Mit Hilfe eines kommerziellen, am Universitätsklinikum Leipzig vorhandenen Navigationssystems (Localite) ist es möglich, Interventionen in einer herkömmlichen MRTUmgebung unter Echtzeitnavigation durchzuführen. In der vorliegenden Arbeit werden die Genauigkeit, Benutzerfreundlichkeit sowie der Zeitaufwand für perkutane Punktionen mit diesem System untersucht. Zur Navigation wird das jeweilige Instrument optisch verfolgt. Die automatische Patientenregistrierung außerhalb des MR-Tunnels erfolgt über eine einmalige 3DLokalisation spezieller MR-Marker. 24 Operateure mit unterschiedlicher radiologischer Erfahrung führten insgesamt 240 unterschiedlich schwere Punktionen an einem selbst entwickelten Phantom durch. Nach diesen Versuchen füllten die Operateure einen Fragebogen zur Handhabbarkeit des Systems aus. Zudem wurden 24 klinische perkutane Interventionen in nicht atemverschieblichen Körperregionen ausgewertet. Für alle Biopsien wurden Zeiten für charakteristische Arbeitsschritte dokumentiert. Die Treffergenauigkeit war im Phantomexperiment für alle Gruppen relativ hoch (Fachärzte: 93%, Assistenzärzte: 88%, Studenten 81%; Cochran p=0,104). Die dazugehörigen durchschnittlichen Zeiten für einen Biopsiezyklus lagen, gemessen in Minuten, bei 4:13 (FÄ), 4:42 (AÄ) und 5:06 (MS) (P<0,001). Die subjektiven Bewertungen des Navigationssystems an Hand der Aussagen (Items) des Fragebogens zeigten keine Abhängigkeit vom Erfahrungsgrad des Operateurs. Die diagnostische Genauigkeit der klinischen Interventionen lag bei 92%. Die mittlere Interventionszeit betrug dabei 18 min. Das Navigationssystem wurde erfolgreich für Interventionen in verschiedenen Körperregionen eingesetzt. Die Genauigkeit und die benötigten Eingriffszeiten sind mit anderen in der Literatur beschriebenen MRT-geführten Interventionen vergleichbar. Auch unerfahrene Operateure konnten das Navigationssystem relativ schnell und sicher anwenden.

Prostate cancer is prevalent among men and one of the few cancer sites where local therapies currently target the entire organ instead of tumour. MRI holds promise in accurately depicting regions of cancer burden within the prostate gland and guiding tumour-targeted diagnostics and therapeutics. The clinical performance of a novel stereotactic MRI-guided needle navigation system for prostate cancer targeting was evaluated. Mean absolute in-plane stereotactic needle-targeting error for 10 patients was 2.2 mm and mean absolute depth error was 6.5 mm, highlighting a need to improve technical accuracy of the system. Consequently, alternative stereotactic registration techniques were investigated. Metrics of performance were in-plane stereotactic needle-targeting error, depth error, and registration time. A Z-shaped fiducial motif using automated registration performed best in phantom experiments with an in-plane error of 2.0 mm and depth error of 1.0 mm. These results will guide further software and hardware development to improve clinical performance.

Prostate cancer is prevalent among men and one of the few cancer sites where local therapies currently target the entire organ instead of tumour. MRI holds promise in accurately depicting regions of cancer burden within the prostate gland and guiding tumour-targeted diagnostics and therapeutics. The clinical performance of a novel stereotactic MRI-guided needle navigation system for prostate cancer targeting was evaluated. Mean absolute in-plane stereotactic needle-targeting error for 10 patients was 2.2 mm and mean absolute depth error was 6.5 mm, highlighting a need to improve technical accuracy of the system. Consequently, alternative stereotactic registration techniques were investigated. Metrics of performance were in-plane stereotactic needle-targeting error, depth error, and registration time. A Z-shaped fiducial motif using automated registration performed best in phantom experiments with an in-plane error of 2.0 mm and depth error of 1.0 mm. These results will guide further software and hardware development to improve clinical performance.

