Background: Breast cancer is the second most common cancer in adults and the most frequent cancer diagnosed in women. In South Africa, breast cancer accounts for 38.5% of cancers diagnosed in women. Since the presence, extent and location of distant metastases is one important prognostic factor in locally advanced breast cancer (LABC), accurate staging at diagnosis is crucial to ensure patients receive the appropriate treatment. Increasing evidence shows that the use of 18F-FDG PET/CT for disease staging of LABC may improve diagnostic sensitivity. Aim: To prospectively assess the difference in diagnostic accuracy between whole-body PET/PET-CT and conventional imagine (CI) for staging LABC. Methods: A total of 42 participants with clinical stage III and a select few stage II breast cancer underwent both 18F-FDG PET/CT and CI. Results: 18F-FDG PET/CT found significantly more (p=0.0077) distant metastatic sites than CI (36% vs. 21%). 18F-FDG PET/CT upstaged 9 (21.4%) of patients from clinical stage IIIa to stage IIIc, and changed management of 54% of patients. Thirty-eight percent (38%) of the patients had their clinical stage unchanged. One of 5 suspected metastatic sites 18F FDG PET/CT was positive for malignancy on biopsy. Conclusion: The 18F-FDG PET/CT is useful for staging locally advanced non-inflammatory infiltrating ductal carcinoma of the breast. Use of 18F-FDG PET/CT was superior to conventional imaging in assessing metastatic mediastinal lymphadenopathy, but with a poor specificity. The use of 18F-FDG PET/CT in LABC is useful, with the biopsy of isolated suspicious lesions for metastasis increasing its accuracy.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20612号 / 医博第4261号 / 新制||医||1023(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 増永 慎一郎, 教授 溝脇 尚志, 教授 小泉 昭夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: Prostate cancer is the most prevalent form of cancer affecting men.In case of biochemical recurrence, positron emission tomography (PET) targeting prostate-specific membrane antigen (PSMA) on prostate tumor cells is primarily used, in combination with computed tomography (CT), for detection and localization of recurrence. Research for optimizing a PSMA-ligand with high affinity for tumor cells and minimal excretion to the urinary bladder is constantly ongoing, in order to allow better evaluation of the prostate and nearby regions. One such ligand is 18F-PSMA-1007, which was expected to be excreted in the urinary bladder at a rate of 5-10%. However, after switching from diagnostic to low-dose CT, the elimination of 18F-PSMA-1007 in the bladder was higher than expected. Purpose: To evaluate whether hydration during the accumulation period could affect the activity concentration in the bladder. Materials and Methods: The study involved analyzing PET-CT scans obtained from two prostate cancer patient groups who underwent 18F-PSMA-1007-PET with low-dose CT. The groups consisted of 20 participants each, with one group hydrating during the tracer’s accumulation time, while scans from the comparison group were obtained from a time point where patients did not receive instructions about water intake. The amount of radioactivity was measured by placing a standardized 3.00 cm Volume of Interest (VOI) on the bladder, which was then adjusted based on the individual size and shape of the patients' bladder. From the VOI, a standardized uptake value (SUV) was determined, which can be represented as either SUVmean or SUVmax. These values represent the average tracer concentration within a VOI and the highest concentration of the tracer in the urinary bladder, respectively. Results: SUV in the urinary bladder was lower for the hydrated group, where the SUVmean was 1,55 vs 4,5 (p=0,011) for the non-hydrated group. Similar values were obtained for SUVmax, 2,3 vs 6,65 (p< 0,003). Conclusion: This retrospective study suggests that water intake during the accumulation period leads to significantly lower activity concentration in the bladder among these patients, which benefits the detection of recurrences in adjacent areas.

