Abstract The purposes of the present research were to evaluate (1) the value of ultrasonographically guided fine-needle aspiration biopsy (US-FNAB) in nonpalpable suspicious breast lesions, (2) the preoperative use of methylene blue staining in nonpalpable galactographically suspicious breast lesions, (3) the determinants of positive histologic margins and residual cancer in wire-guided biopsy (WGB) of nonpalpable breast cancer and in lumpectomy for early breast cancer and the determinants of positive radiologic margins and the correlation between radiologic and histologic margins and residual disease in WGB of nonpalpable breast cancer, (4) the assessment of lumpectomy margins by touch preparation cytology in early breast cancer, and (5) the cosmetic outcome of WGB performed for benign breast lesions. The sensitivity and specificity of US-FNAB in 90 nonpalpable breast lesions were 84% and 93%, respectively. Preoperative methylene blue staining was successful in 22 out of 30 (73%) cases, making subsequent selective minimal volume microdochectomy easy to perform. Multivariate analysis of 21 prospectively evaluated variables was done after 71 WGBs of nonpalpable breast cancer followed by 54 re-excisions. Large mammographic lesions had more often positive radiologic margins. Multifocality, large pathologic size and superficial excision were related to positive histologic margins and multifocality to residual disease in re-excisions. The sensitivity and specificity of specimen radiography for predicting histologic margins were 38% and 81% and those for residual disease 27% and 79%, respectively. The corresponding figures for histologic margins in predicting residual disease were 85% and 59%, respectively. In a prospective series of 55 consecutive lumpectomies for early breast cancer, positive histologic margins were found more often in the presence of intraductal cancer and if the pathologic size of the index tumor was large. Residual disease was found in 38% of the cases with positive and in 15% of the cases with negative histologic margins. A multifocal and nonpalpable index tumor predicted residual cancer in 34 re-excision specimens. The sensitivity and specificity of touch preparation cytology in predicting histologic margins were 38% and 85%, respectively. In WGB, the overall cosmesis 6 months after surgery was satisfactory in 75 % of the 101 prospectively evaluated patients with benign proven lesions. Cosmesis was poorer after deep excisions and complications. The results indicate that US-FNAB is a useful tool in evaluating nonpalpable suspicious breast lesions. Preoperative methylene blue staining crucially facilitates selective minimal volume microdochectomy in three-quarters of cases. To obtain free margins in WGB, mammographically and pathologically large lesions should be removed with wider excisions extending down to the fascia. However, radiologic margins in WGB and histologic margins both in WGB and in lumpectomy for early breast cancer may be misleading. Re-excision of the biopsy site of multifocal tumors after WGB and lumpectomy should be considered. This is also important after superficial excision in WGB due to the considerable risk of residual disease. Touch preparation cytology cannot be recommended for the assessment of margins in lumpectomy specimens of early breast cancer. Cosmetic outcome after WGB of benign breast lesions is satisfactory in 75 % of cases. Deep excisions and complications endanger the cosmetic outcome. Preoperative biopsy and tumor localization methods have proven their utility; nevertheless, free margins are still difficult to obtain and to evaluate accurately. The surgeon may often be forced to choose between free margins and an acceptable cosmetic outcome.

