Im Rahmen dieser Arbeit wurde ein Algorithmus zur semiautomatischen Detektion von pathologischen, skelettalen Mehranreicherungen in der 18F-FDG-PET entwickelt, der gleichzeitig als Grundlage für die Ermittlung des metabolischen, skelettalen Tumorvolumens diente. Hierzu wurden PET/CT-Datensätze von Kindern und Jugendlichen, die an einem Hodgkin-Lymphom erkrankt waren und im Zeitraum von 2007 bis 2013 in der EuroNet-PHL-C1-Studie behandelt wurden, analysiert. Bei 142 Kindern war im Rahmen einer zentralen Referenzbeurteilung im PET/CT ein Skelettbefall diagnostiziert und dokumentiert worden. Auf dieser Basis (Goldstandard) erfolgte die Testung verschiedenster Methoden, von denen sich die nachfolgende als die am besten geeignete erwies: Als Referenzregion zur Bestimmung eines physiologischen Stoffwechselniveaus im Skelett (SUVmean) wurde eine 15 bis 30 ml große VOI in einem nach visueller Einschätzung nicht tumorbefallenen Wirbelkörper (meist LWK 4) platziert. Auf Grundlage des damit ermittelten physiologischen Skelettstoffwechselniveaus identifizierte das Suchprogramm skelettale Läsionen, sofern diese einen SUV > (SUVmean + 2,5 SD) aufwiesen. Dieser in das Programm implementierte Algorithmus wurde an den PET/CT-Datensätzen der 142 Patienten mit visuell detektiertem Skelettbefall validiert. Dabei wurde ein Skelettbefall bei 130 von 142 Patienten (Sensitivität auf Patientenebene von 91,5 Prozent) programmbasiert korrekt diagnostiziert. Von 1015 visuell erfassten skelettalen Läsionen wurden 774 durch das Suchprogramm richtig erkannt (Sensitivität auf Regionenebene von 76,3 Prozent). Von 5375 nicht befallenen Regionen wurden 5137 korrekterweise auch nicht als Läsionen durch das Programm angezeigt (Spezifität auf Regionenebene von 95,6 Prozent). Das Ausmaß das Skelettbefalls in Form des metabolischen, skelettalen Tumorvolumens wurde mit dem ereignisfreien Überleben und dem Gesamtüberleben verglichen: Es ergab sich keine Korrelation. Die Arbeit umfasst 156 Seiten, 59 Abbildungen, 31 Tabellen und 96 Literaturangaben.

Marginal zone (MZ) lymphomas (MZLs) represent a group of lymphomas originating from B lymphocytes of the “marginal zone” which is the external part of the secondary lymphoid follicles. The WHO classifies MZL into 3 entities; extranodal MZL, splenic MZL and nodal MZL. Extranodal marginal zone lymphoma (EMZL) can arise in different tissues, including the stomach, salivary gland, lung, small bowel, thyroid, ocular adnexa and skin. We present a 25 years old female with a history of angioedema and chronic cutaneous eczema who developed an unusual EMZL. Patient presented with a history of rapidly enlarging skin nodule on her left elbow that had been present for almost one year. Over a period of 2-3 weeks she felt the nodule rapidly changed in size and shape. Excisional biopsy of the mass revealed a lymphoid infiltrate based in the reticular dermis and focally extending into the subcutaneous adipose tissue with formation of disrupted lymphoid follicles positive for CD20, CD23 and BCL2 but negative for CD10, Cyclin D1 and SOX11. Diagnosis was consistent with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Patient on presentation did not have any B symptoms other cutaneous lesions, lymphadenopathy or hepatosplenomegaly. PET scan revealed no evidence of abnormal uptake leading to a final Stage IE definition. Patient initiated definitive radiation therapy. EMZL accounts for 5 -10 % of non-Hodgkin lymphoma. It has been described often in organs that are normally devoid of germinal centers. It may arise in reactive lymphoid tissue induced by chronic inflammation in extranodal sites. Primary cutaneous marginal zone lymphoma (PCMZL) is associated with infectious etiologies such as Borrelia burgdorferi and less commonly with viral infections or in relation to autoimmune disorders. Autoimmune disorders, specifically Sjögren's syndrome is associated with a 30-fold increased risk of marginal zone lymphoma. Localized disease can be treated by local radiotherapy, intralesional injections or excision. Widespread skin disease is usually treated with a CD20 directed monoclonal antibody-Rituximab. Patients with PCMZL usually have an indolent clinical course. Extracutaneous dissemination of MALT Lymphoma is uncommon and happens in 6-8 % of patients. The 5 years overall survival is between 98-100%. Family physicians and dermatologists should have a high index of suspicion for this rare lymphoma subtype especially in patients with inflammatory chronic skin conditions and atopy.

