Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 6 uppsatser.

published_or_final_version / Dentistry / Master / Master of Dental Surgery

Head and neck cancer is diagnosed in more than 50,000 Americans each year, resulting in roughly 11,000 deaths. For this disease, a typical therapeutic regimen involves cisplatin, a radiosensitizer, given alongside targeted irradiation. While technological advances such as IMRT have been useful in sparing normal tissues from radiotherapy, the salivary glands occupy much of the head and neck and surround several lymph nodes, and thus, non-diseased salivary glands are often damaged. This causes reduced salivary output, damaged oral mucosa, dysphagia, malnutrition and tooth decay. Often, these side-effects are so severe that patients discontinue treatment, however, in many cases, salivary gland damage is permanent, and treatment options are palliative. Specifically, muscarinic-cholinergic agonists are used to enhance secretion from remaining salivary cells, although due to non-specific action, these drugs have a number of ill-effects. It is clear that therapies are needed to prevent radiation-induced salivary gland damage, as well as to restore glandular function in patients who are already suffering.Previous work from our group has shown that salivary gland dysfunction results from loss of acinar cells to radiation-induced apoptosis. Importantly, a single intravenous dose of IGF1 can prevent apoptosis and preserve salivary output when given immediately prior to irradiation. Because of its broad effects, however, IGF1 may never be a viable clinical option. Instead, our goal is to identify signaling events that mediate the radioprotective effects of IGF1 downstream of Akt. Because radiation-induced apoptosis in salivary glands is p53-dependent, we assessed the contributions of the p53 homologs p63 and p73 to the DNA damage response. Here, we show that IGF1 enhances cell cycle arrest following irradiation by reducing inhibitory binding of deltaNp63 to the p21 promoter. We hypothesize that IGF1-induced cell cycle arrest may allow time for DNA repair, thus preventing apoptosis and maintaining salivary function. In addition, we indicate chronic signaling events downstream of p63 that may contribute to permanent loss of salivary function by blocking differentiation of salivary progenitor cells. Together, these results indicate that p63 may be a valid therapeutic target for both prevention of damage and restoration of function in irradiated salivary glands.

Introduction: Salivary gland obstructive conditions are common and may necessitate imaging of the glands for diagnosis and management purposes. Many imaging options are available but all have limitations. Sialography is considered the gold standard for examining obstructive conditions of the parotid and submandibular glands but it is largely influenced by the imaging technique to which it is coupled. Cone beam computed tomography (cbCT) is a relatively new and very promising imaging modality that has overcome many of the inherent limitations of other imaging modalities used in the past for sialography. Materials and methods: A RANDO®Man imaging phantom was used to determine the effective radiation doses from the series of plain film images that represent the current standard of practice for sialography. Similar experiments were then undertaken to determine the effective radiation doses from cbCT when varying the field-of-view (FOV) size and center, x-ray tube peak kilovoltage (kVp) and milliamperage (mA). Next, cbCT image quality, measured using the signal-difference-to-noise-ratio (SDNR) was used to determine those technical factors that optimized image quality. Finally, using the optimized image acquisition parameters, a prospective clinical study was conducted to test the diagnostic efficacy of cbCT sialography compared to plain film sialography. Results: Effective radiation doses were comparable between the plain film image series and cbCT examinations of the parotid and submandibular glands when a 6” FOV was chosen, and when the x-ray tube was operating at 80 kVp and 10 mA. We also found that these exposure settings optimized the image SDNR. Finally, we demonstrated that the diagnostic capabilities of cbCT sialography were superior to plain film sialography with regards to detecting sialoliths and strictures, and when differentiating normal salivary glands from those with changes secondary to inflammation. Conclusion: We have successfully developed a three dimensional (3D) sialography technique for imaging the parotid and submandibular salivary glands using cbCT that balances radiation effective dose with image quality. We also demonstrated the superior diagnostic capabilities of the new technique in a clinical setting.