Prostate cancer (PCa) is the most common non-skin malignancy of men in developed countries. In spite of treatment with curative intent up to 30-40% of patients have disease recurrence after treatment, resulting from any combination of lymphatic, hematogenous, or contiguous local spread. The concept of early detection of PCa offer benefits in terms of reduced mortality, but at the cost of over-diagnosis and overtreatment of indolent disease. This is largely due to the random nature of conventional biopsies, with a risk of missing significant cancer and randomly hitting indolent disease. In the present thesis, diagnostic performance of MRI DWI and 11C Acetate PET/CT lymph node staging of intermediate and high risk PCa, was investigated, and additionally, predictive factors of regional lymph node metastases were evaluated. Further, additional value of targeted biopsies to conventional biopsies, for detection of clinically significant PCa, was investigated. In paper one and two, 53 and 40 patients with predominantly high risk PCa underwent 11C Acetate PET/CT and 3T MRI DWI, respectively, for lymph node staging, before extended pelvic lymph node dissection (ePLND). The sensitivity and specificity for PET/CT was 38% and 96% respectively. The sensitivity and specificity for MRI DWI was 55% and 90% respectively. In paper three, 53 patients with newly diagnosed PCa were included. All patients underwent multi-parametric MRI, followed by two cognitive targeted biopsies. Five more clinically significant cancers were detected by adding targeted biopsies to conventional biopsies. In paper four the value of quantitative and qualitative MRI DWI and 11C Acetate PET/CT parameters, alone and in combination, in predicting regional lymph node metastases were examined. ADCmean in lymph nodes and T-stage on MRI were independent predictors of lymph node metastases in multiple logistic regression analysis. In conclusion the specificity of diffusion weighted MRI and 11C Acetate PET/CT for lymph node staging was high, although the sensitivity was low. Predictive factors of regional lymph node metastases could be retrieved from diffusion weighted MRI and 11C Acetate PET/CT. By combining targeted biopsies with conventional biopsies the detection rate of clinically significant PCa could be increased.

Introdução e objetivo: A avaliação da gravidade da neoplasia em pacientes com câncer de próstata tem como propósito identificar e tratar somente os pacientes com doença clinicamente significativa. Os parâmetros clínicos e histopatológicos tradicionalmente utilizados na estratificação de risco classificam erroneamente uma parcela importante dos pacientes. O objetivo deste estudo foi avaliar o papel da ressonância nuclear multiparamétrica de próstata (RNMMP) e da biópsia transretal realizada com fusão de imagem e estimativa visual na estratificação precoce dos pacientes em vigilância ativa. Métodos: Foram incluídos prospectivamente pacientes com câncer de próstata de baixo risco candidatos a vigilância ativa: biópsia inicial convencional com no mínimo 12 fragmentos; escore de Gleason <= 6; PSA sérico <= 10,0; <= 3 fragmentos positivos; <= 50% de acometimento de cada fragmento; toque T1c ou T2a. Todos os pacientes foram submetidos à RNMMP e biópsia confirmatória: biópsia aleatória sistemática e biópsia guiada com fusão de imagem (ultrassom e RNMMP) e analisada por método cognitivo de estimativa visual. As regiões suspeitas para câncer foram definidas e classificadas utilizando-se a escala PI-RADS (Prostate Imaging Reporting and Data System). Definimos reclassificação na biópsia confirmatória como aparecimento de escore de Gleason >= 7, > 3 fragmentos positivos ou >= 50% de envolvimento de qualquer fragmento. A performance da RNMMP em prever os resultados da biópsia confirmatória foi estudada. Análise uni e multivariada mediante regressão logística avaliou a relação entre idade, PSA, densidade de PSA, número de fragmentos positivos na biópsia inicial e o escore da RNMMP e a chance de reclassificação na biópsia confirmatória. Resultados: Cento e cinco pacientes estiveram disponíveis para análise final. Quarenta e dois (40%) pacientes apresentaram PI-RADS 1,2 ou 3 e 63 (60%) PI-RADS 4 ou 5. No geral, 87 pacientes foram submetidos à biópsia guiada com fusão. A taxa de reclassificação