded 400 mg/m2. The area under the lonidamine concentration versus time curve (AUC) in dogs receiving 200, 400, and 800 mg/m2 of lonidamine intravenously was a 1.8-, 3.3-, and 8.7-fold higher than in dogs receiving oral lonidamine. This suggests that the bioavailability of oral lonidamine may be limited. However, centrilobular hepatocellular swelling and vacuolation were observed in dogs receiving oral lonidamine. Serum alanine aminotransferase (ALT) activity was increased in dogs receiving intra-venous lonidamine. These findings suggest that lonidamine is hepatotoxic in dogs. However, serum ALT was increased in only 1/4 dogs receiving 400 mg/m2 of lonidamine intravenously and plasma concentration were within the range capable of sensitizing hyperthermia and chemotherapy. Therefore, this dose and route appears to be a viable and controllable method for prospective quantification of lonidamine interaction with systemic chemotherapy and/or hyperthermia.

Administration, Oral↗
PubMed1995

Absence of whole body hyperthermia effect on cisplatin distribution in spontaneous canine tumors.

PURPOSE: This study was conducted to evaluate the effect of whole body hyperthermia (WBH) on cisplatin (CDDP)-derived platinum (Pt) disposition in tumor and normal tissue in dogs with spontaneously arising neoplasia undergoing conventional pretreatment diuresis. METHODS AND MATERIALS: Cisplatin was administered to 12 dogs with terminal stage, metastatic neoplasia. Cisplatin (50 mg/M2 over 1 h) was administered following 4 h of forced fluid diuresis (0.9% saline at 10 ml/kg/h). Six of the 12 dogs underwent a WBH procedure (42 degrees C rectal temperature x 90 min) simultaneously with CDDP infusion. Dogs were euthanized following the CDDP infusion, and samples from critical organs, tumor, and normal tissue adjacent to the tumor were immediately collected. RESULTS: No significant differences existed between groups in serum or normal tissue Pt content. Thirty-eight tumor samples were obtained from 27 tumors in the six dogs included in the normothermic group and 43 tumor samples were obtained from 29 tumors in the six dogs undergoing WBH. Tumor volume varied from 0.08 cm3 to 2270 cm3 and multiple samples were obtained from tumors greater than 3 cm in diameter. Twenty-five paired tissue samples of tumor and adjacent normal tissue were collected from dogs in the normothermic group and 31 paired samples were obtained from the hyperthermic group. No differences were observed between groups in tumor Pt content or in the tumor/normal tissue Pt ratios. CONCLUSION: Pt disposition was unaffected by WBH under conditions reported in this study. A forced diuresis is necessary to clinically administer CDDP at maximally tolerable doses. This maneuver results in increased blood flow to critical normal tissue that seemingly obviates any hyperthermia-induced alterations in drug disposition.

Animals↗
PubMed1995

Oncologic applications of diagnostic imaging techniques.

Before appropriate therapy can be instituted for a cancer patient, the presence and extent of tumor must be evaluated. Deciding which imaging technique to use depends on tumor location, type, and biologic behavior. Conventional radiography provides important information at a relatively low cost compared with other imaging modalities. Ultrasound is a valuable adjunct to radiography, but does not replace it because both imaging modalities provide unique information. Nuclear medicine procedures contribute additional, unique data by providing physiological information, but specificity is lacking. Both CT and MRI provide images with exquisite anatomic detail, but availability and cost prohibit their general use.

Animals↗
PubMed1995

Distribution of hypoxia and proliferation associated markers in spontaneous canine tumors.

The therapeutic response of malignant tumors depends on a number of factors associated with tumor microenvironments including the possibility that these microenvironments change during treatment. Two factors, tumor hypoxia and cell proliferation, have been examined in spontaneous canine tumors undergoing multifraction radiation therapy. The approach utilizes immunohistochemical analyses of hypoxia (CCI-103F) and proliferation associated (PCNA) antigens in biopsy samples taken before and after 5 daily fractions of 3 Gy (total dose 15 Gy). The tissue samples were formalin-fixed and paraffin-embedded for the immunohistochemical study. Immunostaining of the sections for PCNA and hypoxia marker reveals little or no overlap when the analysis is made prior to irradiation. An increased degree of overlap seems to occur after 15 Gy but the situation is complicated by a change towards more diffuse PCNA immunostaining in the cells of the irradiated tissues.

