Diss. (sammanfattning) Göteborg : Univ. , 2009. / Härtill 4 uppsatser.

Thesis (Ph.D. in Reproductive Sciences) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 125-140). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xvi, 218 p.; also includes graphics (some col.). Includes bibliographical references (p. 200-218). Available online via OhioLINK's ETD Center

Thesis (Ph. D.)--University of Virginia, 2007. / Spine title: Mechanism of tolerance to tyrosinase. Includes bibliographical references. Also available online through Digital Dissertations.

Background: Before making any treatment decisions for patients with non-small cell lung cancer (NSCLC), it is crucial to determine whether the cancer has spread to the mediastinal lymph nodes (LNs). The preferred method for mediastinal staging is Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA). However, EBUS-TBNA has been reported to generate inconclusive results as much as 40% of the time. Since this jeopardizes good patient care, there is near-universal consensus on the need to develop and study a novel method for LN staging. Recent research has shown that AI and deep learning are used to accurately interpret images with comparisons to clinicians in radiology, pathology, and cardiology. Additionally, EBUS-Elastography is a novel modality which could be used as an adjunct to EBUS-TBNA for LN staging. This technology uses impedance ultrasonography to measure tissue stiffness. Methods: There are three parts to this thesis. The first part involved the training, validating, and testing NeuralSeg, a deep neural network, to predict LN malignancy based on B-mode EBUS-TBNA images. The second part of this thesis involves EBUS-Elastography, defining the blue colour threshold and the optimal SAR cut-off value based on the blue threshold that most accurately distinguished benign and malignant LN. Finally, this thesis's third part involves validating part II's findings. Results: Part I resulted in an overall accuracy of 80.63% (76.93% to 83.97%), a sensitivity of 43.23% (35.30% to 51.41%), a specificity of 96.91% (94.54% to 98.45%), a positive predictive value of 85.90% (76.81% to 91.80%), a negative predictive value of 79.68% (77.34% to 81.83%), and an AUC of 0.701 (0.646 to 0.755). Part II Level 60 was chosen as the blue threshold with an AUC of 0.89 (95% CI: 0.77-1.00), and the optimal SAR cut off was found to be 0.4959 with a sensitivity of 92.30% (95% CI: 62.10% to 99.60%) and a specificity of 76.50% (95% CI: 49.80% to 92.20%). Using the blue threshold and SAR cut-off, the results of part III resulted in an overall accuracy of 70.59% (95% (CI) 63.50% to 77.01%), the sensitivity of 43.04% (CI: 31.94% to 54.67%), and a specificity of 90.74% (CI: 83.63% to 95.47%). Conclusion: It was observed that both AI and AI-powered EBUS-Elastography achieved high specificities on larger sample sizes, indicative that these methods may be helpful in identifying LN malignancy. However, due to the novelty of these technologies, more extensive multi-centre studies must be conducted before these processes can be standardized. / Thesis / Master of Health Sciences (MSc) / Non-Small Cell Lung Cancer (NSCLC) treatment decisions are made using vital information by performing biopsies to collect tissue from the lymph nodes near the lungs. The current method is called Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA), which involves a scope with a fine needle attached to it. This scope is led down the airway and guided by ultrasound to obtain the tissue needed to determine whether the lymph nodes have cancerous tissue. If the lymph nodes contain cancerous tissue, the patient may need chemotherapy; however, lung surgery may be the best treatment option if they do not. Many factors impact how successfully these tissue samples can be obtained, such as the skill and experience of the surgeon. These factors often lead to inconclusive results, making it difficult to make correct treatment decisions. Novel technologies such as Artificial Intelligence and Elastography are being used to diagnose lung cancer by interpreting images and providing information on tissue stiffness. We trained an Artificial Intelligence program to predict malignancy based on EBUS-TBNA images. Additionally, we trained the AI program to analyze Elastography images to aid us in understanding the relationship between the colour pattern of the elastography images and cancerous tissue. This thesis assesses how these novel technologies contribute to lung cancer diagnosis.

