Thesis (doctoral)--Uppsala University, 1984. / Bibliography: p. 36-49.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2007. / Härtill 4 uppsatser.

Cancer, the uncontrolled growth of morphologically and genetically abnormal cells in the body, is a major worldwide public health problem and there is a great need for novel insights into this disease. The majority of tumors arise from the acquisition of somatic alterations leading to changes in gene function and expression. The clinical success of targeted therapeutics in molecularly defined subsets of patients has highlighted the need for comprehensive characterization of the somatic alterations in individual cancer types. Copy number profiling using SNP arrays is a common approach for profiling the extent of copy number variation across the cancer genome. In addition, next-generation sequencing technologies now offer researchers the ability to also systematically catalog nucleotide substitutions and structural rearrangements in dramatically less time and expense. In this thesis, we describe the application of SNP arrays and whole-exome sequencing to characterize two separate cohorts of cancer samples, as well as describe the development of a software tool to aid in the annotation of mutational data. Specifically, we detailed focal amplifications of PDGFRA and KIT in a combined set of lung adenocarcinoma and squamous cell carcinomas. Furthermore, in a cohort of small bowel neuroendocrine tumors, we characterized the global genetic landscape to show that these tumors are molecularly distinct from other neuroendocrine tumors. Lastly, we report Oncotator, a novel web application and service for comprehensive annotation of point mutations and indels found in cancer. It is hoped that the knowledge gained from these studies will fuel improvements in cancer diagnosis, prognosis, and therapy.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2008. / Härtill 4 uppsatser.

<p>Midgut carcinoid tumours are rare with an incidence of 0.5-2.1/100 000. The primary tumour is usually small and grows slowly but has almost always set metastases at diagnosis. When radically operated, most patients will eventually recur in their disease. </p><p>We evaluated different methods in detecting recurrent disease in 61 malignant midgut carcinoid tumours that had been radically operated. Thirty-eight patients have been diagnosed with a recurrence. In 32/38 of these patients P-Chromogranin A was the first method to indicate a recurrence. We therefore recommend using P-CgA in the work up in these patients.</p><p>We investigated characteristics, survival and independent factors that could be of bad prognostic value. We found that in our 284 malignant midgut carcinoid tumours, 208/284 (73%) had distant metastases and 30/284 (11%) had carcinoid heart disease. Median survival was 115.5 months and five-year survival was 77%. In a multivariate analysis liver metastases and carcinoid heart disease were poor prognostic factors.</p><p>We performed a phase II study with octreotide pamoate investigating the clinical effect in 12 malignant midgut carcinoid tumours in a progressive phase. We found that 9/12 (75%) were stabilised for a median duration of 12 months. We think that this is a good effect considering the advanced stage.</p><p>We investigated the frequency of four different tyrosine kinase receptors, platelet derived growth factor receptor (PDGR) α and β, epidermal growth factor receptor (EGFR) and c-kit, in 36 malignant midgut carcinoid tumours with immunohistochemistry. We found that 13/34 (38%) tumour samples expressed PDGFRα, 29/33 (88%) PDGFRβ, 24/33 (73%) EGFR, whereas none expressed c-kit. This implicates that midgut carcinoid tumours might be susceptible to treatment with tyrosine kinase receptor inhibitors. </p>

<p>In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored.</p><p>It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed.</p><p>In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.</p>

Midgut carcinoid tumours are rare with an incidence of 0.5-2.1/100 000. The primary tumour is usually small and grows slowly but has almost always set metastases at diagnosis. When radically operated, most patients will eventually recur in their disease. We evaluated different methods in detecting recurrent disease in 61 malignant midgut carcinoid tumours that had been radically operated. Thirty-eight patients have been diagnosed with a recurrence. In 32/38 of these patients P-Chromogranin A was the first method to indicate a recurrence. We therefore recommend using P-CgA in the work up in these patients. We investigated characteristics, survival and independent factors that could be of bad prognostic value. We found that in our 284 malignant midgut carcinoid tumours, 208/284 (73%) had distant metastases and 30/284 (11%) had carcinoid heart disease. Median survival was 115.5 months and five-year survival was 77%. In a multivariate analysis liver metastases and carcinoid heart disease were poor prognostic factors. We performed a phase II study with octreotide pamoate investigating the clinical effect in 12 malignant midgut carcinoid tumours in a progressive phase. We found that 9/12 (75%) were stabilised for a median duration of 12 months. We think that this is a good effect considering the advanced stage. We investigated the frequency of four different tyrosine kinase receptors, platelet derived growth factor receptor (PDGR) α and β, epidermal growth factor receptor (EGFR) and c-kit, in 36 malignant midgut carcinoid tumours with immunohistochemistry. We found that 13/34 (38%) tumour samples expressed PDGFRα, 29/33 (88%) PDGFRβ, 24/33 (73%) EGFR, whereas none expressed c-kit. This implicates that midgut carcinoid tumours might be susceptible to treatment with tyrosine kinase receptor inhibitors.

In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored. It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed. In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.