Animals↗
PubMed1995

Physics and treatment planning.

Small changes in delivered radiation dose may have a dramatic effect on the probability of treatment success or complications. Also, radiation therapy is stressful for animal patients, and the treatment procedure results in the consumption of many resources making it expensive for the pet owner. Thus, it is critical that individuals administering radiation therapy to pets with cancer have a sound understanding of the basic physical principles of matter and ionizing radiation, as well as an appreciation for the nuances of treatment planning. In this article, these topics are reviewed and illustrations are provided to aid in the understanding of important principles.

Animals↗
PubMed1995

Soft-tissue sarcomas.

Canine and feline soft-tissue sarcomas are difficult to control with surgery unless aggressive procedures such as compartmental resection or amputation are performed. Additionally, multiple noncurative surgeries result in recurrent tumors that are difficult to control with other modalities. Little is known about the radiation response of soft-tissue sarcomas in animals, but available data suggest they are radioresistant. Various methods of improving radiation response of soft-tissue sarcomas have been evaluated. These include the combination of radiation with radioprotective agents, hyperthermia, and surgery. Of all methods evaluated to date the judicious combination of surgery and radiation seems to hold the most promise for producing permanent local control of a significant percentage of canine and feline sarcomas.

Animals↗
PubMed1995

Palliative radiation therapy.

Animal owners may be reluctant to have pets with incurable cancer subjected to euthanasia. Palliative radiation therapy may provide significant relief of pain in such pets. Palliative irradiation is comprised of a few radiation treatments, frequently given over a short time and using larger than normal fractional doses. Animals tolerate palliative irradiation well, and recent reports attest to the usefulness of palliative radiation to relieve discomfort associated with both skeletal and extraskeletal tumors. Although there is more to learn regarding the response of canine and feline tumors to palliative irradiation, it is a proven modality for relief of pain in many incurable cancer patients.

Animals↗
PubMed1994

Distribution of the hypoxia marker CCI-103F in canine tumors.

PURPOSE: The purpose of this study was to identify the prevalence and distribution of hypoxic tumor cells in spontaneous canine tumors, and to relate these parameters to various tumor and patient characteristics, such as tumor volume, tumor type, or tumor location. METHODS AND MATERIALS: Hypoxic tumor cells were labeled in vivo in 32 primary malignant canine tumors by bioreductive binding of the nitroimidazole hypoxia marker CCI-103F. CCI-103F was given at 40 mg/kg i.v. Tumors were completely excised, and CCI-103F adducts were detected in histologic sections (mean, 138 sections-per-tumor) by peroxidase-antiperoxidase immunostaining. Area fraction (area labeled/total area examined) of labeled regions was measured via computer assisted image analysis. In tumors with a volume < 100 cm3, each cubic centimeter of tumor was examined; in larger tumors 100 randomly selected 1 cm3 samples were examined. RESULTS: There were 13 soft-tissue sarcomas, 11 mast-cell tumors, five carcinomas, two lymphosarcomas, and one melanoma. Tumors varied from < .001 to > 2000 cm3. Labeled cells were present in 31 of 32 canine tumors examined, and varied between 0 and 35%. Mean (+/- SD) % label was 12.2% +/- 16.7%; 13 of the 32 dogs had % labeled area < 5.0%. The area fraction was not related to tumor site, tumor type, tumor volume, presence and degree of necrosis or tumor grade. Dog characteristics such as sex, age, and body size did not affect the degree of labeling of tumors. CCI-103F adducts were randomly distributed grossly, and at the microscopic level were not found near blood vessels or regions containing mitoses. Labeling was seen in a variety of normal tissues; not all binding in normal tissues could be attributed to hypoxia. CONCLUSION: CCI-103F labeling of hypoxic regions in tumors provides a nonradioactive method of detecting nitroimidazole adducts at the cellular level, and allows concurrent histologic examination. The pattern of labeling is consistent with detection of hypoxic tumor cells arising from oxygen diffusion limitations. This method may have clinical applicability in the detection of tumor hypoxia.