Background: At the time of endobronchial ultrasound (EBUS) staging, ultrasonographic features can be used to predict mediastinal lymph node (LN) malignancy. Predictive tools have been developed, however they have not gained widespread use due to lack of research demonstrating validity and reliability. We sought to develop a novel predictive tool, the Canada Score, capable of predicting malignancy and potentially guide LN biopsy decision making. Methods: We prospectively analyzed the ultrasonographic features of LNs from patients with NSCLC. Ultrasonographic features were identified by a single experienced endoscopist, this data was used to develop the Canada Score. Pathological specimens were used as the gold standard for determination of malignancy. Videos were then circulated to endoscopists across Canada, who were also asked to identify ultrasonographic features for each LN. Hosmer- Lemeshow test, logistic regression, receiver operator characteristic (ROC) curve, and Gwet’s AC1 analyses were used to test the performance, discriminatory capacity, and inter-rater reliability of the Canada Score. Results: A total of 300 LNs from 140 patients were analyzed by 12 endoscopists across 7 Canadian centres. Backwards elimination was used to create a multivariate model. Hosmer-Lemeshow test and ROC curves indicated the model was well-calibrated (chi2=11.86, p=0.1567) with good discriminatory power (c- statistic= 0.72 ±0.042, 95%CI: 0.64-0.80). Beta-coefficients were used to create a simplified score out of four. Evaluation of the tool showed that LNs scoring 3 or 4 had odds ratios of 15.17 (p<0.0001) and 50.56 (p=0.001), respectively for predicting malignancy. A score of 4/4 was associated with 99.59% specificity and a positive likelihood ratio of 22.78. Inter-rater reliability for a score ≥ 3 was 0.81 ± 0.02 (95%CI: 0.77-0.85). Conclusions: The Canada Score shows excellent performance in identifying malignant LN at the time of EBUS. A cut-off of ≥ 3 has the potential to inform decision-making regarding biopsy or repeat/mediastinoscopy if the initial results are inconclusive. / Thesis / Master of Science (MSc) / During lymph node staging for lung and esophageal cancer, specific features of lymph nodes can be seen. Using diagnostic tools these features can be used to predict whether a lymph node is cancerous or benign. However, many of these diagnostic tools are inaccurate or unreliable. To address this, this thesis aimed to develop a novel diagnostic tool based on lymph node features seen during staging procedures and determine its clinical usefulness and application to the wider lung and esophageal cancer population. This thesis also aimed to use improved methods to develop this diagnostic tool such that patient and clinician experiences would be significantly improved. The results of this thesis may contribute to a reduction in the number of repeat procedures required for patients undergoing staging prior to their treatment for lung and esophageal cancers.

2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin is well known for its immunotoxic effects on the thymus, as well as on B and T lymphocyte functions. Previous studies suggested that TCDD exerted immunotoxic effects only on cells differentiating in response to antigenic challenge. To this date, no work has been done to characterize the long-term effects of TCDD on the activated cells. Additionally, no studies have been done to determine whether TCDD has any effect on resting T cells. In the current study, therefore, we investigated the effects of TCDD on activated and resting cells within the same animal. T cells in the popliteal lymph node cells were activated by rear footpad immunizations with anti-CD3 antibodies. Distally-located axillary lymph nodes were chosen as a source of naive and resting T cells. Our results demonstrate that TCDD acted at the time of cell differentiation to suppress the immune responses of activated T cells, but failed to suppress, and at times, enhanced the immune responses of resting T cells. The TCDD-induced immunomodulations were temporary; responsiveness of both activated and resting T cells from TCDD-treated animals returned to normal by two weeks post-treatment, suggesting that TCDD does not affect memory cells. Futhermore, we provide direct evidence that the TCDD-induced immunosuppression in activated cells is due to increased apoptosis of CD3+ T cells. TCDD also induced significant changes in cell surface markers expressed by naive and activated T cells. Together our data suggested that TCDD suppresses the proliferative responsiveness of only the activated, but not naive, T cells and that this is accomplished by induction of increased apoptosis of activated T cells. These studies shed new light on the mechanism through which TCDD induces increased susceptibility to infections and cancer in the vertebrate host. / Master of Science