The effect of delayed freezing on muscle glycogen and lactate was investigated to determine the rate of change following excision of samples from an intact muscle. The plantaris muscle was removed and a portion frozen as quickly as possible to establish a zero time reference point. The remaining portion of the plantaris was exposed to room atmosphere for a specific time interval, either 1.00, 4.00, 5.00, 6.00, 10.00, 15.00 minutes, after which they were immediately frozen. he glycogen and lactate values for the timed intervals were subtracted from the zero or initial value. In this way the results could be reported as the net increase or decrease per time interval. The muscle glycogen analysis indicated no difference in the timed intervals (P<0.05) 1.00, 2.00, 4.00, 5.00, 6.00, but at the ten and fifteen minute intervals, significant differences were noted for a net decrease of 9.94 and 10.18 μmoles/g, respectively. In muscle lactate analysis, no significant differences were noted for any of the time intervals. The rate of utilization of glycogen was calculated as 0.523 μmoles/g/min., and lactate formation as 0.214 μmoles/g/min. This study indicates that freezing muscle biopsy specimens may be delayed as long as six minutes after removal from the subject with no significant changes.Ball State UniversityMuncie, IN 47306

<p>Cancer is now the leading cause of death in developed countries. Despite advances in strategies aimed at the prevention and treatment of the disease, early detection of precancerous growths remains the most effective method of reducing associated morbidity and mortality. Pathological examination of physical tissues that are collected via systematic biopsy is the current "gold standard" in this pursuit. Despite widespread acceptance of this methodology and high confidence in its performance, it is not without limitations. Recently, much attention has been given to the development of optical biopsy techniques that can be used clinically and are able to overcome these limitations. This dissertation describes one such optical biopsy technique, angle-resolved low coherence interferometry (a/LCI), its adaptation to a clinical technology, and its evaluation in clinical studies.</p><p> The dissertation presents the theory that underlies the operation of the a/LCI technique, the design and validation of the clinical instrument, and its evaluation by means of two clinical trials. First, an account of the manner in which the depth-resolved angular scattering profiles that are collected by a/LCI can be used to determine nuclear characteristics of the investigated tissues is given. The design of the clinical system that is able to collect these scattering profiles through an optical fiber probe that can be passed through the accessory channel of an endoscope for <italic>in vivo</italic> use is presented. To demonstrate the ability of this system to accurately determine the size of cell nuclei, a set of validation experiments are described.</p><p> In order to evaluate the clinical utility of this a/LCI system, two clinical trials intended to assess the ability of a/LCI to detect the presence of early, pre-cancerous dysplasias in human tissues are presented. The first of these, an <italic>in vivo</italic> study of Barrett's esophagus (BE) patients undergoing routine surveillance for the early signs of esophageal adenocarcinoma, is described. This study represents the first use of the a/LCI technique in vivo, and confirms its ability to provide clinically useful information regarding the disease state of the tissue that it examines, with performance that compares favorably to other optical biopsy techniques. Next, an <italics>ex vivo</italics> study of resected intestinal tissue is presented. The results of this study demonstrate the ability of a/LCI to provide information that can be used to detect dysplasia in the lower gastrointestinal tract with high accuracy. This study will enable future development of the technology to allow conduction of <italic>in vivo</italic> trials of intestinal tissue. The results of these two clinical studies demonstrate the clinical utility a/LCI, illustrating its potential as an optical biopsy technique that has great potential to provide diagnostically relevant information during surveillance procedures. This is particularly relevant in the case of BE, where its successful use has been demonstrated <italic>in vivo</italic>.</p> / Dissertation