Mantle cell lymphoma (MCL) represents a heterogenous subtype of non-Hodgkin lymphoma (NHL), which can present in three distinct clinicopathologic variants: indolent type MCL, classic type MCL and blastoid type MCL. Despite the different variations, MCL, in general, is almost always associated with advanced-stage disease at diagnosis, with a strong predilection for significant extranodal involvement, usually to the bone marrow, CNS, peripheral blood and the gastrointestinal tract. However, the literature review reveals ocular involvement is a more rarely described extranodal site of involvement by MCL. Among the reported cases, the orbit was most commonly involved, followed by the eyelid and the lacrimal gland. We report a 63-year-old male who presented with a nine-month history of progressive symptoms of periorbital swelling and eyelid apraxia, causing bilateral visual disturbances. The patient was initially treated for presumed blepharospasm by his ophthalmologist with botulinum toxin injections; however, his periorbital edema continued to worsen, and he developed a discrete nodule in his right lower eyelid. Biopsy of the right eyelid nodule revealed classic type MCL with immunohistochemical testing positive for CD20, CD5, cyclin D1, SOX11 and Ki67 proliferative index of 40%. Fluorescence in situ hybridization (FISH) analysis detected (11;14) translocation. Mantle Cell Lymphoma International Prognostic Index Combined Biologic Index (MIPIb) score was calculated to be 6.5 points based on his age, ECOG performance status of 0-1, normal serum LDH, normal white blood cell count and elevated Ki67 proliferative index, stratifying patient into the high-risk group, with an estimated median overall survival of 37 months. Due to the bulky MCL involvement in the palpebral conjunctiva affecting his vision and eyelid function, he was immediately treated with radiation therapy to the bilateral orbits. PET-CT revealed adenopathy above and below the diaphragm. Bone marrow biopsy revealed focal involvement (5-10%) by MCL. Brain MRI revealed MCL infiltration in the bilateral orbits and lacrimal glands. Upper and lower endoscopy revealed multiple polyps positive for MCL. Given the advanced stage of the disease and his high-risk stratification, he was started on intensive induction chemotherapy with rituximab, dexamethasone, cytarabine, and carboplatin and received prophylactic intrathecal methotrexate. Systemic imaging after completion of four cycles of treatment revealed near resolution of the majority of the lymphadenopathy and all of the lymph nodes no longer demonstrated any significant metabolic activity. He completed two additional cycles of systemic chemotherapy and is currently being evaluated for autologous hematopoietic stem cell transplantation in complete remission-1 given his excellent response to treatment, his young age, high-risk disease at diagnosis, and good performance status. Despite the diffuse and extensive systemic disease, interestingly, our patient did not exhibit any constitutional or metastasis-associated symptoms and only presented with isolated periorbital swelling. Our case emphasizes the rare extranodal site of involvement by MCL and encourages all medical providers to remain cognizant of the varying ways in which MCL can present clinically.

