Pancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently... Show morePancreatic cancer is an aggressive cancer associated with a poor prognosis as a large proportion of these patients have locally advanced disease or metastases at the time of diagnosis. Currently onlypatients with localized pancreatic tumors can undergo surgery, which is the cornerstone in thetreatment of pancreatic cancer, whether or not preceded by neoadjuvant (chemo/radio)therapy. To establish the diagnosis, imaging techniques are used, tumor tissue must be obtained, and certain tumor markers can be determined in the blood. During surgery, the tumor must be removed in its entirety to prevent early recurrence. This thesis describes the potential role of tumor markers, which can be determined in the blood, and several experimental optical imaging techniques applied to pancreatic cancer. Show less
The aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of... Show moreThe aim of this thesis was to study novel tools and biomarkers for improved detection of vulvar premalignant disease and aid the investigation of potential new drug targets for the indication of vulvar and HPV-driven diseases.Firstly, this thesis focuses on the recognition and validation of imaging-based biomarkers for recognition of diseases of the skin and external genitalia. Clinical studies were performed using 3D photography, dermatoscopy optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) on vulvar HSIL, lichen sclerosus, cutaneous warts and anogenital warts. These techniques were subsequently implemented in a clinical trial in which a novel small molecule was tested for safety and exploratory efficacy for the treatment of cutaneous warts.Furthermore, this thesis explores sequencing-based biomarkers for vulvar disease, facilitating insight into the aetiology of vulvar diseases and identifying potential new therapeutic targets. The currently available literature on the vulvar microbiome composition was investigated and expanded in an observational study characterising the vulvar microbiome composition of healthy volunteers, vulvar HSIL patients and lichen sclerosus patients. Lastly, a perspective on recent developments in the field of premalignant vulvar disease is provided, with recommendations for future applications of the biomarkers studied in this thesis. Show less
Advances in image reconstruction using either single or multimodality imaging data provide increasingly accurate three-dimensional (3D) patient's arterial models for shear stress evaluation using... Show moreAdvances in image reconstruction using either single or multimodality imaging data provide increasingly accurate three-dimensional (3D) patient's arterial models for shear stress evaluation using computational fluid dynamics (CFD). We aim to evaluate the impacts on endothelial shear stress (ESS) derived from a simple image reconstruction using 3D-quantitative coronary angiography (3D-QCA) versus a multimodality reconstruction method using optical coherence tomography (OCT) in patients' vessels treated with bioresorbable scaffolds. Seven vessels at baseline and five-year follow-up of seven patients from a previous CFD investigation were retrospectively selected for a head-to-head comparison of angiography-derived versus OCT-derived ESS. 3D-QCA significantly underestimated the minimum stent area [MSA] (-2.38mm2) and the stent length (-1.46 mm) compared to OCT-fusion method reconstructions. After carefully co-registering the region of interest for all cases with a sophisticated statistical method, the difference in MSA measurements as well as the inability of angiography to visualise the strut footprint in the lumen surface have translated to higher angiography-derived ESS than OCT-derived ESS (1.76 Pa or 1.52 times for the overlapping segment). The difference in ESS widened with a more restricted region of interest (1.97 Pa or 1.63 times within the scaffold segment). Angiography and OCT offer two distinctive methods of ESS calculation. Angiography-derived ESS tends to overestimate the ESS compared to OCT-derived ESS. Further investigations into ESS analysis resolution play a vital role in adopting OCT-derived ESS. Show less
Vascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary... Show moreVascular inflammation, lipid metabolism, and thrombogenicity play a key role not only in atherogenesis but also in the development of acute coronary syndromes. Biomarkers associated with coronary high-risk plaques defined according to intravascular imaging have not been systematically studied. A total of 69 patients with coronary artery disease who underwent both optical coherence tomography and intravascular ultrasound imaging, and who provided blood specimens were included. Comprehensive biomarkers for inflammation, lipid, and coagulation were analyzed. Composite models sought biomarker patterns associated with thin-cap fibroatheroma (TCFA) and "high-risk plaques" (TCFA and large plaque burden). Two different composite models were developed for TCFA, based on the finding that high sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor-1, fibrinogen, IL-6, homocysteine and amyloid A levels were elevated, and high-density lipoprotein cholesterol (HDL) and bile acid levels were decreased in these patients. Both composite models were highly accurate for detecting patients with TCFA (area under curve [AUC]: 0.883 in model-A and 0.875 in model-B, both p < 0.001). In addition, creatinine, hsCRP, fibrinogen, tumor necrosis factor-a, IL-6, homocysteine, amyloid A, HDL, prothrombin, and bile acid were useful for detecting patients with "high-risk plaques". Two composite models were highly accurate for detection of patients with "high-risk plaques" (AUC: 0.925 in model-A and 0.947 in model-B, both p <0.001). Biomarkers useful for detection of patients with high-risk coronary plaques defined according to intravascular imaging have been identified. These biomarkers may be useful to risk stratify patients and to develop targeted therapy. Show less
This thesis involves the eye disease central serous chorioretinopathy. This disease is characterized by an accumulation of subretinal fluid, which can lead to a reduction in vision, changes in... Show moreThis thesis involves the eye disease central serous chorioretinopathy. This disease is characterized by an accumulation of subretinal fluid, which can lead to a reduction in vision, changes in contrast vision and sometimes distortions in the visual field. Central serous chorioretinopathy mainly occurs in men between 40 and 50 years old. In case of prolonged persistence of subretinal fluid, irreversible vision loss may occur. The most common treatments are photodynamic therapy, eplerenone, and micropulse laser, but there is no consensus on the best treatment. The research in this thesis evaluates the effects and comparisons of photodynamic therapy with micropulse laser and also compared to eplerenone. Patients were enrolled in prospective studies and differences in outcomes (including vision, contrast vision) between the treated groups were evaluated. The results of these studies allow us to improve patient counseling and also to provide the right treatment. The studies presented in this thesis, combined with the available scientific literature, indicate that half-dose therapy is currently the preferred option for the treatment of central serous chorioretinopathy. Show less
Kim, H.O.; Jiang, B.; Poon, E.K.W.; Thondapu, V.; Kim, C.J.; Kurihara, O.; ... ; Jang, I.K. 2022
Background: Local hemodynamics are known to play an important role in the development of plaque erosion. Recent studies showed that erosion patients might be treated conservatively without stent... Show moreBackground: Local hemodynamics are known to play an important role in the development of plaque erosion. Recent studies showed that erosion patients might be treated conservatively without stent implantation. We investigated evolution of hemodynamic parameters on the plaque erosion site in conservatively treated patients. Methods: Computational fluid dynamics (CFD) simulations were performed using the coronary angiogram and optical coherence tomography (OCT) images of non-stent treated erosion patients who had serial OCT studies. Calculated CFD parameters included endothelial shear stress (ESS), ESS gradient (ESSG), and oscillatory shear index (OSI).Results: The CFD parameters at the erosion and non-erosion sites were compared among baseline (n = 23), and 1-month (n = 20) and 12-month (n = 16) follow-ups. The erosion site had higher ESS and ESSG