PET/CT with prostate-specific membrane antigen (PSMA)-targeted tracers has been used in the diagnosis and staging of patients with clear cell renal cell carcinoma (ccRCC). For ccRCC primary tumors, PET parameters were shown to predict histologic grade and features. The aim of this study was to correlate PSMA PET/CT with histopathological findings in patients with metastatic recurrence of ccRCC. Patients with ccRCC who underwent PSMA-targeted PET/CT and subsequent histopathological evaluation of suspicious lesions were included. Specimens underwent immunohistochemical marking. Lesion diameter, volume and tracer uptake were correlated with the extent and intensity of molecular PSMA expression and with clinical findings. Twelve PET-positive lesions of nine patients were evaluated. Eleven ccRCC metastases and one prostate carcinoma were detected histopathologically. Molecular PSMA expression was detected in all lesions, which intensity and distribution did not correlate with PET parameters. PSMA-targeted PET/CT is a feasible tool for the evaluation of patients with ccRCC but cannot reliably predict histologic features of metastases. PSMA may also be expressed in malignant lesions other than ccRCC, leading to incidental detection of these tumors.

Early assessment of tumour response has lately acquired big interest in the medical field, given the possibility to modify treatments during their delivery. Radiomics aims to quantitatively describe images in radiology by automatically extracting a large number of image features. In this context, PET/CT (Positron Emission Tomography/Computed Tomography) images are of great interest since they encode functional and anatomical information, respectively. In order to assess the patients' responses from many image features appropriate methods should be applied. Machine learning offers different procedures that can deal with this, possibly high dimensional, problem. The main objective of this work was to develop a method to classify lung cancer patients as responding or not to chemoradiation treatment, relying on repeated PET/CT images. Patients were divided in two groups, based on the type of chemoradiation treatment they underwent (sequential or concurrent radiation therapy with respect to chemotherapy), but image features were extracted using the same procedure. Support vector machines performed classification using features from the Radiomics field, mostly describing tumour texture, or from handcrafted features, which described image intensity changes as a function of tumour depth. Classification performance was described by the area under the curve (AUC) of ROC (Receiving Operator Characteristic) curves after leave-one-out cross-validation. For sequential patients, 0.98 was the best AUC obtained, while for concurrent patients 0.93 was the best one. Handcrafted features were comparable to those from Radiomics and from previous studies, as for classification results. Also, features from PET alone and CT alone were found to be suitable for the task, entailing a performance better than random.

Background Current studies indicate that fluorine-18-fluorodeoxyglucose positron emission tomography/ computed tomography ([18F]FDG PET/CT) is the most accurate imaging modality for the detection of relapsed locally advanced non-small cell lung cancer (NSCLC) after curatively intended chemoradiotherapy. To this day, there is no objective and reproducible definition for the diagnosis of disease recurrence in PET/CT, the reading of which is relevantly influenced by post radiation inflammatory processes. The aim of this study was to evaluate and compare visual and threshold-based semi-automated evaluation criteria for the assessment of suspected tumor recurrence in a well-defined study population investigated during the randomized clinical PET-Plan trial. Methods This retrospective analysis comprises 114 PET/CT data sets of 82 patients from the PET-Plan multi-center study cohort who underwent [18F]FDG PET/CT imaging at different timepoints for relapse, as suspected by CT. Scans were first analyzed visually by four blinded readers using a binary scoring system for each possible localization and the associated reader certainty of the evaluation. Visual evaluations were conducted repeatedly without and with additional knowledge of the initial staging PET and radiotherapy delineation volumes. In a second step, uptake was measured quantitatively using maximum standardized uptake value (SUVmax), peak standardized uptake value corrected for lean body mass (SULpeak), and a liver threshold-based quantitative assessment model. Resulting sensitivity and specificity for relapse detection were compared to the findings in the visual assessment. The gold standard of recurrence was independently defined by prospective study routine including external reviewers using CT, PET, biopsies and clinical course of the disease. Results Overall interobserver agreement (IOA) of the visual assessment was moderate with a high difference between secure (ĸ = 0.66) and insecure (ĸ = 0.24) evaluations. Additional knowledge of the initial staging PET and radiotherapy delineation volumes improved the sensitivity (0.85 vs 0.92) but did not show significant impact on the specificity (0.86 vs 0.89). PET parameters SUVmax and SULpeak showed lower accuracy compared to the visual assessment, whereas threshold-based reading showed similar sensitivity (0.86) and higher specificity (0.97). Conclusion Visual assessment especially if associated with high reader certainty shows very high interobserver agreement and high accuracy that can be further increased by baseline PET/CT information. The implementation of a patient individual liver threshold value definition, similar to the threshold definition in PERCIST, offers a more standardized method matching the accuracy of experienced readers albeit not providing further improvement of accuracy.

