臺灣博碩士論文加值系統

背景與目的：發炎反應是身體對外在刺激及病原體的既有防禦機制，同時也用於修復受損器官組織。然而，過度的發炎反應可能導致不良影響，造成不必要的傷害。2-脫氧-2-18F-氟葡萄糖（2-deoxy-2-18F-fluoro-D-glucose, FDG）正子斷層/電腦斷層掃描（positron emission tomography/computed tomography, PET/CT）在臨床上廣泛使用於非侵入性鑑別和定位癌症和與炎症相關疾病。本研究的目的是以FDG PET/CT具有炎症成像生物標記物的優勢，用於第四型免疫球蛋白G相關疾病（immunoglobulin G4-related disease, IgG4-RD）患者的診斷、病灶定位、識別疾病模式及預測復發相關因子。
方法: 本研究包括三個部分：(1) 以橫斷面研究，評估FDG PET的影像是否能夠區分IgG4-胰臟炎（自體免疫性胰臟炎）和胰腺癌；(2) 比較第四型免疫球蛋白G相關疾病患者和健康志願者的唾液腺特徵；(3) 進行前瞻性世代研究，分析FDG PET檢測出的發炎程度與第四型免疫球蛋白G相關疾病患者接受標準誘導類固醇治療後再復發時間之關係。以Cox比例風險模型分析，辨識顯著因素。
結果: 自2008年9月至2015年5月，將44名診斷為自體免疫性胰臟炎的患者與61名胰臟癌患者進行比較，發現結合四個PET參數（局部腫瘤形態、少於兩個胰臟外的FDG攝取點、原發腫瘤表現較高的最大標準化攝取值（maximum standardized uptake value, SUVmax）以及高灰度區域強調值分析）可將胰臟癌與自體免疫性胰臟炎清楚區分，其敏感性、特異性、陽性預測值和陰性預測值分別為90.2％、81.8％、87.3％和85.7％。(2) 無論是否存在唾液腺炎，第四型免疫球蛋白G相關疾病患者（n=52）唾液腺的SUVmax均比健康對照組（n=134）高。此外，與腮腺相比，IgG4-RD患者的血清IgG4數值和其他病灶的數量與頜下腺的SUVmax更為相關。(3) 世代研究中共分析了48位IgG4-RD患者的治療前FDG PET/CT影像（群體的中位觀察追蹤時間為1913天；分位差為803-2929天）。FDG PET顯示全身總病灶代謝數值(whole-body total lesion glycolysis) > 600為疾病復發的獨立預後分子（調整危險比為2.196 [95％信賴區間：1.080-4.374]；p = 0.030）。
結論: FDG PET/CT 可透過結合形態、胰臟外病灶之數目、SUV 參數和影像特徵分析的方式，區分胰臟癌和自體免疫性胰臟炎。不論是否伴有唾液腺炎，第四型免疫球蛋白G相關疾病患者的唾液腺 FDG 攝取明顯高於健康對照組。此外，在 IgG4-RD 患者中，頜下腺 SUVmax 愈高，代表系統性發炎病灶愈多。接受標準類固醇誘導治療的第四型免疫球蛋白G相關疾病患者，治療後再復發時間唯一顯著因素為治療前FDG PET/CT的全身總病灶代謝數值。

Background and Objectives: Inflammation serves as a natural defense mechanism against external stimuli and pathogens and aids in repairing damaged tissues. However, excessive inflammatory responses can cause adverse effects and lead to unnecessary tissue damage. To non-invasively identify cancer and inflammation-related conditions, 2-deoxy-2-18F-fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) is widely used. The objective of this study is to assess the potential of FDG PET/CT as an inflammatory imaging biomarker for the diagnosis, localization, and identification of patterns and predictors of relapse in individuals with immunoglobulin G4-related disease (IgG4-RD).
Methods: This study comprises three components: (1) a cross-sectional study that evaluates whether metabolic profiles observed in FDG PET can differentiate IgG4-related pancreatitis (autoimmune pancreatitis, AIP) from pancreatic cancer; (2) a comparison of salivary gland features between IgG4-RD patients and healthy volunteers; and (3) a prospective cohort study analyzing whether higher inflammatory levels (by FDG PET) are associated with shorter disease-free survival time before relapse in IgG4-RD patients who underwent standard induction steroid therapy, utilizing multivariable Cox proportional hazard models.
Results: (1) From September 2008 to May 2015, comparing 44 patients diagnosed with AIP and 61 patients with pancreatic cancer, combining four PET parameters (localized tumor morphology, less than two extrapancreatic sites of FDG uptake, primary tumor exhibiting a higher maximum standardized uptake value (SUVmax), and higher high-gray level zone emphasis value in texture analysis) could differentiate pancreatic cancer from AIP with sensitivity, specificity, positive predictive and negative predictive values of 90.2%, 81.8%, 87.3%, and 85.7%, respectively. (2) SUVmax of both salivary glands was greater in IgG4-RD patients (n=52) compared to healthy subjects (n=134) regardless of the presence of sialadenitis. Moreover, serum IgG4 levels and the number of extra-salivary gland lesions in patients with IgG4-RD showed a better correlation with the SUVmax of the submandibular glands than the parotid glands. (3) Pretherapy FDG PET/CT images from 48 IgG4-RD patients were analyzed (median follow-up time for the entire cohort was 1913 days; interquartile range, 803-2929 days). Whole-body total lesion glycolysis > 600 on FDG PET was an independent risk factor for disease relapse (adjusted hazard ratio, 2.196 [95% confidence interval: 1.080-4.374]; p=0.030).
Conclusions: FDG PET/CT can distinguish pancreatic cancer from AIP by using a combination of morphology, number of extrapancreatic lesions, SUV parameters, and texture analysis. Patients with IgG4-RD have significantly higher salivary gland FDG uptake than healthy subjects, regardless of the presence of sialadenitis. Moreover, a higher submandibular SUVmax in IgG4-RD patients indicates a greater number of systemic inflammatory foci. The sole significant factor related to relapse-free survival in patients with IgG4-RD receiving standard steroid induction therapy was the level of whole-body total lesion glycolysis, as observed on pretherapy FDG PET/CT. To assess how FDG PET/CT as an inflammatory imaging biomarker can affect patient care and treatment decisions for those with IgG4-RD, further studies are warranted.