<p>Malignant tumours of the small intestine are rare. Age-standardised incidence in Europe is between 0.5-1.5 per 100 000. As the small intestine represents more than 90 % of the gastrointestinal mucosal surface, it is surprising that it gives rise to less than 2 % of gastrointestinal malignancies. The dominating histological subtypes are carcinoids and adenocarcinomas. </p><p>We used three population-based registries in Sweden to study survival, second malignant tumours, causes of death, and Crohn’s disease as a risk factor for small intestinal adenocarcinoma and carcinoid.</p><p>We evaluated tumour site, sex, age, and year of diagnosis as prognostic factors. For adenocarcinomas there was no difference in survival between duodenal and jejunal/ileal tumours. Women with jejunal/ileal adenocarcinomas showed higher probabilities of survival than men, while no such relation was found for duodenal tumours. Old age correlated with poor survival for duodenal tumours, and prognosis has improved in later years. For carcinoids, duodenal tumours had a more favourable prognosis than jejunal/ileal tumours. There was no difference in survival between sexes. Old age correlated with poor survival, and survival has improved in recent years.</p><p>Female patients with adenocarcinoma had increased risk of acquiring cancer in the genital organs and breasts, and both sexes had increased risks of second tumours in the gastrointestinal tract and skin. Men with carcinoid tumours had increased risk of prostate cancer. Both sexes had increased risk of malignant melanoma and malignancies of endocrine organs.</p><p>Patients with adenocarcinoma had increased risk of dying from malignant diseases other than the primary small intestinal cancer and from gastrointestinal disease. The cohort with carcinoid had higher than expected risk of dying from malignant disease, gastrointestinal disease, and cardiovascular disease.</p><p>Patients with Crohn’s disease had increased risk of small intestinal adenocarcinoma and carcinoid, and the risk has increased for patients diagnosed in recent years.</p>

Tumores carcinoides (neoplasias bem diferenciadas) são tumores neuroendócrinos que podem surgir em diferentes locais anatômicos. Na população a prevalência dos tumores carcinoides é de aproximadamente 10 casos para um milhão de habitantes e sua incidência é maior na quinta e sexta década de vida. Este trabalho propõe um modelo cinético baseado na teoria da análise compartimental em humanos com tumores carcinoides que se submeterão ao tratamento com o radiofármaco [177Lu-DOTA0,Tyr3]Octreotato. Imagens cintilográficas dinâmicas planares, obtidas imediatamente à injeção de 370 MBq (10 mCi) do radiofármaco, foram obtidas com o tomógrafo SPECT (Single Photon Emission Computed Tomography). Por meio da seleção de regiões de interesse (ROI) os resultados foram digitalizados e aplicados ao modelo cinético aqui proposto. A primeira fase do estudo (atividade de 370 MBq) teve como objetivo conhecer os parâmetros cinéticos e subsequentemente, o paciente foi submetido ao protocolo de tratamento radioterápico, a critério médico, aos quatro ciclos de 7,4 GBq (200 mCi) do radiofármaco. Desta forma, foi possível estimar previamente as constantes cinéticas ki,j da biodistribuição do 177Lu-DOTATATO no corpo, sendo ki,j a fração de transferência do i-ésimo compartimento (tecido ou órgão) para o j-ésimo compartimento a partir das ROI demarcadoras dos órgãos de maior captação, a saber: fígado, rins, região vascularizada e tumores carcinoides. A partir das constantes cinéticas ki,j a estimativa de dose absorvida em 26 órgãos foi estimada pelo método MIRD. Os resultados dosimétricos foram compatíveis com outras metodologias descritas na literatura. Para um paciente adulto de 73,6 kg, em termos médios seus rins (sem os protetores renais) recebem a maior intensidade de dose (2,39 mGy/MBq) seguido do fígado (0,70 mGy/MBq). Observou-se que tumores com aproximadamente 100g recebem dose da ordem de 0,52 mGy/MBq independentemente da posição a que se encontram no corpo. Este achado se deve à predominância do dano devido às partículas beta quando comparado à radiação gama que possui pouco rendimento de emissão no processo de decaimento do 177Lu. Portanto, os parâmetros cinéticos que promovem a captação do 177Lu nas células são os principais responsáveis pela composição da dose no tumor e demais órgãos. / Carcinoid tumors (well differentiated neoplasms) are neuroendocrine tumors that may arise in different anatomical locations. The population prevalence of carcinoid tumors is approximately 10 cases per one million inhabitants. Its incidence is higher in the fifth and sixth decade of life. This paper proposes a kinetic model in humans with carcinoid tumors who will underwent treatment with the radiopharmaceutical [177Lu-DOTA0,Tyr3 ]OCTREOTATE based on the theory of compartmental analysis. Dynamic planar scintigraphic images acquired immediately upon injection of 370 MBq (10 mCi) of the radiopharmaceutical were obtained with the SPECT (Single Photon Emission Computed Tomography) tomography. Samples from regions of interest (ROI) were used for the kinetic study applying the kinetic proposed model. The first phase of the study (activity 370 MBq) was aimed to evaluate the kinetic parameters. Subsequently, the patient underwent the [177Lu-DOTA0,Tyr3 ]OCTREOTATE radiotherapy protocol, under the physician\'s prescription (up to four cycles of 7.4 GBq (200 mCi)). Thus, it was possible to previously estimate the kinetic constants ki,j relative to biodistribution of [177Lu-DOTA0,Tyr3 ]OCTREOTATE in the body. The ki,j is the transfer fraction from the ith compartment (a tissue or an organ) to the jth compartment. Only few organs showed significant ROI radioactivity count level, among them: the liver, kidney, blood and carcinoid tumors. The MIRD method and the kinetic constants ki,j were used to estimate the absorbed dose in 26 body organs. The absorbed dose D(mGy/MBq) was comparable to other methods described in the literature. For an adult patient of 73.6 kg, on average, the kidneys (without amino acid protectors) showed the highest dose (2.39 mGy/MBq) followed by liver (0.70 mGy / MBq) and tumor (0.52 mGy/MBq) with a tissue size of approximately 100 g. It was observed that tumors receive the same absorbed dose D(mGy/MBq) regardless their position in the body. This finding is due to the predominance of the tissue radiation damage of beta particles compared to gamma radiation that has little yield emission in the 177Lu decay scheme. Therefore, the kinetic parameters ki,j that promote the uptake of 177Lu in cells are primarily responsible for the absorbed D dose in the tumor and other organs.