Introduction: Salivary gland obstructive conditions are common and may necessitate imaging of the glands for diagnosis and management purposes. Many imaging options are available but all have limitations. Sialography is considered the gold standard for examining obstructive conditions of the parotid and submandibular glands but it is largely influenced by the imaging technique to which it is coupled. Cone beam computed tomography (cbCT) is a relatively new and very promising imaging modality that has overcome many of the inherent limitations of other imaging modalities used in the past for sialography. Materials and methods: A RANDO®Man imaging phantom was used to determine the effective radiation doses from the series of plain film images that represent the current standard of practice for sialography. Similar experiments were then undertaken to determine the effective radiation doses from cbCT when varying the field-of-view (FOV) size and center, x-ray tube peak kilovoltage (kVp) and milliamperage (mA). Next, cbCT image quality, measured using the signal-difference-to-noise-ratio (SDNR) was used to determine those technical factors that optimized image quality. Finally, using the optimized image acquisition parameters, a prospective clinical study was conducted to test the diagnostic efficacy of cbCT sialography compared to plain film sialography. Results: Effective radiation doses were comparable between the plain film image series and cbCT examinations of the parotid and submandibular glands when a 6” FOV was chosen, and when the x-ray tube was operating at 80 kVp and 10 mA. We also found that these exposure settings optimized the image SDNR. Finally, we demonstrated that the diagnostic capabilities of cbCT sialography were superior to plain film sialography with regards to detecting sialoliths and strictures, and when differentiating normal salivary glands from those with changes secondary to inflammation. Conclusion: We have successfully developed a three dimensional (3D) sialography technique for imaging the parotid and submandibular salivary glands using cbCT that balances radiation effective dose with image quality. We also demonstrated the superior diagnostic capabilities of the new technique in a clinical setting.

Radiotherapy of malignancies in the head and neck often involves the major and minor salivary glands in the radiation field. Adverse effects, such as dry mouth symptoms, are common after such therapy. The aim of this thesis was to study longitudinal effects of fractionated irradiation to the head and neck on salivary gland function in man and in the rat and to test radioprotection from antioxidant vitamins (retinol, a-tocopherol and ^-carotene). A sharp decrease in parotid saliva flow rate was seen after one week of irradiation in cancer patients, but in some patients recovery was seen two months after completed treatment. Loss and recovery of salivary gland function were dependent on the total dose given. Irradiation with doses of &gt;65 Gy to the parotid glands led to permanent loss of function in the majority of parotid glands, while recovery could be seen after irradiation with doses of &lt;52 Gy. Concentrations of some proteins and electrolytes in saliva were increased during irradiation but no changes remained 18 months after radiotherapy. However, large inter-individual differences were seen. The irradiation effects observed in rats did not greatly differ from those seen in humans, but no recovery of salivary gland function was seen. On the one hand the impairments of saliva flow and composition w ere dose and time dependent, but on the other hand the response pattem differed between salivary components. Morphological alterations were not seen in the rat salivary' glands after tw'O or five weeks but 26 weeks after irradiation. No single model seems to be optimal for studying all parameters. Therefore, to study effects on salivary glands after irradiation the rat model must be adjusted to meet the questions addressed. Supplementation with vitamin A provided no radioprotection, whereas it w'as found that supplementation with a-tocopherol (3.4 mg/day) and ß-carotene (6 mg/day) during irradiation reduced the degree of inflammation and partly preserved salivary gland function. It did not, however, lead to morphometrically detectable differences in proportions of acinar or ductal cells or stroma.Keywords: Irradiation, salivary glands, saliva composition, antioxidants / <p>S. 1-82: sammanfattning, s. 85-152: 6 uppsatser</p> / digitalisering@umu

Diss. (sammanfattning) Stockholm : Univ., 2004. / Härtill 4 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2006. / Härtill 5 uppsatser.

Thesis (Ph. D. in Cancer Biology)--Vanderbilt University, May 2005. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--School of Biological Sciences. University of Missouri--Kansas City, 1999. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 138-153). Includes bibliographical references.