Hintergrund Durch die Entwicklung neuer in vivo Bildgebungsmethoden, z.B. der Computertomographie (CT) und der Positronen-Emissions-Tomographie (PET), konnte in den letzten Jahren das Verständnis über die Pathophysiologie des akuten Lungenversagens (acute respiratory distress syndrome, ARDS) maßgeblich verbessert werden. So zeigten PET/CT-Messungen, dass beim ARDS pathophysiologische Veränderungen von Lungenbelüftung und -durchblutung zu einer Störung des Gasaustausches beitragen. Die deshalb erforderliche mechanische Beatmung kann allerdings zu einer weiteren Schädigung der Lunge führen (ventilator induced lung injury, VILI). Bisher konnten weder die exakten pathophysiologischen Mechanismen des ARDS noch der potentiell schädigende Einfluss der mechanischen Beatmung vollständig geklärt werden. Fragestellung In dieser Doktorarbeit wurden PET/CT-Bildgebungstechniken für die Quantifizierung der pulmonalen Belüftung, neutrophilischen Inflammation und Perfusion im experimentellen Modell des ARDS verwendet. Hierfür wurden zwei Substudien durchgeführt. Ziel der ersten Substudie war es, in einem tierexperimentellen Modell des ARDS den relativen Einfluss der beiden wesentlichen Mechanismen von VILI, das zyklische Öffnen und Schließen von Alveolen (Atelektrauma) und die alveoläre Überdehnung (Volutrauma), auf die pro-inflammatorische Antwort der Lunge zu untersuchen. Die zweite Substudie hatte das Ziel, die Anwendung von Fluoreszenz-markierten Mikrosphären für Messungen der pulmonalen Perfusionsverteilung in akut geschädigten Lungen zu validieren. Es sollte geprüft werden, ob ex vivo Messungen mittels Fluoreszenz-markierten Mikrosphären alternativ zu in vivo PET/CT-Messungen mittels Gallium-68 (68Ga)-markierten Mikrosphären im experimentellen Modell das ARDS herangezogen werden können. Material und Methoden Es wurden zwei Substudien in analgosedierten, intubierten und mechanisch beatmeten Schweinen durchgeführt. Die Induktion des ARDS erfolgte durch repetitives, bronchoalveoläres Lavagieren mit isotonischer Kochsalzlösung. In der ersten Substudie erfolgten Untersuchungen an 10 Tieren. Nach Rekrutierung beider Lungen wurde eine absteigende Titration des positiven, end-exspiratorischen Drucks (positive end-expiratory pressure, PEEP) durchgeführt. Es folgte eine randomisierte Zuordnung der Versuchstiere zu einer vierstündigen Beatmungstherapie der linken, VILI Lunge zur Induktion eines Atelektraumas oder Volutraumas. In beiden Versuchsgruppen wurde ein vergleichbares Tidalvolumen von 3 ml/kg Körpergewicht appliziert. Zur Induktion von Volutrauma wurde ein hoher PEEP gewählt (2 cmH2O oberhalb des Levels, an dem sich die dynamische Compliance während der PEEP-Titration um mehr als 5 % erhöht). Zur Induktion von Atelektrauma wurde ein niedriger PEEP appliziert (PEEP, bei dem eine mit Volutrauma vergleichbare Atemwegsdruckdifferenz (Differenz aus Spitzendruck und PEEP) auftritt). In der rechten Lunge, welche als Kontrolllunge diente, wurde ein kontinuierlicher, positiver Atemwegsdruck von 20 cmH2O aufrechterhalten. Der Gasaustausch, insbesondere die Eliminierung von Kohlenstoffdioxid, wurde extrakorporal unterstützt. Nach vierstündiger Beatmung der linken, VILI Lunge erfolgte die Bildgebung. Für die Quantifizierung von Ausmaß und regionaler Verteilung der pulmonalen Inflammation wurde 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) intravenös injiziert und die Aktivität mittels dynamischen PET/CT-Aufnahmen erfasst. Die Erfassung der Lungenperfusion erfolgte mittels intravenös injizierten, 68Ga-markierten Mikrosphären und statischen PET/CT-Aufnahmen. Anschließende CT-Aufnahmen während Atemmanövern am Ende der Inspiration, Exspiration und am mittleren Atemvolumen dienten der Bestimmung von Lungenbelüftung, zyklischer Überdehnung und Rekrutierung. In der zweiten Substudie wurde in 7 Schweinen die Perfusion der linken und rechten Lunge untersucht (n = 14 Lungen). Nach jeweils einstündiger mechanischer Beatmung mittels zweiphasigem, positivem Beatmungsdruck überlagert mit einem Anteil an Spontanatmung am Minutenvolumen von 0 % oder > 60 % wurden Fluoreszenzmarkierte und 68Ga-markierte Mikrosphären intravenös injiziert. Unmittelbar im Anschluss erfolgten PET/CT-Messungen der Verteilung der 68Ga-markierten Mikrosphären. Für die Analyse der Verteilung der Fluoreszenz-markierten Mikrosphären wurden die Lungen am Versuchsende entnommen, getrocknet, in Würfel gesägt und die emittierende Fluoreszenz sowie das Gewicht jedes Würfels gemessen. Die in vivo PET-Aktivitätsmessungen wurden auf die mittels CT bestimmte Lungenmasse normalisiert (QRM). Die QRM-Daten wurden auf die Auflösung der Fluoreszenzmessungen herunterskaliert (QRM,downscaled). Die Analyse der ex vivo Fluoreszenzmessungen erfolgte durch Normalisierung auf die Masse der Lungenwürfel (QFM,Mass), auf deren Volumen (QFM,Volume) und auf Würfelmasse und -volumen (QFM,Mass,Volume). Die Auflösung und die äußeren Konturen der Lungen wurden zwischen ex vivo und in vivo Messungen verglichen. Lineare Regressionen von Perfusion und axialer Verteilung jedes Lungenvolumenelementes dienten der Bestimmung von Perfusionsgradienten entlang der ventro-dorsalen und kranio-kaudalen Achse. Die Anstiege der Regressionsgeraden wurden zwischen den Messmethoden verglichen. Für jede Lunge wurde die globale und regionale Perfusionsheterogenität bestimmt und zwischen den Messmethoden verglichen. Ergebnisse In der ersten Substudie verdeutlichten PET/CT-Messungen, dass, trotz vergleichbarer Perfusion, Volutrauma im Vergleich zu Atelektrauma zu einer höheren spezifischen Aufnahme von 18F-FDG in den beatmeten, VILI Lungen führte. Dieser Effekt trat hauptsächlich in zentralen Lungenregionen auf. Weiterhin führte Volutrauma, aber nicht Atelektrauma, zu einer höheren spezifischen 18F-FDG-Aufnahme in den beatmeten, VILI Lungen im Vergleich zu den nicht-ventilierten Kontrolllungen. CT-Aufnahmen verdeutlichten, dass Atelektrauma einen höheren Anteil an nicht belüfteten Lungenkompartimenten und mehr zyklische Rekrutierung zur Folge hatte. Volutrauma bedingte hingegen höhere Anteile an überblähten und normal belüfteten Lungenarealen und mehr zyklische Überdehnung. Die Atemwegsdruckdifferenzen waren anfänglich zwischen den Gruppen vergleichbar, stiegen im Verlauf bei Atelektrauma, aber nicht bei Volutrauma, an. In der zweiten Substudie verdeutlichten sowohl ex vivo QFM,Volume-Messungen, als auch in vivo QRM-Messungen die Existenz von Perfusionsgradienten entlang der ventrodorsalen und kranio-kaudalen Achsen, trotzdem QFM-Messungen eine 21-fach geringere Auflösung aufwiesen und die erforderliche Lungenentnahme und -trocknung eine Lungendeformation bedingte. Beide Messverfahren zeigten stärkere Perfusionen dorsaler und kaudaler im Vergleich zu ventraler und kranialer Lungenareale. Im Vergleich zu QRM,downscaled-Messungen wiesen QRM-Messungen höhere globale Perfusionsheterogenitäten auf. Verglichen mit QRM,downscaled-Messungen wiesen sowohl QFM,Volume-Messungen, als auch QFM,Mass,Volume-Messungen vergleichbare regionale Perfusionsheterogenitäten auf. Schlussfolgerungen In der ersten Substudie führte Volutrauma im Vergleich zu Atelektrauma, trotz vergleichbarem Tidalvolumen, geringerer Atemwegsdruckdifferenz und vergleichbarer Perfusion, zu einer höheren pulmonalen Inflammation. Dies deutet darauf hin, dass in diesem Modell des ARDS die mit Volutrauma assoziierten hohen statischen Drücke im Vergleich zu dynamischen Einflüssen die schädlicheren Mechanismen von VILI sind. Die zweite Substudie verdeutlichte, dass ex vivo Messungen der Verteilung von Fluoreszenz-markierten Mikrosphären bei Volumennormalisierung, trotz geringerer Auflösung und auftretenden Lungendeformationen, vergleichbare Messergebnisse hinsichtlich der Existenz und des Ausmaßes von Lungengradienten mit in vivo PET/CTMessungen aufzeigen. Eine Anpassung der Auflösung der in vivo Perfusionsmessungen an die der ex vivo Messungen verringerte sowohl die globale, als auch die regionale Perfusionsheterogenität. Bei gleicher Auflösung zeigten ex vivo QFM,Volume-Messungen vergleichbare globale und regionale Perfusionsheterogenitäten wie in vivo Messungen. Die Studienergebnisse deuten darauf hin, dass für die Quantifizierung von pulmonalen Perfusionsgradienten ex vivo QFM,Volume-Messungen alternativ zu in vivo PET/CTMessungen durchgeführt werden können.

