Browsing by Author "Vickery, Kate, committee member"

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Open Access
Characterization, quantification, and behavior of neoplastic monoclonal gammopathies in dogs and cats
(Colorado State University. Libraries, 2022) Jeffries, Christina Michelle, author; Moore, A. Russell, advisor; Avery, Paul, advisor; Rao, Sangeeta, committee member; Vickery, Kate, committee member
Monoclonal immunoglobulin (M-protein) production can occur in a number of myeloma related diseases (MRD) in domestic animals, including multiple myeloma (MM), extramedullary plasmacytomas, solitary osseous plasmacytoma, IgM Waldenstroms macroglobulinemia/lymphoplasmacytic lymphoma, immunoglobulin secreting lymphomas and leukemias, and plasma cell leukemia. This thesis seeks to improve upon the current knowledge of MRDs by examining diagnostic methods, possible biases (such as hyperproteinemia), and by describing a large population of dogs and cats with confirmed M-proteins. Differentiation of polyclonal and monoclonal gammopathies can be achieved by serum protein electrophoresis (SPE) and immunofixation (IF). Agarose gel electrophoresis (AGE) is the most commonly used SPE method within veterinary medicine and a previous study validated a method for AGE SPE densitometric M-protein (dM-protein) quantification. Capillary zone electrophoresis (CZE) is another method of SPE that can be performed more rapidly than AGE SPE that may have increased sensitivity with similar specificity. We sought to compare these two methods of SPE to determine if CZE SPE is a comparable alternative method for dM-protein quantification in dogs and cats. We found that these methods performed similarly, and both appear to be acceptable methods for dM-protein quantification, but they should not be used interchangeably. This finding indicates that the previously published method for dM-protein quantification can also be used with CZE SPE in dogs and cats. Hyperglobulinemia, hyperproteinemia, and hypoalbuminemia are frequently used criteria to prompt SPE in dogs and cats, but M-protein production can occur in humans and animals without these criteria being met. The assumption that these criteria need to be present to raise concern for M-protein production may lead to delayed diagnosis in patients that have early MRD or low concentration M-protein production. Retrospective evaluation of samples submitted to our lab for SPE and IF between January 2014 and December 2019 identified 18 cases of confirmed M-proteins in dogs with normal total protein concentrations. Most of these animals had confirmed, or suspected, myeloma related disease or lymphoproliferative disorders which prompted SPE. A subset of these cases were evaluated to highlight the diagnostic utility of IF in cases with low concentration M-proteins. In all 7 cases evaluated, IF was needed to make a definitive diagnosis of an M-protein. Based on these findings, we recommend running SPE and IF in tandem to increase diagnostic accuracy for M-protein detection. Large studies characterizing dogs with monoclonal immunoglobulins are rare within the literature, with the largest study by Matus et al from 1984 describing 60 dogs with MM. We sought to retrospectively evaluate a large population of dogs with SPE and IF confirmed M-proteins to add to the available literature, evaluate previously published MM prognostic indicators, assess for novel prognostic indicators, and evaluate other clinicopathology and clinical variables. 113 canine cases were included in our analysis with a total of 75 cases having complete medical records available for analysis. MM was the most common diagnosis within our population, with fewer cases falling under the spectrum of MRD. The mean age of animals diagnosed with an M-protein was 9.9 years. Treatment of MM with prednisone and melphalan led to statistically longer MSTs in these cases when compared to single agent therapy with prednisone or melphalan. Clinical signs were frequently non-specific, but some cases presented with clinical signs that are potentially more specific for MRD such as collapse, evidence of bleeding diathesis, and musculoskeletal pain. Ancillary diagnostic testing such as PCR for antigen receptor rearrangement (PARR), flow cytometry, and/or immunohistochemistry/immunocytochemistry was required in some cases to fully categorize disease. Adoption of visceral organ involvement as a primary or alternative diagnostic criterion for MM may be more likely to appropriately categorize animals with MM, at least based on the clinical course of disease. Animals within our population also frequently had total hypercalcemia, proteinuria, and occasionally had renal dysfunction. Frequently used negative prognostic indicators failed to demonstrate statistical significance (except for renal disease), but occasionally appeared to have clinically significant impacts on survival time. Similar to dogs, the available literature for cats with monoclonal immunoglobulins is sparse. The largest two studies in cats are Mellor et al and Patel et al, with 24 cats with MRD and 16 cats with MM, respectively. Again, we sought to add to the available data on cats with SPE/IF confirmed M-proteins by looking at the same criteria that were evaluated in dogs. Overall, cats with MRDs had a poorer prognosis when compared to dogs, with the exception of B cell chronic lymphocytic leukemia/lymphoma (BCLL) cases. Evidence of bleeding diathesis was not observed in our cat population and the presence of lytic bone lesions was uncommon. Hypocholesterolemia was a negative prognostic indicator for cats with MRDs (excluding BCLL, which was not included in these analyses). The validity of renal azotemia, hypercalcemia, proteinuria, and BJP as prognostic indicators could not be fully assessed in this study, due to a number of factors. Lastly, the addition of visceral organ involvement to the current veterinary MM diagnostic scheme may be warranted and can make categorization of MRDs and diagnosis of MM easier, while still correlating with the clinical behavior of these diseases in cats. The work within this thesis adds to available knowledge of MRD in dogs and cats. We have shown that the lack of hyperproteinemia does not rule out the possibility of an M-protein, especially in cases with suspected MRD. Additionally, running SPE and IF in tandem can capture cases with M-protein production that may be missed with SPE alone. CZE SPE is an acceptable alternative method for dM-protein quantification and can be used when AGE SPE is not available. Finally, we present the largest retrospective analysis of dogs and cats with confirmed monoclonal immunoglobulins to date. Similar to previous works, we found that the course of disease is more aggressive in cats with MM when compared to MM in dogs. Renal disease in dogs and hypocholesterolemia in cats were found to be negative prognostic indicators in our study, but other negative prognostic factors either failed to reach statistical significance or could not be evaluated. We strongly recommend the consideration of visceral organ involvement as an additional or alternative criterion for the diagnosis of MM in dogs and cats, as animals diagnosed with MM with this scheme had disease courses similar to those diagnosed with the current scheme. Further work should examine the frequency of BJP, proteinuria, bone involvement in MM cases without apparent musculoskeletal clinical signs.