entre pacientes com PI-RADS 1,2,3,4 e 5 foi de 0%, 23.1%, 9.1%, 74.5% e 100%, respectivamente. No geral, a sensibilidade, especificidade, valor preditivo positivo (VPP) e valor preditivos negativo (VPN) da RNMMP para predição de reclassificação foi de 92.5%, 76%, 81% e 90.5%, respectivamente. Daqueles reclassificados, 47 (44.8%) tinham escore de Gleason >= 7 e 11 apresentavam (10.4%) >= 3 fragmentos positivos e >= 50% de envolvimento de qualquer fragmento individualmente. Na análise multivariada, somente a densidade de PSA e a RNMMP permaneceram como fatores preditivos significativos para reclassificação (p < 0,05). Na tabulação cruzada a biópsia aleatória sistemática teria deixado de classificar corretamente 15 pacientes com câncer significativo detectados pela biópsia com fusão de imagem. Por outro lado, a biópsia aleatória sistemática detectou cinco casos de câncer significante que não teriam sido identificados pela biopsia de fusão de imagem isoladamente. Conclusões: A RNMMP é uma ferramenta importante na predição da taxa de reclassificação da gravidade da neoplasia de próstata em pacientes candidatos à vigilância ativa submetidos à biopsia confirmatória. A taxa de reclassificação na biopsia confirmatória é particularmente alta no grupo de pacientes com lesões PI-RADS grau 4-5. Apesar da utilidade da biópsia com fusão de imagem, recomenda-se a manutenção da prática de se retirar fragmentos sistemáticos aleatórios quando da realização da biópsia confirmatória para maximizar a detecção de neoplasia de comportamento agressivo / Introduction and objective: The goal of prostate cancer (PCa) risk stratification is to identify and treat only men with clinically significant disease. Clinical and pathologic parameters currently used to stratify PCa risk misclassify a significant amount of patients. The objective of this study was to evaluate the role of multiparametric magnetic resonance imaging of the prostate (mpMRI) and transrectal guided biopsy with visual estimation (TRUS-Bx) in early risk stratification of patients with prostate cancer on active surveillance. Methods: Study subjects were prospectively enrolled including patients with low risk, low-grade, localized PCa: Gleason <= 6, T1c-T2a, PSA <=10 ng/ml, no more than 3 positive cores and <= 50% involvement of single cores. They were followed with subsequent mp-MRI and confirmatory biopsy (CB): standard biopsy (SB) and visual estimation-guided TRUS-Bx. Cancer-suspicious regions (CSRs) were defined using Prostate Imaging Reporting And Data System (PIRADS) scores. Reclassification occurred if CB confirmed Gleason >= 7, > 3 positive fragments or >= 50% involvement of any core. The performance of mp- MRI on predicting CB results was assessed. Univariate and multivariate logistic regression were performed to study relationships between age, PSA, PSA density, number of positive cores in the initial biopsy and mpMRI grade on CB reclassification. Results: 105 patients were available for analysis. 42 (40%) patients had PIRADS 1,2 or 3 lesions and 63 (60%) had only grades 4 or 5 lesions. Overall, 87 patients underwent visual estimation TRUS-Bx. Reclassification among patients with PI-RADS 1,2,3,4 and 5 was 0%, 23.1%, 9.1%, 74.5% and 100%, respectively. Overall, mpMRI sensitivity, specificity, PPV and NPV for disease reclassification were 92.5%, 76%, 81% and 90.5%, respectively. Of men reclassified 47 (44.8%) were upstaged because of Gleason >= 7, 11 (10.4%) because of >= 3 positive fragments plus >= 50% involvement. On multivariate analysis, only PSA density and mpMRI remained significant for reclassification (p < 0,05). On cross-tabulation SB would have missed 15 significant cases detected by targeted biopsy. On the other hand SB detected 5 cases of significant cancer not detected by targeted biopsy alone. Conclusions: Multiparametric magnetic resonance imaging is a significant tool for predicting cancer severity reclassification on CBx among AS candidates. The reclassification rate on CBx is particularly high in the group of patients who have PI-RADS grades 4 or 5 lesions. Despite the usefulness of visual-guided biopsy, it still remains highly recommended to retrieve standard fragments during CBx in order to avoid missing significant tumors