Hintergrund: Der EGILS (European Gastro-Intestinal Lymphoma Study) Consensus Report von 2011 enthält als zentralen Therapiebaustein die H.p.-Eradikationsbehandlung mit nachfolgendem „Watch-and-Wait“ bzw. die Nachsorge nach Vollremission. Voraussetzung für eine strukturierte Nachsorge ist eine gute Patientencompliance. Eine Studie über Dauer und praktische Umsetzbarkeit der Nachsorge, insbesondere nach Vollremission, gibt es bisher nicht. Ziel: Ziel dieser retrospektiven Arbeit war es zu überprüfen, ob die von der EGILS empfohlenen Nachsorgeintervalle von den Patienten nach einer alleinigen H.p.-Eradikation eingehalten werden. Ferner sollte auf dieser Grundlage und unter Berücksichtigung des Therapieerfolgs eine Empfehlung für optimale Nachsorgeintervalle nach klinischer Vollremission erarbeitet werden. Methode: 106 Patienten (50 weiblich; 56 männlich); Alter 59 (33 – 85) Jahre mit beliebigem H.p.Status, histologisch gesichertem gastralem MALT-Lymphom und alleiniger H.p.-Eradikationsbehandlung wurden eingeschlossen. Grundlage zur Beurteilung war, bis zur Vollremission, das Nachsorgeschema gemäß EGILS (alle 4-6 Monate); danach erfolgte die Nachsorge alle 6 bis 12 Monate. Die Compliance wurde bei jedem Patienten als das Verhältnis aus erfüllter Nachsorgepflicht zu individueller Gesamtdauer der Nachsorge berechnet und über alle Patienten gemittelt. Ergebnisse: Die meisten Patienten erreichen nach alleiniger H.p.-Eradikation unabhängig vom H.p.-Status eine Vollremission (ca. 71%). Die Nachsorgen wurden über den gesamten Beobachtungszeitraum zu ca. 55% eingehalten. Patienten mit Interesse an einer Nachsorge nehmen diese über Jahre hinweg sehr zuverlässig war. In dieser Patientengruppe liegt die Compliance bei ca. 95%. Schlussfolgerung: Die exzellente Prognose gastraler MALT-Lymphome, unabhängig vom H.p.-Status, und die hohe Bereitschaft der Patienten für Nachsorgeuntersuchungen auch nach Vollremission erhöht die Attraktivität einer „Watch-and-Wait“-Strategie. Nach klinischer Vollremission sind jährliche endoskopische Nachsorgeuntersuchungen praktisch umsetzbar. / Background: The European gastrointestinal lymphoma study (EGILS) consensus report from 2011 included as a central therapy basis the H pylori eradication treatment with subsequent “watch and wait” as well as follow-up care after full remission. The main requirement for a structured follow up care is good patient compliance. A study about the duration and the practical feasibility of follow up care, especially after full remission has not been carried out to date. Aims: The aim of this retrospective work was to review whether patients were complying with the EGILS recommended follow-up intervals after a single H pylori eradication treatment. Furthermore, on this basis and in consideration of treatment success, a recommendation for the optimal follow-up interval after a full clinical remission should be developed. Methods: 106 patients (50 females, 56 males) with an average age of 59 years (33-85) with a variable H pylori status, histologically confirmed gastric MALT-lymphoma and a single H pylori eradication treatment, were included. The basis of assessment was, up to full remission, the follow-up scheme in accordance with EGILS (4-6 months) thereafter follow up in 6-12 months. The compliance for every patient was calculated as the ratio of fulfilled follow-up care obligations to individual duration of follow-up care and averaged out over all Patients. Results: The majority of patients reached a full remission after a single H pylori eradication independent of H pylori status (ca. 71%). Ca 55% of the follow-up care was adhered to the whole observation period. Patients with an interest continued to take part reliably in follow-up care for many years. The compliance in this patient group was ca 95%. Conclusion: The excellent prognosis of gastric MALT-lymphoma, independent of H pylori status and the willingness of the patients to have aftercare-check-ups even after a full remission, increases the attraction of a “watch and wait” strategy. After a full clinical remission, yearly endoscopic check-ups can be easily implemented.

The aim of the research is to provide a computationally efficient neural network model for the study of deep brain stimulation efficacy in the treatment of Parkinson's disease. An Izhikevich neuron model was used to accomplish this task and four classes of neurons were modeled. The parameters of each class were estimated using a genetic algorithm with a fitness function based on spike frequency as a function of input current. After computing the optimal parameters the neurons were interconnected to form the network model. The estimated parameters were capable of replicating the normal firing characteristics for each type of neuron, but failed to replicate richer spiking characteristics such as post-inhibitory bursting and tonic firing. Without these characteristics, the network was unable to produce biologically feasible results. Findings indicate the Izhikevich model relies heavily on manual tuning and must be trained under an extensive set of conditions to allow for the majority of spiking characteristics to be learned. The use of the Izhikevich model in a network simulation will always be limited to the characteristics trained on a single neuron. When connected to the network the neuron may be exposed to a variety of unlearned conditions and therefore may not be capable of replicating biologically realistic behavior. / Electrical and Computer Engineering

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24496号 / 医博第4938号 / 新制||医||1064(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 滝田 順子, 教授 上野 英樹, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In this thesis, we introduce several closely related stochastic models which generalize the deterministic Hodgkin-Huxley formalism to an SDE framework. We provide analytical results on the existence and uniqueness of solutions as well as the exact formulas for the moments of a simplified model, with simplifications motivated by the experiments performed by Hodgkin and Huxley in their seminal paper.For more complicated models, we provide an approach for the approximation and simulation of solutions to the corresponding SDEs, and show several realizations of the sample paths and moments of these simulations to verify qualitative behavior in this case. All code for the project is written in the Julia language and can be obtained upon request by the reader.

