京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第18218号 / 薬博第808号 / 新制||薬||238(附属図書館) / 31076 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 佐治 英郎, 教授 橋田 充, 教授 髙倉 喜信 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Deep brain stimulation (DBS) is a neurosurgical intervention now established for the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, several prospective case series have been reported, but few centres worldwide have published findings from patients treated during the last decade using current standards of technology. This thesis seeks to survey the current clinical status of DBS for pain, investigate its mechanisms and their interactions with autonomic function, its clinical limitations and ablative alternatives. Presented first is a review of the current status of analgesic DBS including contemporary clinical studies. The historical background, scientific rationale, patient selection and assessment methods, surgical techniques and results are described. The clinical outcomes of DBS of the sensory thalamus and periventricular / periaqueductal grey (PAVG) matter in two centres are presented including results from several pain and quality of life measures. A series of translational investigations in human subjects receiving DBS for pain elucidating mechanisms of analgesic DBS and its effects upon autonomic function are then presented. Single photon emission tomography comparing PAVG, VP thalamus and dual target stimulation is described. Somatosensory and local field potential (LFP) recordings suggesting PAVG somatotopy are shown. ABPM results demonstrating changes with PAVG DBS are given and Portapres studies into heart rate variability changes with ventral PAVG DBS are detailed. Investigations using naloxone are then shown to hypothesise separate dorsal opioidergic and ventral parasympathetic analgesic streams in the PAVG. Finally, cingulotomy in lung cancer to relieve pain and dyspnoea results are discussed in the context of altering pain and autonomic function by functional neurosurgery. Pain and autonomic interactions and mechanisms in deep brain surgery for pain are then discussed alongside its limitations with proposals made for optimising treatment and improving outcomes.

Thesis (MMed)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Hybrid imaging using single photon emission computed tomography/low dose (x-ray) computed tomography (SPECT/LDCT) is of benefit in preoperative scintigraphy of primary hyperparathyroidism. The role of SPECT/LDCT in preoperative assessment of renal hyperparathyroidism has not yet been examined. The aim of the study was to determine whether SPECT/LDCT conferred any benefit over SPECT alone in terms of detection and/or localization of hyperfunctioning parathyroid tissue in this patient group. Methods: A retrospective study of patients with renal hyperparathyroidism and positive planar and SPECT scintigraphy was undertaken. All patients underwent planar scintigraphy using 99mTc-pertechnetate immediately followed by 99mTc-sestamibi as well as SPECT/LDCT 60 min after sestamibi injection and a delayed static image to assess for differential washout at 2-3 hours. Planar subtraction images were generated. For each patient, two nuclear physicians reported on planar+ SPECT images followed by planar + SPECT/LDCT images (assisted by a radiologist). Confidence for the presence of hyperfunctioning parathyroid tissue as well as confidence of location was scored on a Likert-type scale. Interpretation of planar + SPECT was compared with interpretation of planar + SPECT/LDCT. The impact of LDCT on equivocal lesions and number of ectopic lesions detected was also assessed. Results: Twenty patients (M:13; F:7) imaged between February 2008 and June 2011 were included [mean age: 40 years (24 – 55)]. Mean creatinine was 687 μmol/l (169-1213), mean corrected calcium: 2.55 mmol/l (1.95-3.33) and median PTH 167 pmol/l (2.4 - >201). Thirty-five lesions were detected on planar and SPECT and this was unchanged after assessment of the LDCT data. Confidence for the presence of parathyroid pathology changed in 5 patients (5 lesions) with the addition of LDCT. LDCT changed the mean confidence of parathyroid pathology from 3.17 to 3.29 (p=0.16). Addition of LDCT reduced the number of equivocal lesions from 18 (14 patients) to 14 (10 patients) (p=0.13). The addition of LDCT changed localization in 4 lesions (3 patients). Confidence in localization of pathology changed in 9 lesions (7 patients) and the mean