Aproximadamente 40% dos casos de Linfoma não Hodgkin (LNH) se originam fora dos linfonodos, sendo então denominados linfomas extralinfonodais. No trato gastrointestinal (TGI), o estômago é o local mais freqüentemente envolvido, representado pelo linfoma MALT e pelo linfoma difuso de grandes células B (LDGCB). No Brasil, apesar da sua freqüência e importância, existem poucos dados epidemiológicos em relação aos linfomas, especialmente no que se refere aos linfomas de origem extralinfonodal. Para avaliar as características dos linfomas primários gástricos em uma população brasileira, 60 casos foram avaliados retrospectivamente. Trinta e oito (63,3%) foram classificados como LDGCB e 22 (36,6%) como MALT. Entre os dois grupos, não houve diferenças significativas em termos de sexo, idade, sintomas dispépticos, sintomas B, presença de massa Bulky, infiltração de medula óssea, estádio, infecção por H. pylori, achados laboratoriais e endoscópicos. Foram adotados diferentes protocolos de tratamento. A taxa de remissão completa foi de 73,1% no LDGCB e de 95% no linfoma MALT. A taxa de sobrevida livre de doença em 7 anos foi de 84,8% no LDGCB e de 94,1% no linfoma MALT. A taxa de sobrevida global em 7 anos foi de 65,7% no LDGCB e de 92,9% em 5 anos no linfoma MALT. Como não conseguimos demonstrar diferenças entre os dois tipos histológicos, concluímos que o diagnóstico histológico correto é essencial para a terapêutica mais adequada. / Approximately 40% of the non-Hodgkins Lymphoma arises outside lymph node tissue, being then termed extranodal lymphoma. In the gastrointestinal tract, gastric is the commonest localization represented by MALT and diffuse large B-cell lymphoma (DLBCL). In Brazil, despite its importance and frequency there are very few epidemiological data concerning lymphomas, specially the extranodal ones. In order to study the primary gastric lymphoma features in a Brazilian population, 60 patients were retrospectively evaluated. Thirty eight cases (63.3%) were classified as DLBCL and 22 (36.6%) as MALT lymphoma. There were no significant differences between the 2 groups in terms of sex, age, gastric symptoms, B symptoms, Bulky disease, bone marrow infiltration, stage, H. pylori infection, laboratory and endoscopic findings. Different treatment methods were adopted. The complete remission rate was 73.1% for DLBCL and 95% for MALT lymphoma. The disease free survival in 7 years was 84.8 for DLBCL and 94.1% for MALT lymphoma. The 7 year overall survival (OS) rate for DLBCL was 65.7% and 5 year OS for MALT was 92.9%. Because we could not demonstrate differences between the two histological groups, we conclude that the correct histological diagnosis is essential for choosing the best therapeutic approach.

A identificação e biópsia do primeiro linfonodo a receber a linfa de uma formação neoplásica, ou seja, do linfonodo sentinela, fornecem informações essenciais para o tratamento e prognóstico de pacientes humanos acometidos por neoplasia. Entretanto, em Medicina Veterinária existem poucos estudos sobre a drenagem linfática dos órgãos e o conceito de linfonodo sentinela ainda não é amplamente aplicado ao tratamento oncológico dos animais. Desta forma, nosso objetivo no presente estudo foi estabelecer um protocolo de aquisição cintilográfica linfática, ou linfocintilográfica, capaz de fornecer informações funcionais e topológicas da drenagem linfática mamária, pois, em cadelas, as glândulas mamárias ainda são uns dos principais órgãos acometidos por neoplasias. Neste estudo, a linfocintilografia foi utilizada para caracterização topológica e funcional in vivo da drenagem linfática de glândulas mamárias sadias de 30 fêmeas da espécie canina (Canis familiares), sem raça definida e peso aproximado de 10 Kg. O radiofármaco [99mTc]-dextran70 foi administrado por via intraparenquimatosa mamária em quatro pontos ao redor da papila (0,1 ml cada), na dose de 18,5 MBq. As imagens foram obtidas em duas seqüências de projeções laterais e ventrais, sendo uma logo após a administração do [99m</SUP Tc]-dextran70 e a outra após uma hora. O radiofármaco administrado nas glândulas mamárias torácicas craniais foi drenado pelos linfocentros torácico ventral e axilar, sendo que em duas destas 5 glândulas (40%) o radiofármaco também foi para o linfocentro cervical superficial. Este resultado foi semelhante para as glândulas torácicas caudais, entretanto, em nenhuma das linfocintilografias destas glândulas o linfocentro cervical superficial foi identificado. A drenagem das glândulas abdominais craniais foi realizada exclusivamente pelo linfocentro axilar. Os linfocentros inguinais superficial e profundo drenaram as glândulas abdominais caudais e inguinais, porém, uma das glândulas abdominais caudais foi drenada também pelo linfocentro cervical superficial e outra pelo linfocentro mediastínico. A técnica linfocintilográfica utilizada possibilitou a identificação de comunicações linfáticas entre os linfonodos axilares próprio e acessório, entre o axilar próprio e o cervical superficial e entre os linfonodos inguinais superficial e profundo. O número de linfocentros e linfonodos, a taxa de drenagem dos linfocentros e seu funcionamento variaram entre as glândulas mamárias e entre os animais. Em conclusão, o protocolo de aquisição linfocintilográfica adotado foi simples, rápido e eficaz para a caracterização da drenagem linfática mamária. As informações topológicas e funcionais obtidas neste estudo poderão ser aplicadas nos procedimentos investigativos como a ultra-sonografia e a biópsia dos linfonodos mamários em pacientes acometidos por neoplasias mamárias, uma vez que os vasos linfáticos representam vias de disseminação para células neoplásicas. / The knowledge of lymphatic drainage has prognostic and surgical value for oncological treatment. Once you know the lymph nodes that drain the organ, you can predict the possible neoplasic cell route and avoid or predict metastasis. The lymphoscintigraphy is not common in Veterinary Nuclear Centers, however this technique has high applicability in oncological studies. During this study, the lymphoscintigraphie was used to characterize topological and functional aspects of lymphatic health mammary drainage in 30 adult mongrel female dogs, 10Kg in weigh. Lymphoscintigraphies were performed immediately after 4 intramammary peripapilare injections (0, 1 ml each) of 18,5 MBq of [99mTc]-dextran70 and one hour later. Animals were imaged by lateral and ventral projections. Cranial thoracic glands were drained by ventral thoracic and axillary lymph centers, but we observed the simultaneous participation of superficial cervical lymph center in 40% of these (2 animals). This result was similar for caudal thoracic mammary glands, but not for cervical lymph center drainage, that was not observed in caudal thoracic glands lymphoscintigraphies. Cranial abdominal glands were drained exclusively by the axillary lymph center. Superficial and deep inguinal lymph centers drained caudal abdominal and inguinal mammary glands, but we observed one superficial cervical lymph center participation in a caudal abdominal mammary gland drainage. Our lymphoscintigraphic technique provided image of lymphatic communication between axillary lymph nodes and between superficial and deep inguinal lymph nodes. The number of lymph centers and lymph nodes, the lymph center drainage rate and functional behavior of each lymph nodes were variable. In conclusion, the lymphoscintigraphic protocol performed was simple, quickly and provided the lymphatic drainage characterization. Technique, topologic and functional information provided by the present study can be applied to understand neoplasic mammary cells dissemination routes, which has prognostic and treatment value for patients. Veterinary centers that have no Nuclear Medicine facilities can use these topologic and functional information of the present study in other diagnostic procedures such as the abdominal ultra-sound and lymph node biopsy of patients with mammary neoplasia.

