Browsing by Author "LaRue, Susan M., advisor"
Now showing 1 - 5 of 5
Results Per Page
Sort Options
Item Open Access Chromosomal aberrations in the tumor and peripheral blood and changes in aberrations during treatment of canine lymphoma(Colorado State University. Libraries, 2008) Devitt, Jennifer J., author; LaRue, Susan M., advisorLymphoma is the most frequently diagnosed hematopoietic malignancy in dogs. Untreated, the survival times are approximately one month. Chemotherapy is the current standard of care and can initiate and temporarily maintain remission, with average survival times of one year. Cytogenetic abnormalities can aid in diagnosing tumors as well as in giving a more accurate prognosis for the specific mutations present. In human lymphoma patients, chromosomal changes from peripheral lymphocytes have been used prognostically and to document response to treatment. Evaluating peripheral lymphocytes instead of tumor cells is less invasive for the patient and technically easier. Recurrent aberrations have been reported in canine lymphomas. Since this cancer parallels human Non-Hodgkin's Lymphoma which has recurrent chromosomal anomalies that have been correlated with clinical behavior of the tumor and patient survival, it reasons that canine lymphoma would as well. This study was designed to investigate a correspondence between numerical aberrations detected in the tumor and the peripheral blood in dogs with lymphoma. Additionally, the peripheral blood aberrations were monitored during the course of treatment to document changes seen during remission and at the time of disease recurrence. Twenty-five dogs with lymphoma had one lymph node excised, a peripheral blood sample drawn, and a bone marrow aspirate performed. A portion of the lymph node was submitted for histopathology and immunophenotyping and another portion was retained for cytogenetic analysis. The peripheral blood sample was cultured for chromosome counting and cytogenetic analysis. The bone marrow aspirate was used for staging purposes. A significant correspondence between the numerical aberrations in the tumor and the peripheral blood was found with six out of the seven numerical aberrations demonstrating predictive value of the peripheral blood. During the course of treatment, the quality and quantity of aberrations changed, likely due to DNA damaging treatment modalities. Once treatment ended, the frequency of aberrations diminished. A prognostic significance could not be determined using the additional diagnostic information that was garnered such as age, gender, histological classification, breed, immunophenotype, or stage of disease. This was probably due to a limited sample size and is worthy of further investigation.Item Open Access Feline oral squamous cell carcinoma: a comprehensive approach to improve treatment outcome(Colorado State University. Libraries, 2013) Yoshikawa, Hiroto, author; LaRue, Susan M., advisor; Ehrhart, E. J., committee member; Randall, Elissa, committee member; Thamm, Douglas, committee memberTo view the abstract, please see the full text of the document.Item Open Access Outcomes of pelvic irradiation in normal and tumor-bearing dogs(Colorado State University. Libraries, 2013) Nolan, Michael W., author; LaRue, Susan M., advisor; Biller, Barbara J., committee member; Custis, James T., committee member; Ehrhart, E. J., committee member; Kraft, Susan L., committee member; Marolf, Angela J., committee memberThe purpose of this research was to better understand the effects of abdominopelvic irradiation in dogs. Three studies were performed to that end. The first was a clinical investigation, performed by retrospective data analysis, of safety and activity of intensity-modulated and image-guided radiation therapy (IM-IGRT) for treatment of genitourinary (GU) carcinomas in dogs. The second was a prospective study which developed dogs as a novel animal model for studying radiation-induced erectile dysfunction (RI-ED). The third study reviewed pathological changes associated with unexpected colorectal toxicities encountered in the development of the RI-ED model. As mentioned, the objective of the first study was to assess local tumor control, overall survival and toxicosis following IM/IGRT for treatment of genitourinary carcinomas (CGUC) in dogs. Medical records of patients for which there was intent to treat with a course of definitive-intent IM/IGRT for CGUC were reviewed. Primary tumors were located in the prostate, urinary bladder or urethra of 21 dogs. The total radiation dose ranged from 54-58 Gy, delivered in 20 daily fractions. Grade 1 and 2 acute gastrointestinal toxicoses developed in 33% and 5% of dogs, respectively. Grade 1 and 2 acute genitourinary, and grade 1 acute integumentary toxicoses were documented in 5%, 5% and 20% of dogs, respectively. Four dogs experienced late grade 3 gastrointestinal or genitourinary toxicosis. The subjective response rate was 60%. The median event-free survival was 317 days; the overall median survival time was 654 days. Neither local tumor control nor overall survival were statistically dependent upon location of the primary tumor. In conclusion, IM/IGRT is generally well-tolerated and provides an effective option for locoregional control of CGUC. And, as compared with previous reports in the veterinary literature, inclusion of IM/IGRT in multimodal treatment protocols for CGUC can