計算機超聲引導針放置模擬系統近年受到醫學界密切關注。在過去十年，為應付各種需要，大量模擬系統被研發。與傳統訓練方法比較，使用計算機模擬系統作訓練擁有多種優點。例如：可控訓練環境，能重複使用的數據庫，以及客觀評核。至今，研究的主要方向依然是物理建構的模擬。雖然，更真實及更仔細的模擬系統能引發新的教學概念，系統開發的重點應該著眼於對訓練的影響。 / 本論文研究計算機超聲引導針放置模擬系統的最新發展。首先，我們會介紹計算機模擬系統的各個範疇及於醫學訓練的基本應用。使用計算機模擬系統作訓練用途的成效會被討論。然後，我們會討論幾種針對訓練成效的改進技術。這些技術包括一個動態訓練場景生成框架，綜合遊戲概念的方法，以及一種以臨床技術為本的穿刺提示規劃法則。它們對訓練的影響利用實驗作驗證。接著，我們介紹一個評核穿刺軌跡可視化技術的框架。我們的研究發現，穿刺軌跡的可視化技術對用家放置針的準確度有顯著的影響。這意味著模擬系統中穿刺軌跡的可視化技術需要經過非常小心的設計。最後，我們介紹一個超聲材質的描述器。這個描述器針對超聲材質的比較而設計。超聲材質的比較不止是在超聲模擬系統中重要的一環，更能被應用在各種醫學圖像的研究中。 / Computer-based ultrasound guided needle placement simulators have gained extensive attention of the medical society. In the last decade, a lot of simulators have been proposed to suit different purposes. Advantages of using computer-based simulators over traditional training include controlled training environment, reusable case database and objective evaluation. Yet, the most studied aspect of computer-based simulators remains the simulation of physical situations. Though a more realistic and detailed simulation enables new training concepts, the origin of any development shall be its effect on training. / This thesis studies the latest development of computer-based ultrasound guided needle placement simulators. We first introduce basic aspects of computer-based simulators and their applications on medical training. The effects on computer-based training over traditional methods are discussed. Secondly, we present various techniques that aim for effective training. These techniques include a framework for dynamic case generation, an integration of serious game concepts, and a recommendation scheme based on clinical practices. Their impacts on training are evaluated through various experiments. Thirdly, we present an evaluation framework for the visualization of needle access pathway. Our study shows that the adoption of visualization techniques significantly affects users' performance of needle alignment. This implies that a careful design of the visual effect inside a simulator is necessary. Lastly, we present a descriptor for ultrasound textures. This descriptor is designed for ultrasound textural comparison which is an important step for not only ultrasound simulators but also other medical imaging applications. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Chan, Wing Yin. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 100-114). / Abstracts also in Chinese. / Chan, Wing Yin.

Introdução e objetivo: A avaliação da gravidade da neoplasia em pacientes com câncer de próstata tem como propósito identificar e tratar somente os pacientes com doença clinicamente significativa. Os parâmetros clínicos e histopatológicos tradicionalmente utilizados na estratificação de risco classificam erroneamente uma parcela importante dos pacientes. O objetivo deste estudo foi avaliar o papel da ressonância nuclear multiparamétrica de próstata (RNMMP) e da biópsia transretal realizada com fusão de imagem e estimativa visual na estratificação precoce dos pacientes em vigilância ativa. Métodos: Foram incluídos prospectivamente pacientes com câncer de próstata de baixo risco candidatos a vigilância ativa: biópsia inicial convencional com no mínimo 12 fragmentos; escore de Gleason <= 6; PSA sérico <= 10,0; <= 3 fragmentos positivos; <= 50% de acometimento de cada fragmento; toque T1c ou T2a. Todos os pacientes foram submetidos à RNMMP e biópsia confirmatória: biópsia aleatória sistemática e biópsia guiada com fusão de imagem (ultrassom e RNMMP) e analisada por método cognitivo de estimativa visual. As regiões suspeitas para câncer foram definidas e classificadas utilizando-se a escala PI-RADS (Prostate Imaging Reporting and Data System). Definimos reclassificação na biópsia confirmatória como aparecimento de escore de Gleason >= 7, > 3 fragmentos positivos ou >= 50% de envolvimento de qualquer fragmento. A performance da RNMMP em prever os resultados da biópsia confirmatória foi estudada. Análise uni e multivariada mediante regressão logística avaliou a relação entre idade, PSA, densidade de PSA, número de fragmentos positivos na biópsia inicial e o escore da RNMMP e a chance de reclassificação na biópsia confirmatória. Resultados: Cento e cinco pacientes estiveram disponíveis para análise final. Quarenta e dois (40%) pacientes apresentaram PI-RADS 1,2 ou 3 e 63 (60%) PI-RADS 4 ou 5. No geral, 87 pacientes foram