<p>Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis.</p><p>Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk.</p><p>In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively.</p><p>In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection.</p><p>Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively.</p><p>In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not.</p><p>In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.</p>

Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis. Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk. In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively. In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection. Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively. In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not. In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.

The main objective of radiation therapy is to obtain the highest possible probability of tumor cure while minimizing adverse reactions in healthy tissues. A crucial step in the treatment process is to determine the location and extent of the primary tumor and its loco regional lymphatic spread in relation to adjacent radiosensitive anatomical structures and organs at risk. These volumes must also be accurately delineated with respect to external anatomic reference points, preferably on surrounding bony structures. At the same time, it is essential to have the best possible physical and radiobiological knowledge about the radiation responsiveness of the target tissues and organs at risk in order to achieve a more accurate optimization of the treatment outcome. A computerized whole body Atlas has therefore been developed to serve as a dynamic database, with systematically integrated knowledge, comprising all necessary physical and radiobiological information about common target volumes and normal tissues. The Atlas also contains a database of segmented organs and a lymph node topography, which was based on the Visible Human dataset, to form standard reference geometry of organ systems. The reference knowledgebase and the standard organ dataset can be utilized for Atlas-based image processing and analysis in radiation therapy planning and for biological optimization of the treatment outcome. Atlas-based segmentation procedures were utilized to transform the reference organ dataset of the Atlas into the geometry of individual patients. The anatomic organs and target volumes of the database can be converted by elastic transformation into those of the individual patient for final treatment planning. Furthermore, a database of reference treatment plans was started by implementing state-of-the-art biologically based radiation therapy planning techniques such as conformal, intensity modulated, and radiobiologically optimized treatment planning. The computerized Atlas can be viewed as a central framework that contains different forms of optimal treatment plans linked to all the essential information needed in treatment planning, which can be adapted to a given patient, in order to speed up treatment plan convergence. The Atlas also offers a platform to synthesize the results of imaging studies through its advanced geometric transformation and segmentation procedures. The whole body Atlas is anticipated to become a physical and biological knowledgebase that can facilitate, speed up and increase the accuracy in radiation therapy planning and treatment optimization.

Background: Laparoscopic surgery for colorectal cancer is a novel healthcare technology, for which much research evidence has been published. The objectives of this work were to compare the oncologic outcomes of this technology across different study types, and to define patterns of adoption on the basis of the literature. Methods: A comprehensive systematic review of the literature was conducted using 1) existing systematic reviews, 2) randomized controlled trials (RCTs), and 3) observational studies. Outcomes of interest were overall survival, and total lymph node harvest. Outcomes were compared for congruence. Adoption was evaluated by means of summary expert opinions in the literature. Results: 1) Existing systematic reviews were of low to moderate quality and displayed evidence of overlap and duplication. 2) Laparoscopy was not inferior to open surgery in terms of oncologic outcomes in any study type. 3) Oncologic outcomes from RCTs and observational studies were congruent. 4) Expert opinion in the literature has been supportive of this technology, paralleling the publication of large RCTs. Conclusions: The evaluation of laparoscopic surgery for colorectal cancer in RCTs and observational studies suggests that it is not inferior to open surgery. Adoption of this technology has paralleled RCT evidence.

Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

Dextran-coated ultra-small, superparamagnetic, iron oxide particles (USPIO) have been proposed as magnetic resonance (MR) lymph node contrast agents. This thesis analyzed the topographic distributions of the pelvic and inguinal lymph nodes and quantified their spatial relations with the adjacent vascular system. We hypothesized that USPIO would facilitate identification of normal lymph nodes in a manner superior to that afforded by computed tomography or unenhanced MR, but using current clinically available scanners would be unlikely to identify microscopic nodal metastases. We have constructed a high quality nodal atlas describing probability distributions for lymph node number, size and position. Using this model, we then defined a generic three-dimensional nodal clinical target volume and a means of accurate delineation of this volume in a three-dimensional representation. This is the most quantitative assessment of the pelvic and inguinal lymphatics to date and will help to improve the successful targeting of lymph nodes for radiotherapy.

Dextran-coated ultra-small, superparamagnetic, iron oxide particles (USPIO) have been proposed as magnetic resonance (MR) lymph node contrast agents. This thesis analyzed the topographic distributions of the pelvic and inguinal lymph nodes and quantified their spatial relations with the adjacent vascular system. We hypothesized that USPIO would facilitate identification of normal lymph nodes in a manner superior to that afforded by computed tomography or unenhanced MR, but using current clinically available scanners would be unlikely to identify microscopic nodal metastases. We have constructed a high quality nodal atlas describing probability distributions for lymph node number, size and position. Using this model, we then defined a generic three-dimensional nodal clinical target volume and a means of accurate delineation of this volume in a three-dimensional representation. This is the most quantitative assessment of the pelvic and inguinal lymphatics to date and will help to improve the successful targeting of lymph nodes for radiotherapy.