result in superior survival times. The etiopathology of RI-ED is poorly understood, though this is a common complication of men treated for prostate cancer. Purported mechanisms include cavernosal, arteriogenic and neurogenic injuries. Radiation dose to the posterolateral prostatic neurovascular bundles (NVB) and penile bulb (PB) have been associated with RI-ED. Herein, a canine model is described that has been developed to study the pathogenesis of RI-ED. Stereotactic body radiotherapy (SBRT) was used to irradiate the prostate gland, NVB and/or PB of purpose-bred, intact male dogs. Manual evaluation was used to characterize erectile function and quality. Ultrasound of the internal pudendal arteries, prostate and penis, dynamic contrast-enhanced MRI of the NVB and prostate, and electrophysiology of sensory and motor nerves as well as muscle were performed before and after irradiation. Gross necropsy and histopathology was also performed. Erectile dysfunction was a repeatable finding in subjects for whom the prostate, neurovascular bundles and penile bulb were irradiated with 50 Gy, as documented via subjective and objective manual evaluations following SBRT. Irradiated dogs were found to have a decreased extravascular, extracellular volume in the glans penis, longer systolic rise times in the pudendal artery following papaverine injection, abnormal spontaneous EMG activity in the bulbocavernosus muscle, and slower pudendal nerve motor conduction velocities. Radiation dose-dependent changes in internal pudendal arterial function and dysfunction of the pudendal nerve due to axonal loss may contribute to RI-ED. Measurable endpoints have been developed for evaluation of RI-ED in dogs, that should be used in future studies to refine this novel animal model and perform additional studies aimed at further elucidating the etiopathologic processes underlying RI-ED. The objective of the final study was to describe the dose-response relationship and time-dependency of late radiation-induced colorectal complications endured by dogs in the RI-ED study. The prostates of nineteen intact male mixed breed hounds were irradiated with one of four different dose/fractionation schemes. Subjects were monitored for signs of colorectal toxicosis for up to one year following irradiation. Gross necropsy and histopathology were performed upon euthanasia. All toxicoses were graded according to the RTOG criteria for gastrointestinal toxicity. The frequency and severity of colorectal ulceration were higher in dogs treated 5 fractions of 10 Gy delivered on consecutive days, as compared with those treated on an every other day schedule. The mechanism for this time-dependency is unclear, but likely related to completeness of epithelial regeneration. Vascular sclerosis and serosal thickening occurred in all treatment groups, in a dose-responsive fashion.Item Open Access Single high dose irradiation: applicability of cell survival curve modeling and in vivo evaluation of tumor biologic response(Colorado State University. Libraries, 2015) Swancutt, Katy Lynn, author; LaRue, Susan M., advisor; Custis, James T., committee member; Liber, Howard L., committee member; Page, Rodney L., committee memberThe observed clinical success of stereotactic radiation therapy (SRT), in which radiation therapy treatment is delivered in one to five, high-dose fraction of ionizing radiation, has generated interest in the biologic mechanisms by which SRT achieves tumor control. Since the use of linear quadratic formalism to predict tumor cell kill and clinical tumor control has not been corroborated by clinical trial results, it has been proposed that alternative mechanistic responses occur in response to high dose irradiation in addition to mitotic cell death of tumor clonogens in direct response to radiation-induced DNA damage. One suggested mechanism based on observations of tumor endothelial cell apoptosis following doses above 8 to 10 Gy proposes that tumor vascular damage may increase cell killing of associated tumor parenchyma, thus explaining the clinical success of SRT. The work described herein sought to determine whether tumor cell killing behaved predictably at high doses based on established survival curve models using in vitro techniques and whether parameters to tumor vascular response in vivo were impacted differently at high doses versus low doses. In addition, the role of vascular dysfunction as a potentially impactful process in the tumor response to high dose, single fraction irradiation was investigated by measuring microenvironmental changes in the time period between irradiation and the expected peak of endothelial cell apoptotic events. For both in vitro and in vivo experiments, canine tumors were chosen as the optimal model for human cancers due to the similarities between canine and human tumor size, cellular kinetics, and initiation from similar environmental exposures (among numerous other reasons). Using the standard clonogenic assay, cell survival curves were constructed for eight different canine cancer cell lines and one normal canine endothelial cell line. Careful conduction of experiments allowed for collection of data at doses above 10 Gy (in many cases up to 14 or 15 Gy). Modeling of these data was conducted using the linear quadratic formula, the well-established single-hit multitarget model, the new Kavanagh-Newman universal survival curve, and a