Orientador: Luiz Carlos Zeferino / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T23:00:31Z (GMT). No. of bitstreams: 1 Silva_LeonardoRobertoda_M.pdf: 1256988 bytes, checksum: f80a4677bb94a6755e6004d6c8021f20 (MD5) Previous issue date: 2015 / Resumo: Introdução: Os carcinomas luminais de mama apresentam resposta variável à quimioterapia neoadjuvante. A identificação precoce das pacientes que se beneficiarão desse tratamento é importante para se evitar tratamento desnecessário e suas decorrentes toxicidades. O objetivo desse estudo é identificar preditores de resposta à quimioterapia neoadjuvante no carcinoma luminal de mama. Metodologia: Nós incluímos pacientes com carcinoma luminal de mama tratadas com quimioterapia pré-operatória em nosso serviço, no anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram coletados. Análises de imunoistoquímica para receptores de estrogênio e progesterona, HER2 e Ki67 foram realizadas em amostras obtidas antes do tratamento. A quimioterapia foi composta por esquema baseado em antraciclinas e taxanos. Resposta patológica completa (RPC) foi definida como ausência de doença invasora nas peças cirúrgicas da mama e da axila. Resultados: Foram incluídas cento e vinte pacientes, totalizando 131 tumores. As taxas de RPC foram de 6,11% na amostra geral, 5,26% para tumores luminais B-like (HER2-negativos) e 12,9% para luminais B-like (HER2-positivos). Nenhum preditor independente de RPC foi identificado. Cinquenta e dois tumores (39,7%) apresentaram resposta clínica completa, e grau histológico III (OR=9,05; IC95% 1,07-7,98; p=0,04), status pré-menopausal (OR=9,05; IC95% 2,01-40,87; p=0,004), e índice de Ki67 ? 20% (OR=2,71; IC95% 1,04-6,99; p=0,04) foram preditores independentes desse desfecho. A análise da curva ROC mostrou que o índice de Ki67 pré-tratamento tem baixo desempenho na identificação de pacientes que apresentarão resposta clínica completa (área sob a curva=0,660; IC95% 0,563-0,758). Pacientes com resposta clínica completa apresentaram maior chance de serem submetidas a cirurgia conservadora. Conclusões: A taxa de RPC é baixa entre os carcinomas luminais de mama submetidos a quimioterapia neoadjuvante. No entanto, parâmetros clinico-patológicos podem ajudar a identificar pacientes que apresentarão resposta clínica completa / Abstract: Purpose: Luminal breast cancers show a variable response to neoadjuvant chemotherapy. The early determination of those patients who will benefit from this treatment is important to avoid overtreatment and the resulting toxicity. The purpose of this study is to identify predictors of response to neoadjuvant chemotherapy in luminal breast cancer. Methods: We included patients with luminal breast cancer treated with neoadjuvant chemotherapy at the institution in 2013 and 2014. Demographic, clinical, and pathological data were collected. Immunohistochemistry analyses of estrogen and progesteron receptors, HER2 and Ki67 were conducted in samples obtained before treatment. Chemotherapy consisted in anthracycline/taxane-based scheme. Pathologic complete response was defined as the absence of invasive disease in the breast and axilla surgical specimens. Results: One hundred and twenty patients, totaling 131 tumors were included. Pathologic complete response rates were 6.11% in the overall sample, 5.26% for luminal B-like (HER2-negative) tumors and 12.9% for luminal B-like (HER2-positive) tumors. None independent predictor of pathologic complete response was identified. Fifty-two tumors (39,7%) showed complete clinical response, and histologic grade III (OR=2.92; 95% CI 1.07-7.98; p = 0.04), premenopausal status (OR=9.05, 95% CI 2.01-40.87; p = 0.004), Ki67 index ? 20% (OR=2.71, 95% CI 1.04 to 6,99; p = 0.04) were independent predictors for this outcome. ROC curve analysis showed that Ki67 index has a poor performance in identifying patients who will present complete clinical response (area under the curve=0.660, 95% CI 0.563-0.758). Patients with complete clinical response were more likely to be submitted to conservative surgery. Conclusions: Pathologic complete response rate is low among luminal tumors undergoing neoadjuvant chemotherapy. However, clinicopathological parameters can help identify patients who will present complete clinical response / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde

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<p>Karcinom pluća predstavlja vodeći uzrok smrtnosti među svim malignim obolenjima, a uprkos dostignućima u dijagnostici i terapiji u poslednjih 30 godina nije do&scaron;lo do bitnog pobolj&scaron;anja izuzetno niske ukupne stope petogodi&scaron;njeg preživljavanja kod ovih pacijenata. U momentu otkrivanja bolesti preko trećine svih novootkrivenih slučajeva nalazi se u IV stadijumu bolesti. Precizno i adekvatno praćenje odgovora tumora na terapijski tretman kod obolelih od karcinoma pluća u IV stadijumu kao i &scaron;to ranije utvrđivanje progresije bolesti, odnosno neefikasnosti terapijskog tretmana kod ove grupe bolesnika od velikog je značaja, jer za ove pacijente hemioterapija predstavlja jedinu terapijsku opciju. Postojeće konvencionalne metode jednodimenzionalnih merenja i procena tumorskog odgovora na terapijski tretman prema RECIST kriterijumima ne koriste sve prednosti CT dijagnostike i oslanjaju se na subjektivnost manuelnih merenja. Primena naprednih radiolo&scaron;kih tehnika, poput volumetrije, mogu doprineti razvoju imidžing praćenja terapijskog odgovora tumora kod pacijenata sa karcinomom pluća. Cilj istraživanja je evaluacija primene jednodimenzionalnog i volumetrijskog merenja u proceni terapijskog odgovora karcinoma pluća vi&scaron;eslojnom kompjuterizovanom tomografijom. Metodologija: Istraživanjem po tipu prospektivne studije obuhvaćeno je 100 pacijenata obolelih od karcinoma pluća u IV stadijumu bolesti u vreme otkrivanja, koji su ispitivani u periodu od 2013. do 2016. godine u Institutu za plućne bolesti Vojvodine u Sremskoj Kamenici i koji su ispunili kriterijume za ulazak u studiju. Kod svih pacijenata obuhvaćenih istraživanjem, dva radiologa nezavisno su evaluirali sve CT preglede grudnog ko&scaron;a, izvr&scaron;ili jednodimenzionalna manuelna i volumetrijska merenja odabranih target lezija &scaron;to je omogućilo utvrđivanje unutarčitačke i međučitačke varijabilnosti i slaganja rezultata merenja target lezija primenom ispitivanih metoda. Na osnovu rezutata izvr&scaron;enih merenja urađena je kategorizacija terapijskog odgovora tumora primenom konvencionalnih RECIST kriterijuma kao i primenom modifikovanog sistema kategorizacije za volumetrijsku evaluaciju terapijskog odgovora sa modifikovanim optimalnim graničnim vrednostima za klasifikovanje progresije bolesti i pozitivnog odgovora na terapiju, izračunatim na osnovu ispitivanog uzorka (model 3Dindividual). Urađeno je poređenje manuelne i volumetrijske procene terapijskog odgovora primenom razičitih ispitivanih sistema klasifikacije uz utvrđivanje stepena različite klasifikacije i analizu preživljavanja pacijenata do pojave progresije bolesti. Uticaj morfolo&scaron;kih karakteristika &ldquo;target&rdquo; lezija na rezultate volumetrijskog merenja određen je analizom odstupanja izmerenog volumena tumora u odnosu na aritmetičku sredinu između grupa lezija ispitivanih morfoo&scaron;kih karakteristika. Rezultati: Primena volumetrijskog merenja, na ispitivanom uzorku, dovodi do niže stope varijabilnosti rezultata merenja dimenzija target lezija u odnosu na konvencionalnu manuelnu metodu merenja i u slučaju međučitačke varijabilnosti (0,9% vs 6,5%) i u pogledu unutarčitačke varijabilnosti (4,9% vs 0,9%). Volumetrijskom evaluacijom terapijskog odgovora tumora uz primenu modifikovanih graničnih vrednosti kategorizacije (model 3D-individual) postiže se značajno različita klasifikacija terapijskog odgovora u odnosu na primenu konvencionalnih RECIST kriterijuma. U slučaju volumetrijske evaluacije terapijskog odgovora, klasifikovanje pacijenata primenom novog sistema kategorizacije &rdquo;3D-individual&rdquo; dovodi do različite klasifikacije u 22,2 % slučajeva u poređenju sa RECIST ekvivalent kriterijumima za volumetriju, uz održavanje jednako dobre predikcije PFS ova dva sistema. Rezultati istraživanja pokazali su da izgled ivica lezija i odnos lezije prema okolnim anatomskim strukturama imaju srednji uticaj na varijabilnost rezultata volumetrijskih merenja. Zaključak: Primena volumetrijskog merenja kao novog aspekta morfolo&scaron;ke procene odgovora karcinoma pluća na primenjenu terapiju može unaprediti dono&scaron;enje terapijskih odluka kako u lečenju individualnih bolesnika tako i u vođenju kliničkih istraživanja.</p> / <p>Lung cancer is the leading cause of mortality among all malignancies, and despite advances in diagnostics and therapy over the past 30 years, there has been no significant improvement in the extremely low overall rate of a five-year survival with these patients. At the time of the diagnosis, more than a third of all newly discovered cases are at the IV stage of the disease. Precise and adequate monitoring of the response of the tumor to therapeutic treatment with lung cancer patients in IV stage, as well as the early detection of progression of the disease or inefficiency of therapy in this group of patients is of great importance as chemotherapy is the only therapeutic option for these patients. The existing conventional methods of one-dimensional measurement and assessment of tumor response to therapeutic treatment according to RECIST criteria do not use all the