Lymph node metastasis is a critical prognostic factor for lung cancer. Effective therapy to control lymphatic metastasis may improve survival. The work described in this thesis focuses on the development of a microparticulate lymphatic targeting system, which can be applied as an adjuvant therapy in the control of lymphatic metastasis in lung cancer. The study shows that intrapleural administered colloidal particulates are predominantly taken up by regional lymphatic tissue in rat models including healthy rats, rats bearing orthotopic lung tumours and rats following pneumonectomy. The effect of particle size on lymphatic particle distribution was examined by intrapleural administration of 111In-aminopolystyrene beads. Approximately 2 µm is a suitable size for intrapleural lymphatic targeting. Biodegradable polylactide-co-glycolide (PLGA) microparticles containing the anticancer agent paclitaxel (PTX) were subsequently formulated in the desired size by spray drying. PLGA-PTX microspheres were incorporated into a biodegradable and biocompatible gelatin sponge matrix to form an implantable lymphatic targeted drug delivery system. The system was characterized in vitro and its lymphatic targeting ability was examined in vivo. Fluorescence labeled microspheres embedded within the sponge were selectively taken up by regional lymphatics as the sponge matrix disintegrated following intrapleural implantation. A pharmacokinetic study showed that the total PTX exposure in lymphatic tissue was dramatically higher than that achieved through intravenous administration. The peak plasma drug concentration, which governs systemic toxicity, was significantly reduced. The low but persistent detection of plasma PTX indicates that PTX was control released from the system after intrapleural implantation. In a therapeutic efficacy study performed in the H460 orthotopic lung cancer model, gelatin sponges containing PLGA-PTX microspheres were placed in the pleural cavity as an adjuvant treatment after surgical resection of the primary lung tumour. Trans-lymphatic chemotherapy resulted in a significantly lower incidence of lymphatic tumour recurrence (20%) compared to no treatment and placebo control animals (100%). PLGA-PTX microspheres were seen in regional lymphatic tissue over 4 weeks after the sponge placement. It is concluded that the trans-lymphatic targeting drug delivery system described in this thesis may improve the control of lymphatic metastasis in lung cancer.

Background: Laparoscopic surgery for colorectal cancer is a novel healthcare technology, for which much research evidence has been published. The objectives of this work were to compare the oncologic outcomes of this technology across different study types, and to define patterns of adoption on the basis of the literature. Methods: A comprehensive systematic review of the literature was conducted using 1) existing systematic reviews, 2) randomized controlled trials (RCTs), and 3) observational studies. Outcomes of interest were overall survival, and total lymph node harvest. Outcomes were compared for congruence. Adoption was evaluated by means of summary expert opinions in the literature. Results: 1) Existing systematic reviews were of low to moderate quality and displayed evidence of overlap and duplication. 2) Laparoscopy was not inferior to open surgery in terms of oncologic outcomes in any study type. 3) Oncologic outcomes from RCTs and observational studies were congruent. 4) Expert opinion in the literature has been supportive of this technology, paralleling the publication of large RCTs. Conclusions: The evaluation of laparoscopic surgery for colorectal cancer in RCTs and observational studies suggests that it is not inferior to open surgery. Adoption of this technology has paralleled RCT evidence.

Introduction: Globally, one in four persons infected with the human immunodeficiency virus (HIV) who are living with the acquired immunodeficiency syndrome (AIDS) will die of tuberculosis (TB). The estimated number of HIV-infected children who die of tuberculosis, especially extrapulmonary TB (EPTB), in Haiti, is only loosely based on facts or investigation. This study proposes to describe demographics of children with EPTB in a pediatric TB hospital in Haiti. The objectives are two-fold. The first objective is to describe the population of children discharged from Grace Children's Hospital with a confirmed diagnosis of tuberculosis overall, and broken down by whether or not the child had an extrapulmonary manifestation of the TB disease. Specifically, we describe the demographic characteristics and the prevalence of HIV and other co-morbidities of the children, in-hospital mortality, and the diagnostic tools used to determine TB infection including the sputum test, and th e documentation of family members also infected. As part of the descriptive process, by examining those with only pulmonary TB (PTB) and EPTB separately, we investigate if they appear to be different sub-populations based on demographic characteristics and clinical measures. The second objective of this work is to determine if there is a positive association between HIV infection and the EPTB manifestation in children with a confirmed diagnosis of TB, both crudely and after adjusting for demographic variables and co-morbidities. Methods: A cross-sectional study design was used to review medical charts of clinically diagnosed pediatric TB cases for a five-year period (January 1, 1999 -- December 31, 2003). This included 492 pulmonary TB and 210 extrapulmonary TB cases. Variables measured included clinical measures and demographic characteristics. Results: Data for 615 hospitalized, clinically diagnosed pediatric TB cases were reviewed. There were 315 (51.4%) males and 298 (48.6%) females with a mean age of 5.40 years (range 0.17 - 14 years), with 214 (37.9%) of the patients aged 0-2 years. Percent males were 47.8% and 57.9% in PTB and EPTB groups respectively (p<0.05). One hundred and seven (17.4%) of patients were HIV positive. Three hundred eighty-eight (63%) of the patients had one or more additional co-morbidities: [anemia 299 (48.6%), intestinal parasites 93 (15.1%), malaria 58 (9.4%) and gastroenteritis 19 (3.1%)]. Nearly 85% of the children were undernourished. Eighty-three child patients (13.5%) died in the hospital. Children with EPTB were much more likely to be over the age of two (74% vs. 56% in PTB group), resulting in a highly significant Chi-square stati stic. The overall difference in mean age, however, was only borderline significant with children with EPTB being slightly older [p=0.059] and age was only weakly associated with TB group. They were much less likely to be HIV positive (8.6% vs. 22%, p<0.01). Children in the EPTB group were somewhat less likely to die in the hospital (10.0% vs. 15.4%, p=0.066). The OR was greater than 4 for HIV and was greater than 2 for poor nutrition status [p<0.01 for each]. Conclusion: There was no association in this model between EPTB and mortality. The apparent univariate association between EPTB and reduced mortality can be explained by lower prevalence of HIV and poor nutrition status in this sub-sample. This study has implications for hospital-based pediatric TB diagnosis and epidemiology in resource-poor countries.