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Le syndrome néphrotique idiopathique (SNI) est une néphropathie glomérulaire définie par une protéinurie massive associée à une hypoalbuminémie, sans lésions inflammatoires rénales, ni dépôts de complexes immuns circulants. Les travaux réalisés au cours de ma thèse concernent l’étude du rôle potentiel du gène c-mip dans la physiopathologie du SNI.Dans un premier temps, nous avons étudié la physiopathologie moléculaire de l’association maladie de Hodgkin et SNI. Nous avons démontré que cette association était liée à une forte induction de c-mip à la fois dans les cellules de Reed Sternberg (dont la présence signe le lymphome hodgkinien) et les podocytes qui sont des cellules spécialisées du glomérule rénal (Audard, et al. 2010). Nous avons montré que l’induction de c-mip résultait d’un défaut quantitatif et/ou qualitatif du gène Fyn, à la fois chez les patients et dans un modèle de souris déficiente en Fyn. Nous avons trouvé que c-mip était fortement induit dans les podocytes au cours du SNI ainsi que dans la glomérulopathie extramemenbraneuse (GEM). La surexpression de c-mip par transgénèse chez la souris déclenche une protéinurie néphrotique dont le mécanisme implique une rupture, médiée par c-mip, de la voie de signalisation de la néphrine (Science Signaling, 2010 co-auteur). L’étude de la néphrite de Heyman, le modèle expérimental de la GEM humaine, a permis de montrer que l’induction de c-mip coincidait avec l’apparition de la protéinurie et était associée à l’inhibition de l’activité RhoA, à une perte de la synaptopodine, à une diminution du VEGF tandis que l’expression de la DAPK (death-associated protein kinase) est fortement augmentée (Audard et al, manuscrit soumis 1). Nous avons recherché si l’hypogammaglobulinémie au cours du SNI était associée à des anomalies fonctionnelles des lymphocytes B (LB). Nous avons trouvé que c-mip interagit avec la sous unité régulatrice de la PI3 kinase et empêche la dissociation de la sous unité catalytique, p110, nécessaire à l’activation de la PI3 kinase. Enfin, l’expression de l’IL 21, une cytokine–clé secrétée par les lymphocytes T et intervenant dans la commutation isotypique, était fortement réduite dans le SNI (Audard et al, manuscrit en préparation 2). Ces résultats donnent un éclairage nouveau sur la physiopathologie moléculaire du SNI et suggèrent un rôle crucial de c-mip dans les anomalies lymphocytaires et podocytaires observées chez les patients / Idiopathic nephrotic syndrome comprises several podocyte diseases of unknown origin, affecting the glomerular podocyte, which plays a key role in controlling the permeability of the kidney filter to proteins. It is characterized by massive proteinuria and hypoalbuminemia, with no inflammatory lesions or cell infiltration. This works focused on the potential role of c-mip in the pathogenesis of INS. We showed that occurrence of minimal change nephrotic syndrome in the course of Hodgkin lymphoma (cHL-MCNS) is closely related to the induction of c-mip in both Hodgkin-Reed Sternberg cells and podocytes (Audard, et al. 2010), which is caused by a qualitative and/or quantitative defect in Fyn in both HRS and podocytes cells. We found that c-mip is upregulated in podocytes of patients with membranous nephropathy (MN). Transgenic mice overproducing c-mip in the podocytes developed heavy proteinuria without morphological alterations, inflammatory lesions or cell infiltrations. We showed that c-mip turned off podocyte proximal signaling by preventing the interaction between Fyn and nephrin, resulting in the inhibition of nephrin signaling pathway (Science signaling, 2010 coauthor). Moreover, the induction of c-mip in passive type Heymann nephritis (the experimental model of MN) was concomitant to proteinuria occurrence and is associated with reduction of RhoA activity, downregulation of synaptopodin and VEGF expression whereas DAPK expression is significantly increased (Audard et al manuscript submitted 1).We demonstrated that hypogammaglobulinemia, a common feature in INS patients, may result from a defect in B lymphocytes. We found that c-mip interacts with p85 regulatory subunit and prevent its dissociation from p110 catalytic subunit, resulting in inactivation of PI3 kinase. Finally, the expression of IL21, a key cytokine involved in class switching recombination, is repressed in active phases of INS, which may contribute for immunoglobulin disorders commonly observed in these patients (Audard et al manuscript in progress 2).Altogether, these results suggest that c-mip is a major player of lymphocyte and podocytes dysfunction observed in patients with INS