advantages of CT diagnostics and rely on the subjectivity of manual measurements. Advanced radiological techniques, such as volumetry, can contribute to the development of the image monitoring of the therapeutic response of tumors in patients with lung cancer. The aim of this study is to evaluate the application of one-dimensional and volumetric measurement in the assessment of the therapeutic response to lung cancer with multslice computerized tomography. Methodology: A study per type of prospective study included 100 patients with lung cancer at the IV stage of the disease at the time of detection, which were tested in the period between 2013 and 2016 at the Institute of Pulmonary Diseases of Vojvodina in Sremska Kamenica and met the criteria for entering the study. With all patients involved in the study, two radiologists independently assessed all CT chest exams, performed one-dimensional manual and volumetric measurements of selected target lesions, which enabled the determination of intraobserver and interobserver variability and the agreement of the target lesion measurement results using the test method. Based on the results of the performed measurements, the categorization of the therapeutic response of the tumor with conventional RECIST criteria, as well as the application of a modified categorization system for volumetric assessment of the therapeutic response with modified optimal limit values for classification (progression of the disease and positive response to the therapy) was performed, calculated on the basis of the tested sample. Comparison of manual and volumetric estimates of the therapeutic response was made using various classification systems with the determination of the degree of difference in classification and analysis of survival of patients until the progression of the disease. The influence of morphological characteristics of target lesions on the results of volumetric measurement was determined by the analysis of the deviation of the measured tumor volume relative to the arithmetic mean between the groups of lesions of the examined morphological characteristics. Results: The application of volumetric measurements on the test sample leads to a lower rate of variability in the results of measuring the dimensions of the target lesions compared to the conventional manual measurement method, and in the case of interobserver variability (0.9% versus 6.5%) and in terms of intraobserver variability (4.9% to 0.9%). The volumetric assessment of the therapeutic response of the tumor using modified boundary categorization values (3Dindividual model) results in a significantly different classification of the therapeutic response in relation to the use of conventional RECIST criteria. In the case of volumetric assessment of the therapeutic response, the classification of patients using the new &ldquo;3D-individual&rdquo; categorization system leads to a misclassification in 22.2% of cases compared to RECIST equivalent to volumetric criteria, reflecting the equally good predictability of PFS in these two systems. The results of the study showed that the appearance of the lesion margins and relation to the surrounding anatomical structures influenced the variability of the results of volumetric measurements. Conclusion: The application of volumetric measurements as a new aspect of the morphological evaluation of lung cancer response to applied therapies can help in making therapeutic decisions both in the treatment of individual patients and in the conduct of clinical trials.</p>

A administração intravenosa de solução salina hipertônica (HSS) induz alterações sistêmicas circulatórias como o aumento da pressão arterial e do volume circulante efetivo, além de ter efeitos locais sobre a microcirculação. No presente estudo foram analisados os efeitos produzidos pela administração de solução salina hipertônica 7,5% sobre a hemodinâmica do tumor através de estudos de imagem funcional e posteriormente, foi avaliado o seu potencial de otimizar a entrega de moléculas no tumor. A velocidade do sangue nos vasos tumorais estimada por Ultrassom Color Doppler foi aumentada após a injeção da HSS em comparação ao controle PBS em tumores de melanoma (B16F10 (p=0,019), SK-MEL-147 (p =0,028)) e de mama (4T1 (p=0,015)). Este mesmo efeito não foi observado nas artérias segmentarias do rim (p=0,476). Ultrassonografia com contraste por microbolhas (CEUS) foi realizada em xenoenxertos de tumor de melanoma (B16F10), carcinoma de cólon (HCT-116) e mama (MDA-MB-231), e como controle foi realizada imagem no rim e no músculo nos animais portadores destes tipos tumorais (n=3 por grupo). Após a injeção da HSS, o volume relativo de sangue foi aumentado nos tumores B16F10 (p=0,022) e HCT-116 (P = 0,039), mas o