Radiation and medical drugs are used to fight head and neck cancer, but unfortunately in some cases these treatments cause development of other diseases and injuries. Osteoradionecrosis (ORN) and medical-related osteonecrosis of the jaw (MRONJ) are dreaded late complications in jaws from radiation therapy and medical drugs and cause great suffering to those affected. The full extent of ORN and MRONJ may be difficult to diagnose due to visualizing problems in quantifying boundaries of osteonecrosis and healthy tissues. Maxillofacial surgeons now use radiology and clinical appearance to differ affected bone, which may result in unprecise estimation of the area that is affected. As a possible adjuvant diagnostic procedure, visualizing osteonecrosis by examining neutrophil elastase (NE) activity in jaws was tested in patients. A newly developed positron emission tomography (PET) tracer specific for NE was used for observation and measurement in PET/CT images. An image processing software was used for visualization, segmentation, and analysis. Areas with osteonecrosis were identified in the ORN patients, but not in their entirety and all activity could not be equated with osteonecrosis as undiagnosed areas as well absorbed the tracer. Visualization of MRONJ displayed unexpectedly low activity in the diagnosed area.    The conclusion drawn from the results and the analysis is that NE activity can be found in osteonecrosis patients, but the activity itself does not provide complete information to visualize and quantify the diseased area and it cannot be equated with osteonecrosis. To verify NE activity as osteonecrosis, tissue samples from the affected area need to be collected for histological examination

Introduction: Targeted pharmaceuticals for labelling with radio-isotopes for very specific imaging (and possibly later for targeted therapy) play a major role in Theranostics which is currently an important topic in Nuclear Medicine as well as personalised medicine. There was a need for a very specific lung cancer radiopharmaceutical that would specifically be uptaken in integrin 3 expression cells to image patients using a Positron Emission Tomography- Computed Tomography (PET-CT) scanner. Background and problem statement: Cold kits of c (RGDyK)–SCN-Bz-NOTA were kindly donated by Seoul National University (SNU) to help meet Steve Biko Hospital’s need for this type of imaging. These cold kits showed great results internationally in labelling with a 0.1 M 68Ge/68Ga generator (t1/2 of 68Ge and 68Ga are 270.8 days and 67.6 min, respectively). However the same cold kits failed to show reproducible radiolabeling with the 0.6 M generator manufactured under cGMP conditions at iThemba LABS, Cape Town and distributed by IDB Holland, the Netherlands. Materials and methods: There was therefore a need for producing an in-house NOTA-RGD kit that would enable production of clinical 68Ga-NOTA-RGD in high yields from the IDB Holland/iThemba LABS generator. Quality control included ITLC in citric acid to observe labelling efficiency as well as in sodium carbonate to evaluate colloid formation. HPLC was also performed at iThemba LABS as well as Necsa (South African Nuclear Energy Corporation). RGD was obtained from Futurechem, Korea. Kit mass integrity was determined by testing labelling efficiency of 10, 30 and 60 