hypothetical model based on the linear quadratic model with an added component proportional to dose cubed. It was determined that no single model provided the best fit for all cell lines and the linear quadratic model failed to describe data in the high dose region in a majority of cell lines. Rank order analysis of cell lines showed consistency between measured surviving fractions in the low dose region (SF2 versus SF8), but extrapolation of measured high-dose data to calculate surviving fraction values at 24 Gy (SF24) produced rank orders nearly opposite of those at low doses. The reversal of ranks indicated crossing of survival curves at some point beyond the limits of experimental measurement, suggesting that perhaps some unique mechanisms (in isolated tumor cells, in the absence of stromal components) occur at high doses that have not been observed. Extrapolated SF24 values, representing cell survival following a single fraction of 24 Gy, were compared to surviving fraction calculations for a dose fractionation schedule of three fractions of 8 Gy to total 24 Gy by calculating the cubed value of each cell line’s SF8. The in vitro studies indicated that a single fraction of 24 Gy resulted in several orders of magnitude more cell killing than three fractions of 8 Gy, leading to the prediction that a single 24 Gy treatment would be more clinically efficacious than a treatment delivering 24 Gy divided among three equal fractions. Such in vitro studies may be useful in guiding the design of dose fractionation protocols for SRT. To investigate the role of tumor vasculature in tumor response to single fraction, high-dose irradiation, spontaneously occurring canine soft tissue sarcomas were treated with either 2, 8, or 24 Gy in a randomized clinical trial. Tumor microenvironmental factors related to vascular function were monitored before and after irradiation. These factors included tumor oxygenation, interstitial fluid pressure, and perfusion. Samples were taken for quantification of endothelial cell apoptosis, plasma nitrate and nitrite as long-lived indicators of nitric oxide, serum ASMase and oxidative stress. The timeline of events in which high dose, single fraction irradiation induced changes in the tumor microenvironment was of particular interest, and measurements were taken for three hours immediately after irradiation and again at twenty four and forty eight hours after irradiation. Interim analysis of the clinical trial following enrollment of nine dogs suggests that oxygenation following a single fraction of 2 Gy behaved consistently with expectations at twenty four and forty eight hours. Tumors treated with 24 Gy showed a trend of increasing oxygenation within one to two hours of irradiation, which decreased again by three hours. It was concluded that more dogs are needed to clarify any trends observed in this study, given the high degree of heterogeneity of tumor microenvironmental factors within a tumor and between individuals.Item Open Access Tumor microenvironment in spontaneously occuring tumors and in vitro evaluation of hypoxia associated mutagenesis(Colorado State University. Libraries, 2008) Trncic, Nadira, author; LaRue, Susan M., advisorThe importance of the tumor oxygenation status in tumor progression and tumor response to radiation and other forms of treatment has been investigated in many experimental and clinical studies. Oxygen status can impact cell killing associated with radiation treatment and, interestingly radiation can also impact subsequent oxygen levels. Part I of my dissertation is concerned with this phenomenon of reoxygenation. A multiparameter study was conducted in naturally occurring canine tumors to evaluate physiological changes in the tumor microenvironment following a 3 Gy fraction of radiation. Pre-treatment values of partial pressure of oxygen, interstitial fluid pressure, microvascular perfusion, level of apoptosis, and microvessel density were compared to the 24 hours post-radiation measurements in the same location. I analyzed changes in all parameters and evaluated the relationship between parameters and pO2. In disagreement with my working hypothesis, I only found inverse correlation between changes in oxygen level and changes in IFP. In Part II, I used the CHO AL mutation assay to investigate the role of hypoxia alone in the induction of mutagenesis. After exposing cells to different hypoxic conditions I found that only severe hypoxia can cause mutations in human-hamster hybrid cells (AL). Level of oxygen that induced mutations was less than 0.63 mm Hg. Both the complement-mediated AL mutation assay and the flow cytometry mutation assay were done. Mutant cells were sorted from the mutant peak, and the clonal populations of cells were analyzed with the AL flow cytometry assay to determine if cells were really mutated (negative for CD59) and not just downregulated in hypoxia. Quantitative analysis of mutations that were performed did not detect any changes in the CD59 gene. Tumor reoxygenation, as shown here, may not be associated with improved tumor perfusion, but rather with other factors such as decreased oxygen consumption. These studies proved that severe hypoxia can cause mutations and possibly tumor genetic instability, and that those levels of oxygenation can be found in spontaneous tumors in dogs, which are a great tumor model for translating findings to human cancers.