localization confidence score was improved from 4.2 to 4.46 (p=0.002) with LDCT. The number of lesions classified as ectopic increased from 5 (on planar+SPECT) to 8 (with addition of LDCT) (p=0.25). Conclusion: In renal hyperparathyroidism SPECT/LDCT altered localization of lesions detected on planar and SPECT alone and improved reader confidence of localization accuracy. SPECT/LDCT conferred no additional benefit over SPECT in terms of detection, confidence of parathyroid pathology or ability to distinguish equivocal from non-equivocal parathyroid lesions. The addition of LDCT did not detect significantly more ectopic lesions. Whereas the minor improvement in reader confidence of localization (with addition of LDCT) was of questionable clinical significance, we speculate that the changed and presumably improved localization of lesions on SPECT/LDCT had potential clinical impact in a significant proportion of patients. On this basis we recommend the use of hybrid SPECT/LDCT in imaging of renal hyperparathyroidism when surgery is considered. / AFRIKAANSE OPSOMMING: Agtergrond: Hibriedbeelding met enkelfoton emissie rekenaartomografie / lae dosis rekenaartomografie (EFERT/LDRT) is voordelig in pre-operatiewe beelding van primêre hiperparatiroïedisme. Die rol van EFERT/RT in pre-operatiewe evaluering van renale hiperparatiroïedisme is nog nie ondersoek nie. Die doel van hierdie studie was om in hierdie pasiëntgroep te bepaal of EFERT/RT 'n voordeel bo EFERT alleen verleen. Metode: 'n Retrospektiewe studie van pasiënte met renale hiperparatiroïedisme en positiewe planare en EFERT flikkergrafie is onderneem. Na die toediening van 99mTc-pertegnetaat is planare beelding op alle pasiënte gedoen, onmiddellik gevolg deur 99mTc-sestamibi sowel as EFERT/RT beelding 60 min na sestamibi inspuiting en 'n laat statiese beeld vir differensiële uitwas op 2-3 uur. Planare subtraksiebeelde is verkry. Twee kerngeneeskundiges het die planare + EFERT beelde van elke pasiënt gerapporteer, waarna die planare + EFERT/RT beelde met die hulp van 'n radioloog gerapporteer is. Sekerheid oor die teenwoordigheid van hiperfunksionerende paratiroïedweefsel sowel as die sekerheid oor die lokalisering daarvan, is op 'n Likert-tipe skaal verkry. Interpretasie van planare + EFERT is vergelyk met die interpretasie van planare + EFERT/RT. Die impak van LDRT op twyfelagtige letsels en die aantal ektopiese letsels waargeneem, is ook bepaal. Resultate: Twintig pasiënte (M:13; F:7) met beelding tussen Februarie 2008 en Junie 2011 is ingesluit [gemiddelde ouderdom: 40 jaar (24-55)] . Die gemiddelde kreatinien was 687 μmol/l (169-1213), gemiddelde gekorrigeerde kalsium 2.55 mmol/l (1.95-3.33) en mediaan PTH 167 pmol/l (2.4->201). Vyf en dertig letsels is op planare en EFERT beelde waargeneem en was onveranderd na assessering van die LDRT-data. Sekerheid oor die teenwoordigheid van paratiroïedpatologie het verander in 5 pasiënte (5 letsels) met die toevoeging van LDRT. LDRT het die gemiddelde sekerheid van paratiroïedpatologie van 3.17 tot 3.29 verander (p = 0.16). Toevoeging van LDRT het die aantal twyfelagtige letsels van 18 (14 pasiënte) tot 14 (10 pasiënte) verminder (p = 0.13). Die byvoeging van LDRT het die lokalisering in 4 letsels (3 pasiënte) verander. Sekerheid oor die lokalisering van patologie is in 9 letsels (7 pasiënte) verander en die gemiddelde lokalisering betroubaarheidswaarde is verbeter van 4.2 tot 4.46 (p = 0.002) met LDRT. Met die byvoeging van LDRT het die aantal letsels geklassifiseer as ektopies van 5 tot 8 (p = 0.25) toegeneem. Gevolgtrekking: In renale hiperparatiroïedisme het EFERT/RT die lokalisering van letsels wat op planare + EFERT beelding alleen waargeneem is, verander en die leser se vertroue om akkuraat te lokaliseer verbeter. EFERT/LDRT het geen bykomende voordeel bo EFERT in terme van die opsporing, sekerheid van paratiroïedpatologie of onderskeidingsvermoë tussen twyfelagtige teenoor nie-twyfelagtige paratiroïedletsels verleen nie. Met die byvoeging van LDRT is nie beduidend meer ektopiese letsels gevind nie. Terwyl die geringe verbetering in die sekerheid van lokalisering (met die byvoeging van LDRT) van twyfelagtige kliniese betekenis was, spekuleer ons dat die verandering en vermoedelik verbeterde lokalisering van letsels op EFERT/LDRT ʼn potensiële kliniese impak het in 'n beduidende aantal pasiënte. Die gebruik van EFERT/LDRT in die beelding van renale hiperparatiroïedisme wanneer chirurgie oorweeg word, word dus vir bogenoemde rede aanbeveel.