μg of RGD per cold kit. The RGD was buffered with sodium acetate trihydrate. The original kits were dried in a desiccator and in later studies only freeze dried. Manual labelling was also tested. The radiolabelled in-house kit’s ex vivo biodistribution in healthy versus tumour mice were examined by obtaining xenografts. The normal biodistribution was investigated in three vervet monkeys by doing PET-CT scans on a Siemens Biograph TP 40 slice scanner. Results: Cold kit formulation radiolabeling and purification methods were established successfully and SOPs (standard operating procedures) created. HPLC results showed highest radiochemical purity in 60 μg cold kit vials. 68Ga-NOTA-RGD showed increased uptake in tumours of tumour bearing mouse. The cold kit also showed normal distribution according to literature with fast blood clearance and excretion through kidneys into urine, therefore making it a suitable radiopharmaceutical for clinical studies. Conclusion: The in-house prepared cold kit with a 4 month shelf-life was successfully tested in mice and monkeys. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014

Introduction: Targeted pharmaceuticals for labelling with radio-isotopes for very specific imaging (and possibly later for targeted therapy) play a major role in Theranostics which is currently an important topic in Nuclear Medicine as well as personalised medicine. There was a need for a very specific lung cancer radiopharmaceutical that would specifically be uptaken in integrin 3 expression cells to image patients using a Positron Emission Tomography- Computed Tomography (PET-CT) scanner. Background and problem statement: Cold kits of c (RGDyK)–SCN-Bz-NOTA were kindly donated by Seoul National University (SNU) to help meet Steve Biko Hospital’s need for this type of imaging. These cold kits showed great results internationally in labelling with a 0.1 M 68Ge/68Ga generator (t1/2 of 68Ge and 68Ga are 270.8 days and 67.6 min, respectively). However the same cold kits failed to show reproducible radiolabeling with the 0.6 M generator manufactured under cGMP conditions at iThemba LABS, Cape Town and distributed by IDB Holland, the Netherlands. Materials and methods: There was therefore a need for producing an in-house NOTA-RGD kit that would enable production of clinical 68Ga-NOTA-RGD in high yields from the IDB Holland/iThemba LABS generator. Quality control included ITLC in citric acid to observe labelling efficiency as well as in sodium carbonate to evaluate colloid formation. HPLC was also performed at iThemba LABS as well as Necsa (South African Nuclear Energy Corporation). RGD was obtained from Futurechem, Korea. Kit mass integrity was determined by testing labelling efficiency of 10, 30 and 60 μg of RGD per cold kit. The RGD was buffered with sodium acetate trihydrate. The original kits were dried in a desiccator and in later studies only freeze dried. Manual labelling was also tested. The radiolabelled in-house kit’s ex vivo biodistribution in healthy versus tumour mice were examined by obtaining xenografts. The normal biodistribution was investigated in three vervet monkeys by doing PET-CT scans on a Siemens Biograph TP 40 slice scanner. Results: Cold kit formulation radiolabeling and purification methods were established successfully and SOPs (standard operating procedures) created. HPLC results showed highest radiochemical purity in 60 μg cold kit vials. 68Ga-NOTA-RGD showed increased uptake in tumours of tumour bearing mouse. The cold kit also showed normal distribution according to literature with fast blood clearance and excretion through kidneys into urine, therefore making it a suitable radiopharmaceutical for clinical studies. Conclusion: The in-house prepared cold kit with a 4 month shelf-life was successfully tested in mice and monkeys. / MSc (Pharmaceutics), North-West University, Potchefstroom Campus, 2014