mesmo não foi observado com o tumor MDA-MB-231 (p=0,186). Além disso, não houve alterações nos tecidos normais (rim p = 0,957; músculo p = 0,104). Todos os testes estatísticos foram bicaudais. Quando a HSS foi utilizada como veículo para entrega de moléculas de baixo peso molecular como cisplatina e doxorrubicina no tratamento de tumores B16F10 e 4T1 respectivamente, não houve aumento da eficácia terapêutica, avaliada através do crescimento tumoral e peso dos tumores. O efeito da HSS sobre a retenção de macromoléculas nos tumores SK-Mel- 147 e 4T1, avaliado através de imagem por epifluorescência do contraste ótico IR-783, não foi suficientemente notório para rejeitar a hipótese nula. Assim, a HSS induz um aumento transitório na velocidade do sangue e do volume sanguíneo, de maneira relativamente seletiva para os tumores avaliados, com exceção do MDA-MB-231. Portanto, esta pode ser uma estratégia útil para aumentar a entrega de moléculas e otimizar tanto o efeito terapêutico, quanto o diagnóstico por imagem / Intravenous administration of Hypertonic saline solution (HSS) induces systemic circulatory changes including blood pressure rising, effective circulating volume increase as well as local effects on microvasculature. We analyzed the effects produced by Hypertonic Saline 7,5% administration on tumor hemodynamics through functional imaging studies as well as whether it enhances molecular delivery in tumor tissue when used as a vehicle. Blood velocity assessed by Color Doppler Ultrasound was increased after HSS injection compared to PBS in the following tumors: B16F10 (p=0,019), SKMEL- 147 (p=0,028) and 4T1 (p=0,015). No statistical difference was observed on the segmental kidney arteries (p=0,476). Dynamic Contrast enhanced ultrasound (CEUS) was done in B16F10, HCT-116 and MDA-MB-231 tumor xenografts, kidney and muscle tissues (n=3 per group). After HSS injection, relative blood volume was increased in B16F10 (p=0,022) and HCT-116 (p=0,039) but not on MDA-MB-231 (p=0,186). Changes on normal tissues were not statistically different (kidney p=0,957; muscle p=0,104). All statistical tests were two-sided. Administration of HSS as a vehicle for low molecular weight molecules cisplatin and doxorubicin in the treatment of B16F10 and 4T1 tumors respectively had no significant improvement of therapeutic efficacy, estimated by tumor growth and tumor weight measurements. Effect of HSS over retention of macromolecules in tumors SK-Mel-147 and 4T1, evaluated by epifluorescence imaging of the optical contrast IR- 783 was not large enough to reject the null hypothesis. HSS induces a transient increase in velocity of the blood as well as the blood volume that is relatively selective for the evaluated tumors with exception of MDA-MB-231. Data suggest that HSS administration might be a useful strategy to increase the delivery of molecules and optimize both therapy and diagnostic imaging

A administração intravenosa de solução salina hipertônica (HSS) induz alterações sistêmicas circulatórias como o aumento da pressão arterial e do volume circulante efetivo, além de ter efeitos locais sobre a microcirculação. No presente estudo foram analisados os efeitos produzidos pela administração de solução salina hipertônica 7,5% sobre a hemodinâmica do tumor através de estudos de imagem funcional e posteriormente, foi avaliado o seu potencial de otimizar a entrega de moléculas no tumor. A velocidade do sangue nos vasos tumorais estimada por Ultrassom Color Doppler foi aumentada após a injeção da HSS em comparação ao controle PBS em tumores de melanoma (B16F10 (p=0,019), SK-MEL-147 (p =0,028)) e de mama (4T1 (p=0,015)). Este mesmo efeito não foi observado nas artérias segmentarias do rim (p=0,476). Ultrassonografia com contraste por microbolhas (CEUS) foi realizada em xenoenxertos de tumor de melanoma (B16F10), carcinoma de cólon (HCT-116) e mama (MDA-MB-231), e como controle foi realizada imagem no rim e no músculo nos animais portadores destes tipos tumorais (n=3 por grupo). Após a injeção da HSS, o volume relativo de sangue foi aumentado nos tumores B16F10 (p=0,022) e HCT-116 (P = 0,039), mas o mesmo não foi observado com o tumor MDA-MB-231 (p=0,186). Além disso, não houve alterações nos tecidos normais (rim p = 0,957; músculo p = 0,104). Todos os testes estatísticos foram bicaudais. Quando a HSS foi utilizada como veículo para entrega de moléculas de baixo peso molecular como cisplatina e doxorrubicina no tratamento de tumores B16F10 e 4T1 respectivamente, não houve aumento da eficácia terapêutica, avaliada através do crescimento tumoral e peso dos tumores. O efeito da HSS sobre a retenção de macromoléculas nos tumores SK-Mel- 147 e 4T1, avaliado através de imagem por epifluorescência do contraste ótico IR-783, não foi