Attrition rates for anticancer drugs are much higher than any other therapeutic area. Only 5%#37; of the agents that demonstrate anticancer activity in the preclinical stages of development demonstrate clinical efficacy in phase III trials. This high attrition rate becomes alarming when we consider that the cost of research and development can amount to 1 billion dollars. To exacerbate this problem, many new cancer drugs are being discontinued, withdrawn or suspended. The reasons for this high attrition rate are complex and may be partly attributed to suboptimal preclinical strategies such as the use of two-dimensional (2D) cell culture systems to evaluate new agents during the development and testing stages. Cancer cells cultured in 2D do not mimic the complexity of the three-dimensional (3D) milieu of tumors in vivo. There is overwhelming evidence that in vitro 3D culture systems more accurately reflect the tumor microenvironment and present better predictive value for assessing the efficacy of new chemotherapeutic agents. The development of 3D culture systems for anticancer drug development remains an unmet need. Despite progress, a simple, rapid, scalable and inexpensive 3D-tumor model that recapitulates in vivo tumorigenesis is lacking. Herein, we report on the development and characterization of a 3D nanofibrous scaffold produced by electrospinning a mixture of poly(lactic-co-glycolic acid) (PLGA) and a block copolymer of polylactic acid (PLA) and mono-methoxy polyethylene glycol (mPEG) designated as 3P. Cancer cells cultured on the 3P scaffold formed tight aggregates similar to in vivo tumors, referred to as tumoroids that depended on the topography and net charge of the scaffold. 3P scaffolds induced tumor cells to undergo the epithelial-to-mesenchymal transition (EMT) as demonstrated by up-regulation of vimentin and loss of E-cadherin expression. 3P tumoroids showed higher resistance to anticancer drugs than the same tumor cells grown as monolayers. Inhibition of ERK and PI3K signal pathways prevented EMT conversion and reduced tumoroid formation, diameter and number. Fine needle aspirates, collected from tumor cells implanted in mice when cultured on 3P scaffolds formed tumoroids, but showed decreased sensitivity to anticancer drugs, compared to tumoroids formed by direct seeding. These results show that 3P scaffolds provide an excellent platform for producing tumoroids from tumor cell lines and from biopsies and that the platform can be used to culture patient biopsies, test for anticancer compounds and tailor a personalized cancer treatment.

In the U.S., the number of prostate biopsies increases annually. This is partly due to elevated prostate specific antigen (PSA) values identified during PC screening. This study's goal was improving prostate cancer (PC) detection through developing a clinical decision rule (CDR), based on an elevated PSA and laboratory biomarkers. This decision rule could be used after an elevated PSA, providing the patient and clinician information to consider prior to biopsy. This cross-sectional study evaluated men from the Tampa, Florida, James A. Haley (JH) VA (N=1,378), from January 1, 1998, through April 15, 2005. The study hypothesized that specific lab biomarkers among JH VA PC cases would differ significantly from JH VA patients without PC. The following biomarkers were related to PC: hemoglobin (HGB) (OR=1.42 95%CI 1.27, 1.59); red blood cell count (RBC) (OR=2.52 95%CI 1.67, 3.78); PSA (OR=1.04 95%CI 1.03, 1.05); and, creatinine (OR=1.55 95%CI 1.12, 2.15). This study attempted to determine whether including specific biomarkers (that are related to systemic diseases associated with advancing PC) could improve PC prediction (versus PSA alone). Comparing all PC stages versus non-cancerous conditions, the Receiver Operator Characteristic (ROC) curve area under the curve (AUC) expanded (increasing the probability of correctly classifying PC): PSA (alone) 0.59 (95% CI 0.55, 0.61); CDR model 0.68 (95%CI 0.65, 0.71), and the positive predictive value (PPV) increased: PSA 44.7%; CDR model 61.8%. Comparing PC (stages B, C, D) vs. other, the ROC AUC increased: PSA (alone) 0.63 (95% CI 0.58, 0.66); CDR model 0.68 (95% CI 0.68, 0.75), and the PPV increased: 20.6% (PSA); CDR model 55.3%. These results suggest evaluating certain biomarkers might improve PC prediction prior to biopsy. Moreover, the biomarkers may be more helpful in detecting clinically relevant PC. Follow-up studies should begin with replicating the study on different U.S. VA data-sets involving multiple practices.