submetidos à biópsia guiada com fusão. A taxa de reclassificação entre pacientes com PI-RADS 1,2,3,4 e 5 foi de 0%, 23.1%, 9.1%, 74.5% e 100%, respectivamente. No geral, a sensibilidade, especificidade, valor preditivo positivo (VPP) e valor preditivos negativo (VPN) da RNMMP para predição de reclassificação foi de 92.5%, 76%, 81% e 90.5%, respectivamente. Daqueles reclassificados, 47 (44.8%) tinham escore de Gleason >= 7 e 11 apresentavam (10.4%) >= 3 fragmentos positivos e >= 50% de envolvimento de qualquer fragmento individualmente. Na análise multivariada, somente a densidade de PSA e a RNMMP permaneceram como fatores preditivos significativos para reclassificação (p < 0,05). Na tabulação cruzada a biópsia aleatória sistemática teria deixado de classificar corretamente 15 pacientes com câncer significativo detectados pela biópsia com fusão de imagem. Por outro lado, a biópsia aleatória sistemática detectou cinco casos de câncer significante que não teriam sido identificados pela biopsia de fusão de imagem isoladamente. Conclusões: A RNMMP é uma ferramenta importante na predição da taxa de reclassificação da gravidade da neoplasia de próstata em pacientes candidatos à vigilância ativa submetidos à biopsia confirmatória. A taxa de reclassificação na biopsia confirmatória é particularmente alta no grupo de pacientes com lesões PI-RADS grau 4-5. Apesar da utilidade da biópsia com fusão de imagem, recomenda-se a manutenção da prática de se retirar fragmentos sistemáticos aleatórios quando da realização da biópsia confirmatória para maximizar a detecção de neoplasia de comportamento agressivo / Introduction and objective: The goal of prostate cancer (PCa) risk stratification is to identify and treat only men with clinically significant disease. Clinical and pathologic parameters currently used to stratify PCa risk misclassify a significant amount of patients. The objective of this study was to evaluate the role of multiparametric magnetic resonance imaging of the prostate (mpMRI) and transrectal guided biopsy with visual estimation (TRUS-Bx) in early risk stratification of patients with prostate cancer on active surveillance. Methods: Study subjects were prospectively enrolled including patients with low risk, low-grade, localized PCa: Gleason <= 6, T1c-T2a, PSA <=10 ng/ml, no more than 3 positive cores and <= 50% involvement of single cores. They were followed with subsequent mp-MRI and confirmatory biopsy (CB): standard biopsy (SB) and visual estimation-guided TRUS-Bx. Cancer-suspicious regions (CSRs) were defined using Prostate Imaging Reporting And Data System (PIRADS) scores. Reclassification occurred if CB confirmed Gleason >= 7, > 3 positive fragments or >= 50% involvement of any core. The performance of mp- MRI on predicting CB results was assessed. Univariate and multivariate logistic regression were performed to study relationships between age, PSA, PSA density, number of positive cores in the initial biopsy and mpMRI grade on CB reclassification. Results: 105 patients were available for analysis. 42 (40%) patients had PIRADS 1,2 or 3 lesions and 63 (60%) had only grades 4 or 5 lesions. Overall, 87 patients underwent visual estimation TRUS-Bx. Reclassification among patients with PI-RADS 1,2,3,4 and 5 was 0%, 23.1%, 9.1%, 74.5% and 100%, respectively. Overall, mpMRI sensitivity, specificity, PPV and NPV for disease reclassification were 92.5%, 76%, 81% and 90.5%, respectively. Of men reclassified 47 (44.8%) were upstaged because of Gleason >= 7, 11 (10.4%) because of >= 3 positive fragments plus >= 50% involvement. On multivariate analysis, only PSA density and mpMRI remained significant for reclassification (p < 0,05). On cross-tabulation SB would have missed 15 significant cases detected by targeted biopsy. On the other hand SB detected 5 cases of significant cancer not detected by targeted biopsy alone. Conclusions: Multiparametric magnetic resonance imaging is a significant tool for predicting cancer severity reclassification on CBx among AS candidates. The reclassification rate on CBx is particularly high in the group of patients who have PI-RADS grades 4 or 5 lesions. Despite the usefulness of visual-guided biopsy, it still remains highly recommended to retrieve standard fragments during CBx in order to avoid missing significant tumors