Animals↗
PubMed1994

ELISA quantification of CCI-103F binding in canine tumors prior to and during irradiation.

PURPOSE: The purpose of this work was to evaluate multiple injections of CCI-103F, a marker of hypoxia, as a method to quantify alterations in tumor hypoxia during irradiation. METHODS AND MATERIALS: Twelve dogs with spontaneous solid tumors were given intravenous CCI-103F, and tumor biopsies were taken at various times after injection. Two tumor samples were taken at each biopsy procedure. CCI-103F antigen concentration was quantified by ELISA. Four of the dogs were given one injection of CCI-103F, and the other eight received two injections. In dogs receiving two injections, CCI-103F was administered before irradiation and 7 days later, following a total dose of 15.0 Gy. Plasma CCI-103F pharmacokinetics were assessed in dogs receiving two injections. RESULTS: CCI-103F antigen was detectable in the initial biopsy in each of the four dogs receiving one injection, and the amount of detectable antigen decreased in subsequent biopsies with an initial half life of approximately 19 h. This suggests that multiple injections of CCI-103F could be used in the same subject to monitor tumor hypoxia as a function of time or during a course of treatment. In the eight dogs receiving two injections of CCI-103F, the CCI-103F antigen concentration in the 24 h samples ranged from 4.66-151.9 mumol CCI-103F antigen/kg tumor, a difference of a factor of approximately 33. The ratio of maximum to minimum concentration of CCI-103F antigen in 51 paired biopsy samples ranged from 1.01-4.07, with a mean (+/- s.d.) of 1.67 +/- 0.67. Seventy-five percent of the ratios were < or = 2.02. There was no apparent relationship between the magnitude of the ratio, i.e., intratumoral variation, and tumor volume or the absolute tumor concentration of CCI-103F antigen. Absolute radiobiologic hypoxic fraction was not known but the pattern of change in amount of intratumoral CCI-103F antigen in dogs given two injections of CCI-103F was consistent with little change in pretreatment oxygen status in six dogs, and an increase in tumor oxygenation in two dogs. CONCLUSION: It appears possible to obtain an estimate of the change in tumor hypoxia in an individual tumor over time by assaying biopsy samples for CCI-103F antigen concentration.

Animals↗
PubMed1994

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy.

PURPOSE: The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. METHODS AND MATERIALS: Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorous spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. RESULTS: A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of > or = 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. CONCLUSION: Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.

Adenosine Triphosphate↗
PubMed1994

An enzyme-linked immunosorbent assay for hypoxia marker binding in tumours.

An enzyme-linked immunosorbent assay (ELISA) has been developed for measuring the in vivo binding of a hexafluorinated 2-nitroimidazole (CCI-103F) in tumour tissue biopsies. The binding of CCI-103F is believed to reflect the presence of hypoxia in tumours. The ELISA provides a sensitive and convenient method of measuring CCI-103F binding which does not require the injection of radioactive reagents. The ELISA is based on reagents prepared from synthetic antigens formed by the reductive activation and binding of CCI-103F to proteins in novel test tube experiments. Calibration of the ELISA involved comparing the ELISA with the radioactivity contained either in protein-CCI-103F adducts formed in vitro with tritiated CCI-103F or in tissues isolated from a tumour-bearing dog which had been injected with tritium-labelled CCI-103F. The two approaches to calibration are compared. The scope and limitation of the ELISA for measuring the binding of CCI-103F is discussed and an example of the application of the ELISA to measuring changes in tumour hypoxia in canine patients undergoing fractionated radiation therapy is presented.

Animals↗