Objectives: MRI is of great clinical utility for the guidance of special diagnostic and therapeutic interventions. The majority of such procedures are performed iteratively (\"in-and-out\") in standard, closed-bore MRI systems with control imaging inside the bore and needle adjustments outside the bore. The fundamental limitations of such an approach have led to the development of various assistance techniques, from simple guidance tools to advanced navigation systems. The purpose of this work was to thoroughly assess the targeting accuracy, workflow and usability of a clinical add-on navigation solution on 240 simulated biopsies by different medical operators. Methods: Navigation relied on a virtual 3D MRI scene with real-time overlay of the optically tracked biopsy needle. Smart reference markers on a freely adjustable arm ensured proper registration. Twenty-four operators – attending (AR) and resident radiologists (RR) as well as medical students (MS) – performed well-controlled biopsies of 10 embedded model targets (mean diameter: 8.5 mm, insertion depths: 17-76 mm). Targeting accuracy, procedure times and 13 Likert scores on system performance were determined (strong agreement: 5.0). Results: Differences in diagnostic success rates (AR: 93%, RR: 88%, MS: 81%) were not significant. In contrast, between-group differences in biopsy times (AR: 4:15, RR: 4:40, MS: 5:06 min: sec) differed significantly (p<0.01). Mean overall rating was 4.2. The average operator would use the system again (4.8) and stated that the outcome justifies the extra effort (4.4). Lowest agreement was reported for the robustness against external perturbations (2.8). Conclusions: The described combination of optical tracking technology with an automatic MRI registration appears to be sufficiently accurate for instrument guidance in a standard (closed-bore) MRI environment. High targeting accuracy and usability was demonstrated on a relatively large number of procedures and operators. Between groups with different expertise there were significant differences in experimental procedure times but not in the number of successful biopsies.

<p>Background and Aims: While a single &ldquo / high quality&rdquo / oral liquid based cytology (LBC) study has shown a high sensitivity and specificity for the technique in detection of oral dysplasia and malignancy, the high unit cost of this technology cannot be borne by the developing African countries. This study aims to evaluate the efficiency of an alternative cost-effective technique, Shandon PapSpin (PS) LBC in&nbsp / diagnosis of oral and oropharyngeal dysplasia and malignancy. Materials and Methods.We compared the diagnostic accuracy of Shandon PS LBC with that of scalpel biopsy in 69 patients. Transepithelial cytology specimens were obtained using a cervical Cytobrush. The cytology specimens were graded and scored using a novel oral cytologic grading and scoring system respectively. Results: Histological diagnosis of dysplasia or invasive squamous cell carcinoma was made in 51 of the 69 cases. Histology confirmed the cytological diagnosis of dysplasia or malignancy in 49 of the 51 cases. There were two false negative and no false positive cases. The sensitivity was 96% and the specificity 100%. The cytologic grade correlated positively with histologic grade. The best cut off value for distinguishing reactive/mildly dysplastic lesions from high 9 grade/invasive squamous cell carcinoma was determined as a cytologic score of 3, representing a sensitivity of 95% and a specificity of 96%. Conclusion: The Shandon PS LBC in association with transepithelial brush biopsy technique (TBBT) is a highly sensitive, specific and economical screening test in detection of oral and oropharyngeal dysplasia and malignancy. The proposed oral cytologic grading system correlates well with histology. The novel oral cytologic scoring system shows promise as a simple, reliable and reproducible scoring system. In addition, the liquid residual allows for immunocytochemical (Podoplanin) testing.</p>

Diss. Uppsala : Univ., 2003.