This study examined the effect of neurotoxic chemical exposures on brain processes using Single Photon Emission Computed Tomography (SPECT). A control group carefully screened for good health and minimal chemical exposures was compared to two groups of patients diagnosed with health problems following exposure to pesticides or to organic solvents.

L'utilisation de filtres plissés dans le domaine du traitement de l'air est extrêmement fréquente en raison de leur simplicité d'utilisation et de maintenance. Néanmoins, au cours du colmatage, la perte de charge augmente considérablement avec le dépôt de particules. Par conséquent le débit de filtration n'est plus maintenu et une détérioration des médias peut se produire. Il est essentiel de caractériser cette évolution en fonction des conditions opératoires pour mieux concevoir ces équipements. Les travaux ont consisté en une étude expérimentale de l'influence des conditions opératoires sur la géométrie du dépôt par des observations en Tomographie d'Émission MonoPhotonique. Une approche numérique a consisté, dans un premier temps, en une étude de la perméabilité de médias bien caractérisés afin de valider le code GeoDict. Dans un deuxième temps, une étude de la vitesse de l'air a été entreprise sur les médias plissés. La confrontation des résultats numériques avec les données expérimentales nous a permis une validation du code dans les gammes de propriétés des médias et de vitesses typiques. Concernant les médias bimodaux, l'acquisition rapide de données a permis de tester différentes corrélations analytiques afin de classifier les modèles existants d'une manière qui facilite leur utilisation. Si les résultats expérimentaux obtenus sur la localisation du dépôt préférentiel initial dans les filtres plissés sont encourageants, notamment vis-à-vis des simulations d'écoulement réalisées avec GeoDict, ceux issus des acquisitions sur les filtres précolmatés sont à prendre avec prudence et suggèrent d'apporter un certain nombre d'amélioration à notre technique / Pleated filters are widely used in air treatments because of the advantageous effective surface to overall dimension ratio they offer. Their major drawback though resides in their reduced lifetime which still needs to be controlled. Indeed, when clogging, the pressure drop considerably increases, the filtration flow is then no longer maintained which might lead to the deterioration of the media. It is then crucial to characterize the evolution of the pressure drop under operating conditions in order to best design these equipments. Part of our work consisted in studying how the operating conditions influence the geometry of the deposit. To do so, we used Single-Photon Emission Computed Tomography (SPECT), a non-destructive imaging technique that keeps intact the particle structuring. The visualization of aerosol deposit at the beginning of the filtration process allows observing preferential particle deposition on the whole height of the pleat. A numerical approach was used to study the permeability of bimodal fibrous media and we experimentally studied the local velocity as well as the biphasic flow inside pleated filter media. Comparison between experiments and simulations allowed us to validate the Geodict code for a wide range of media properties and velocities. Regarding bimodal fibrous media, the fast data acquisition has allowed testing several existing models which resulted in classifying them in a unique way. If the experimental results on the initial deposition in pleated filters are encouraging, those related to beforehand clogging point to several improvements regarding the technique we used

INTRODUÇÃO: A avaliação do mediastino quanto à presença de metástases linfonodais é importante na escolha do tratamento dos pacientes com câncer de pulmão de não pequenas células. Apesar da tomografia computadorizada ser o exame de imagem de escolha no estadiamento do câncer de pulmão, tem limitações conhecidas quanto à avaliação dos linfonodos regionais. O objetivo deste trabalho é avaliar a acurácia do SPECT/TC utilizando o radiofármaco 99mTc-sestamibi no estadiamento linfonodal do mediastino em pacientes com diagnóstico de carcinoma de pulmão de não pequenas células e candidatos a tratamento cirúrgico. MÉTODOS: Foi realizada coleta prospectiva de dados de 41 pacientes