Open Access
Creating optically stimulated luminescence 3D printing filament and synthesizing radiosensitive optically stimulate luminescence crystals
(Colorado State University. Libraries, 2025) DeVincenzo, Evan Ross Burson, author; Leary, Del, advisor; Boss, Keara, committee member; Sudowe, Ralph, committee member; Vickery, Kate, committee member
In radiotherapy, radiation oncologists use Megavoltage (MV) photon beams to deliver dose to target areas of a patient due to the MV's skin-sparing characteristics, but if the target area is near the surface of the patient, material referred to as a bolus is added to the patient's surface to provide dose build up and bring the maximum dose delivered close to the patient surface. Boluses are 3D printed to minimize air gaps between the patient and the bolus to deliver the dose accurately. Optically stimulated dosimeters (OSLD) are passive dosimeters that collect dosimetric information and are read later by using a stimulating laser to stimulate luminescence from the dosimeter, while a photomultiplier tube (PMT) measures the intensity of the luminescing light. We theorized that it was possible to combine 3D printing technology with OSLD crystals to make OSLD 3D printing filament so that an oncologist could 3D print a patient-specific bolus for a patient receiving radiotherapy treatment, and this bolus would function as a patient-specific dosimeter, ensuring precise, accurate, and safe delivery of dose- enhancing the overall quality of radiation therapy treatment. The first chapter of this study explores how we incorporated OSLD crystals, Al2O3:C, which has a robust field of study exploring its radiosensitivity, with NinjaFlex TPU, a filament used to 3D print patient specific boluses, to create an OSLD filament for oncologists to use to 3D print a bolus which would read by a commercially available LANDAUER microSTAR reader, a reader that utilizes Pulsed Optically Stimulated Luminescence (POSL) technology. We did this by cutting LANDAUER nanoDots, whose primary component is alpha carbon-doped aluminum oxide, into 1 mm or smaller pieces and cutting clear NinjaFlex TPU 3D printing filament into small, less than 1 mm pieces, mixing both at a ratio of 1:90, adding the mixture to a Filabot EX2 extruder, and extruding the mixture at low speed at 180 degrees Celsius. Afterward, the extruded filament was cut and re-extruded 2 more times, then warmed on a hot plate, compressed between 2 glass microscope slides, and cut into 8 mm diameter dots to create Filament Dot (FD) dosimeters. The FDs' dosimetric properties were tested and compared to LANDAUER Dot (LD) dosimeters, whose primary component is Al2O3:C crystals, using a Precision small animal irradiator (SAI). We found that the FDs' dosimetric characteristics were mostly similar to those of the LDs. This is the first study of this type, and we conclude that the results warrant further exploration into integrating OSLD material into 3D printing filament to 3D print radiosensitive patient boluses and 3D other radiosensitive models. LANDAUER had recalled all their nanoDot dosimeters while we were conducting the first chapter of this study, so we decided to explore new ways to synthesize radiosensitive carbon-doped aluminum oxide crystals that the LANDAUER microSTAR could still read. We developed two methodologies: the Arc Furnace methodology, which utilizes an arc furnace to melt aluminum oxide (Al2O3) crystals with carbon (C) powder, and the Hot Acid methodology, which involves mixing alpha-phase aluminum oxide crystals with carbon powder in nitric acid and boiling the nitric acid off then firing the remaining powder in a muffle furnace. The Arc Furnace (AF), Hot Acid (HA), and unmodified aluminum oxide samples were exposed to 1940 cGy using the Precision Small Animal Irradiator. When read by the microSTAR, we found that the AF samples had the strongest luminescence compared to the unmodified aluminum oxide, and the HA samples had no significant difference compared to the unmodified aluminum oxide. Then, to assess if the samples were more sensitive to low energy x-rays, we exposed the samples to an unfiltered beam from the SAI, and we found that the AF samples had a stronger-than-expected increase in luminescence strength when read by the microSTAR, indicating that the AF samples are acutely sensitive to low energy x-rays. We conclude that the Arc Furnace and Hot Acid methodologies created radiosensitive crystals by which the dose can be measured with the LANDAUER microSTAR, and we conclude further research should be conducted to refine these methods. The first study chapter has shown that we can incorporate OSLD crystals into 3D printing filament and the second chapter explores two methodologies to synthesize the crystals. We conclude that further research should be conducted into the methods to synthesize the crystals and the method to integrate the OSLD into the 3D printing filament. This will lead to new methods to create OSLD filament, which can be 3D printed to make radiosensitive boluses that will improve patient outcomes and 3D printing of other objects that researchers will use in other radiotherapy research.