suficientemente notório para rejeitar a hipótese nula. Assim, a HSS induz um aumento transitório na velocidade do sangue e do volume sanguíneo, de maneira relativamente seletiva para os tumores avaliados, com exceção do MDA-MB-231. Portanto, esta pode ser uma estratégia útil para aumentar a entrega de moléculas e otimizar tanto o efeito terapêutico, quanto o diagnóstico por imagem / Intravenous administration of Hypertonic saline solution (HSS) induces systemic circulatory changes including blood pressure rising, effective circulating volume increase as well as local effects on microvasculature. We analyzed the effects produced by Hypertonic Saline 7,5% administration on tumor hemodynamics through functional imaging studies as well as whether it enhances molecular delivery in tumor tissue when used as a vehicle. Blood velocity assessed by Color Doppler Ultrasound was increased after HSS injection compared to PBS in the following tumors: B16F10 (p=0,019), SKMEL- 147 (p=0,028) and 4T1 (p=0,015). No statistical difference was observed on the segmental kidney arteries (p=0,476). Dynamic Contrast enhanced ultrasound (CEUS) was done in B16F10, HCT-116 and MDA-MB-231 tumor xenografts, kidney and muscle tissues (n=3 per group). After HSS injection, relative blood volume was increased in B16F10 (p=0,022) and HCT-116 (p=0,039) but not on MDA-MB-231 (p=0,186). Changes on normal tissues were not statistically different (kidney p=0,957; muscle p=0,104). All statistical tests were two-sided. Administration of HSS as a vehicle for low molecular weight molecules cisplatin and doxorubicin in the treatment of B16F10 and 4T1 tumors respectively had no significant improvement of therapeutic efficacy, estimated by tumor growth and tumor weight measurements. Effect of HSS over retention of macromolecules in tumors SK-Mel-147 and 4T1, evaluated by epifluorescence imaging of the optical contrast IR- 783 was not large enough to reject the null hypothesis. HSS induces a transient increase in velocity of the blood as well as the blood volume that is relatively selective for the evaluated tumors with exception of MDA-MB-231. Data suggest that HSS administration might be a useful strategy to increase the delivery of molecules and optimize both therapy and diagnostic imaging

<div>Cancer is responsible for the second highest cause of death in the United States, and lung cancer accounts for 13% of new cancer diagnoses, with the highest rate of cancer death at 24%. Almost 85% of these cases represent non-small cell lung cancer (NSCLC), which includes lung adenocarcinoma, the most common NSCLC subtype. Traditional cancer treatments often only temporarily stop the spread of the disease, but immunotherapies, which are becoming a standard of care, are much more promising. Natural killer (NK) cells are powerful effectors of innate immunity, and genetically engineered NK cells as immunotherapies have had encouraging clinical responses in the treatment of various cancers. However, more progress is needed for solid tumor treatment, especially for lung adenocarcinoma. The activation of cancer-associated ectoenzymes, CD39 and CD73 catalyze the phosphorylation of ATP to AMP to produce extracellular adenosine (ADO), which is a highly immunosuppressive mechanism contributing to the pathogenesis of solid tumors. Understanding adenosine effects on NK cells will help develop more robust immunotherapeutic treatments to improve cytotoxicity against solid tumors. Here, we established that tumor microenvironment ADO results in impaired metabolic and anti-tumor functions of cytokine-primed NK cells. Specifically, peripheral blood-derived NK cells stimulated with IL-2, IL-15, or a combination of IL-12 and IL-15 showed suppressed anti-tumor immunity due to ADO. This was observed by the downregulation of activation receptor expression, cytotoxicity inhibition, impairment of metabolic activity, and alterations in gene expression. To target ADO-producing CD73 on cancer cells, we redirected NK cells by fusing CD73 ScFv with intracellular and transmembrane regions of NK cell specific signaling components derived from FCyRIIIa (CD16). Engineered NK cells were shown to be cytotoxic against lung adenocarcinoma <i>in vitro</i> and impede tumor growth in a lung adenocarcinoma mouse model <i>in vivo</i>. Engineered cells also had higher levels of degranulation and cytokine release, as well as more infiltration into tumors and longer survival time in mice. In summary, the microenvironment of solid tumors is highly immunosupressive, and redirecting NK cell function using a NK-specific anti-CD73 targeting construct will help to promote anti-tumor immunity and</div><div>inhibit cancer growth for a potentially powerful new immunotherapy against solid tumors.</div>