entre dezembro de 2006 a fevereiro de 2009. Os pacientes foram submetidos à tomografia computadorizada de tórax e ao SPECT/TC com 99mTc-sestamibi no prazo máximo de 30 dias antes da cirurgia. O SPECT/TC foi considerado positivo quando havia captação no mediastino e a tomografia de tórax, quando havia linfonodos maiores do que 10 mm no menor eixo. Os resultados da interpretação do SPECT/TC com sestamibi e da TC de tórax foram comparados aos encontrados na patologia, definido como método padrão ouro. RESULTADOS: O SPECT/TC identificou de maneira correta seis dos 19 casos com envolvimento dos linfonodos hilares e um dos sete casos com metástases ganglionares no mediastino pela patologia. Os valores de sensibilidade, especificidade, valores de predição positivo e negativo para o 99mTc-sestamibi SPECT/TC na avaliação do hilo foram respectivamente de: 31,6%, 95,5%, 85,7% e 61,8% e para o mediastino de 14,3%, 97,1%, 50% e 84,6%. A tomografia de tórax encontrou sensibilidade para a análise dos linfonodos hilares e mediastinais de 47,4% e 57,1%, especificidade de 95,5%, e 91,2%, valores de predição positivo de 90% e 57,1% e negativo de 67,7% e 91,2%, respectivamente. CONCLUSÃO: Nos pacientes com câncer de pulmão de não pequenas células com doença inicial e ressecável o SPECT/TC com 99mTc-sestamibi no estadiamento linfonodal do mediastino apresentou baixa sensibilidade e acurácia, apesar da alta especificidade. O SPECT/TC não adicionou informações relevantes à TC de tórax, que poderiam justificar o seu emprego no estadiamento pré-operatório do carcinoma de pulmão de não pequenas células / INTRODUCTION: The proper nodal staging of non-small cell lung cancer is important to choose the best treatment modality. Although CT is the first-line imaging test for primary staging of lung cancer, it is well known its limitations on mediastinum nodal staging. The aim was to evaluate the accuracy of SPECT/CT using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and potential candidates towards surgical treatment. METHODS: A prospective data collection of 41 patients was conducted from December 2006 to February 2009. The patients underwent chest CT and SPECT/CT with 99mTc-sestamibi within 30 days interval before surgery. SPECT/CT was considered positive when there was focal uptake of sestamibi in the mediastinum and CT scan when there was lymph nodes larger than 10 mm in short axis. The results of SPECT/CT and CT were correlated with pathology findings after surgery. RESULTS: SPECT/CT correctly identified six of 19 cases with involvement of hilar lymph nodes and one of seven cases with nodal metastases in the mediastinum. The sensitivity, specificity, positive and negative predictive value for 99mTc-sestamibi SPECT/CT in the assessment of the hilum were respectively: 31.6%, 95.5%, 85.7% and 61.8% and for the mediastinum 14.3%, 97.1%, 50% and 84.6%. Chest tomography showed a sensitivity of hilar and mediastinal lymph nodes of 47.4% and 57.1%, specificity of 95.5% and 91.2%, positive predictive value of 90% and 57.1% and negative predictive value of 67.7% and 91.2%, respectively. CONCLUSION: SPECT/CT with 99mTc-sestamibi showed very low sensitivity and accuracy for nodal staging of patients with non-small cell cancer despite its high specificity. Moreover, the performance of SPECT/CT added no relevant information compared to CT that could justify its use in the routine preoperative staging of non-small cell lung carcinoma

INTRODUÇÃO: A avaliação do mediastino quanto à presença de metástases linfonodais é importante na escolha do tratamento dos pacientes com câncer de pulmão de não pequenas células. Apesar da tomografia computadorizada ser o exame de imagem de escolha no estadiamento do câncer de pulmão, tem limitações conhecidas quanto à avaliação dos linfonodos regionais. O objetivo deste trabalho é avaliar a acurácia do SPECT/TC utilizando o radiofármaco 99mTc-sestamibi no estadiamento linfonodal do mediastino em pacientes com diagnóstico de carcinoma de pulmão de não pequenas células e candidatos a tratamento cirúrgico. MÉTODOS: Foi realizada coleta prospectiva de dados de 41 pacientes entre dezembro de 2006 a fevereiro de 2009. Os pacientes foram submetidos à tomografia computadorizada de tórax e ao SPECT/TC com 99mTc-sestamibi no prazo máximo de 30 dias antes da cirurgia. O SPECT/TC foi