TABLE OF CONTENTS
口試委員會審定書 i
致謝 ii
摘要 iii
ABSTRACT v
TABLE OF CONTENTS viii
FIGURES xi
TABLES xiii
Chapter One Introduction 1
1.1 Inflammation 1
1.1.1 Inflammation is an important disease mechanism in diseases caused by immunological mechanisms and by environmental insults. 1
1.2 Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disorder 2
1.2.1 Clinical features of Immunoglobulin G4-related disease 2
1.2.2 Diagnosis of Immunoglobulin G4-related disease 3
1.2.3 Treatment of Immunoglobulin G4-related disease 10
1.2.4 Long-term prognosis of Immunoglobulin G4-related disease 13
1.3 Positron Emission Tomography (PET) Imaging as an Inflammatory Biomarker: Using 2-deoxy-2-18F-fluoro-D-glucose (FDG) 14
1.3 Positron Emission Tomography (PET) Imaging as an Inflammatory Biomarker: Using 2-deoxy-2-18F-fluoro-D-glucose (FDG) 15
1.3.1 Glycolysis pathway elucidated by 2-deoxy-2-18F-fluoro-D-glucose (FDG) 15
1.3.2 Imaging protocol 17
1.3.3 Image interpretation 19
1.4 Research Gap 22
1.4.1 Differentiating malignant conditions from organs involved by Immunoglobulin G4-related disease 22
1.4.2 Salivary glands features in Immunoglobulin G4-related disease 23
1.4.3 Clinical useful biomarker to predict treatment response 24
Chapter Two Study Hypothesis 25
2.1 Differentiating malignant conditions from organs involved by Immunoglobulin G4-related disease 25
2.2 Salivary glands features in Immunoglobulin G4-related disease 25
2.3 Clinical useful biomarker to predict treatment response 25
Chapter Three Materials and Methods 26
3.1 Differentiating malignant conditions from organs involved by Immunoglobulin G4-related disease 26
3.1.1 Study design 26
3.1.2 Study population, inclusion and exclusion criteria 26
3.1.3 Imaging analysis 27
3.1.4 Statistical analysis 32
3.2 Salivary glands features in Immunoglobulin G4-related disease 33
3.2.1 Study population, inclusion and exclusion criteria 33
3.2.2 Imaging analysis 34
3.2.3 Statistical analysis 36
3.3 Clinical useful biomarker to predict treatment response 36
3.3.1 Study design 36
3.3.2 Study population, inclusion and exclusion criteria 37
3.3.3 Imaging analysis 39
3.3.4 Statistical analysis 40
Chapter Four Results 42
4.1 Differentiating malignant conditions from organs involved by Immunoglobulin G4-related disease 42
4.1.1 Patient characteristics 42
4.1.2 PET parameters 43
4.1.3 Univariable and multivariable analyses 44
4.1.4 Pancreatic Cancer Identified in Patients Initially Suspected of AIP 44
4.2 Salivary glands features in Immunoglobulin G4-related disease 45
4.2.1 Patient characteristics 45
4.2.2 Metabolic activity of the salivary glands 46
4.2.3 CT attenuation values 47
4.3 Clinical useful biomarker to predict treatment response 47
4.3.1 Patients 47
4.3.2 Univariable and multivariable analyses 48
4.3.3 The relationship between serum IgG4 levels and whole body total lesion glycolysis 49
Chapter Five Discussion 50
5.1 Differentiating malignant conditions from organs involved by Immunoglobulin G4-related disease 50
5.1.1 Main Findings 50
5.1.2 Relationships to findings of other studies 50
5.1.3 Strength 52
5.1.4 Clinical implications 53
5.1.5 Limitation 54
5.2 Salivary glands features in Immunoglobulin G4-related disease 56
5.2.1 Main Findings 56
5.2.2 Relationships to findings of other studies 57
5.2.3 Strength and clinical implications 58
5.2.4 Limitation 58
5.3 Clinical useful biomarker to predict treatment response 59
5.3.1 Main Findings 59
5.3.2 Relationships to findings of other studies 60
5.3.3 Strength 62
5.3.4 Clinical implications 63
5.3.5 Limitation 64
5.4 Summary and future perspective 65
REFERENCES 68
FIGURES 88
TABLES 106
APPENDIX 118

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