The most important prognostic factor in breast cancer is the presence or absence of metastases in axillary lymph nodes. Frozen section and touch imprint cytology are conventional intra-operative methods used in the detection of metastatic breast cancer with varying sensitivities and specificities. The limitation of these methods led to the development of alternative molecular diagnostic tests, such as GeneSearch, a commercial real-time quantitative Polymerase Chain Reaction (RT-qPCR) assay that allows for an intra-operative diagnosis of metastatic breast cancer. When the GeneSearch assay was discontinued, Metasin was developed as an in-house RT-qPCR replacement assay. Metasin targets the epithelial cell marker cytokeratin 19 (CK19) and the breast marker mammaglobin (MGB) mRNA to confirm the presence or absence of metastatic disease, whilst the reference gene porphobilinogen deaminase (PBGD) acts as a positive control for the performance of the assay. The optimised assay can produce a result within 32 minutes allowing it to be used in the intra-operative setting to detect metastatic breast cancer in sentinel lymph nodes. 154 archived lymph node homogenates that were previously analysed by both GeneSearch and histology in parallel were used to validate Metasin. Out of 154 cases, 148 showed concordance with both GeneSearch and Metasin with 111 cases being negative and 37 cases being positive. There were six discordant cases, four in which only Metasin detected metastases and two in which only GeneSearch picked up metastases. Out of the four Metasin-only positive cases, three were found to be positive on histology after deeper levels were cut in the slices sent for histological assessment. Therefore, one case could not be shown histologically to be positive for metastases. There were two cases that were missed by Metasin but picked up by GeneSearch. One case was positive on histology and the second case negative for histology. The error rate for Metasin was 3.89%. The sensitivity and specificity of the Metasin assay were found to be 95% and 98% respectively, and the positive and negative predictive values were 90% and 98% respectively. These results are comparable to those of GeneSearch. Metasin had an assay time of less than 45 minutes and was operated by biomedical scientists. The results of the validation process were deemed acceptable for the assay to be run live and used in the clinical setting. Metasin continues to provide breast cancer patients at Princess Alexandra Hospital with all the advantages that a molecular intra-operative diagnostic service provides.