considerado positivo quando havia captação no mediastino e a tomografia de tórax, quando havia linfonodos maiores do que 10 mm no menor eixo. Os resultados da interpretação do SPECT/TC com sestamibi e da TC de tórax foram comparados aos encontrados na patologia, definido como método padrão ouro. RESULTADOS: O SPECT/TC identificou de maneira correta seis dos 19 casos com envolvimento dos linfonodos hilares e um dos sete casos com metástases ganglionares no mediastino pela patologia. Os valores de sensibilidade, especificidade, valores de predição positivo e negativo para o 99mTc-sestamibi SPECT/TC na avaliação do hilo foram respectivamente de: 31,6%, 95,5%, 85,7% e 61,8% e para o mediastino de 14,3%, 97,1%, 50% e 84,6%. A tomografia de tórax encontrou sensibilidade para a análise dos linfonodos hilares e mediastinais de 47,4% e 57,1%, especificidade de 95,5%, e 91,2%, valores de predição positivo de 90% e 57,1% e negativo de 67,7% e 91,2%, respectivamente. CONCLUSÃO: Nos pacientes com câncer de pulmão de não pequenas células com doença inicial e ressecável o SPECT/TC com 99mTc-sestamibi no estadiamento linfonodal do mediastino apresentou baixa sensibilidade e acurácia, apesar da alta especificidade. O SPECT/TC não adicionou informações relevantes à TC de tórax, que poderiam justificar o seu emprego no estadiamento pré-operatório do carcinoma de pulmão de não pequenas células / INTRODUCTION: The proper nodal staging of non-small cell lung cancer is important to choose the best treatment modality. Although CT is the first-line imaging test for primary staging of lung cancer, it is well known its limitations on mediastinum nodal staging. The aim was to evaluate the accuracy of SPECT/CT using 99mTc-sestamibi in the nodal staging of patients with non-small cell lung cancer and potential candidates towards surgical treatment. METHODS: A prospective data collection of 41 patients was conducted from December 2006 to February 2009. The patients underwent chest CT and SPECT/CT with 99mTc-sestamibi within 30 days interval before surgery. SPECT/CT was considered positive when there was focal uptake of sestamibi in the mediastinum and CT scan when there was lymph nodes larger than 10 mm in short axis. The results of SPECT/CT and CT were correlated with pathology findings after surgery. RESULTS: SPECT/CT correctly identified six of 19 cases with involvement of hilar lymph nodes and one of seven cases with nodal metastases in the mediastinum. The sensitivity, specificity, positive and negative predictive value for 99mTc-sestamibi SPECT/CT in the assessment of the hilum were respectively: 31.6%, 95.5%, 85.7% and 61.8% and for the mediastinum 14.3%, 97.1%, 50% and 84.6%. Chest tomography showed a sensitivity of hilar and mediastinal lymph nodes of 47.4% and 57.1%, specificity of 95.5% and 91.2%, positive predictive value of 90% and 57.1% and negative predictive value of 67.7% and 91.2%, respectively. CONCLUSION: SPECT/CT with 99mTc-sestamibi showed very low sensitivity and accuracy for nodal staging of patients with non-small cell cancer despite its high specificity. Moreover, the performance of SPECT/CT added no relevant information compared to CT that could justify its use in the routine preoperative staging of non-small cell lung carcinoma

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 Jun 16

Thesis (D.Tech.: Radiography)-Dept. of Radiography, Durban Institute of Technology, 2006 xxiii, 166 leaves / The purpose of this study was to evaluate 99mTc- methoxyisobutylisonitrile (MIBI) imaging, in terms of sensitivity and specificity, for non invasively detecting extracutaneous involvement of Kaposi’s sarcoma (KS) and for differentiating pulmonary infection from malignancy in acquired immunodeficiency syndrome (AIDS) patients before and after treatment. Current investigations are invasive.

Thesis (D.Tech.: Radiography)-Dept. of Radiography, Durban Institute of Technology, 2006 xxiii, 166 leaves / The purpose of this study was to evaluate 99mTc- methoxyisobutylisonitrile (MIBI) imaging, in terms of sensitivity and specificity, for non invasively detecting extracutaneous involvement of Kaposi’s sarcoma (KS) and for differentiating pulmonary infection from malignancy in acquired immunodeficiency syndrome (AIDS) patients before and after treatment. Current investigations are invasive.