values than the non-erosion sites at baseline (mean ESS: 3.00 vs 1.36 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.65 Pa/mm, p = 0.01), 1-month (mean ESS: 2.89 vs 1.19 Pa, p < 0.01; mean ESSG: 1.71 vs. 0.60 Pa/mm, p < 0.01), and 12-month (mean ESS: 3.26 vs 1.59 Pa, p < 0.01; mean ESSG: 1.87 vs. 0.78 Pa/mm, p < 0.01). OSI was not different between erosion and and non-erosion sites. Conclusions: ESS and ESSG values were higher at the plaque erosion sites compared to non-erosion sites. Elevated ESS and ESSG at the erosion site persisted up to 12 months. These data indicate that a local thrombogenic milieu related to hemodynamic perturbation persists up to 12 months at the plaque erosion sites following conservative treatment. Show less
Zandvoort, L.J.C. van; Otsuka, K.; Villiger, M.; Neleman, T.; Dijkstra, J.; Zijlstra, F.; ... ; Daemen, J. 2021
Background: Intravascular polarization-sensitive optical frequency domain imaging (PS-OFDI) offers a novel approach to measure tissue birefringence, which is elevated in collagen and smooth muscle... Show moreBackground: Intravascular polarization-sensitive optical frequency domain imaging (PS-OFDI) offers a novel approach to measure tissue birefringence, which is elevated in collagen and smooth muscle cells, that in turn plays a critical role in healing coronary thrombus (HCT). This study aimed to quantitatively assess polarization properties of coronary fresh and organizing thrombus with PS-OFDI in patients with acute coronary syndrome (ACS).Methods and Results:The POLARIS-I prospective registry enrolled 32 patients with ACS. Pre-procedural PS-OFDI pullbacks using conventional imaging catheters revealed 26 thrombus-regions in 21 patients. Thrombus was manually delineated in conventional OFDI cross-sections separated by 0.5 mm and categorized into fresh thrombus caused by plaque rupture, stent thrombosis, or erosion in 18 thrombus-regions (182 frames) or into HCT for 8 thrombus-regions (141 frames). Birefringence of coronary thrombus was compared between the 2 categories. Birefringence in HCTs was significantly higher than in fresh thrombus (Delta n=0.47 (0.37-0.72) vs. Delta n=0.25 (0.17-0.29), P=0.007). In a subgroup analysis, when only using thrombus-regions from culprit lesions, ischemic time was a significant predictor for birefringence (ss (Delta n)=0.001 per hour, 95% CI [0.0002-0.002], P=0.023).Conclusions: Intravascular PS-OFDI offers the opportunity to quantitatively assess the polarimetric properties of fresh and organizing coronary thrombus, providing new insights into vascular healing and plaque stability. Show less
Ueki, Y.; Yamaji, K.; Losdat, S.; Karagiannis, A.; Taniwaki, M.; Roffi, M.; ... ; Raber, L. 2021
We aimed to evaluate the diagnostic agreement between radiofrequency (RF) intravascular ultrasound (IVUS) and optical coherence tomography (OCT) for thin-cap fibroatheroma (TCFA) in non-infarct... Show moreWe aimed to evaluate the diagnostic agreement between radiofrequency (RF) intravascular ultrasound (IVUS) and optical coherence tomography (OCT) for thin-cap fibroatheroma (TCFA) in non-infarct-related coronary arteries (non-IRA) in patients with ST-segment elevation myocardial infarction (STEMI). In the Integrated Biomarker Imaging Study (IBIS-4), 103 STEMI patients underwent OCT and RF-IVUS imaging of non-IRA after successful primary percutaneous coronary intervention and at 13-month follow-up. A coronary lesion was defined as a segment with >= 3 consecutive frames (approximate to 1.2 mm) with plaque burden >= 40% as assessed by grayscale IVUS. RF-IVUS-derived TCFA was defined as a lesion with > 10% confluent necrotic core abutting to the lumen in > 10% of the circumference. OCT-TCFA was defined by a minimum cap thickness < 65 mu m. The two modalities were matched based on anatomical landmarks using a dedicated matching software. Using grayscale IVUS, we identified 276 lesions at baseline (N = 146) and follow-up (N = 130). Using RF-IVUS, 208 lesions (75.4%) were classified as TCFA. Among them, OCT identified 14 (6.7%) TCFA, 60 (28.8%) thick-cap fibroatheroma (ThCFA), and 134 (64.4%) non-fibroatheroma. All OCT-TCFA (n = 14) were confirmed as RF-TCFA. The concordance rate between RF-IVUS and OCT for TCFA diagnosis was 29.7%. The reasons for discordance were: OCT-ThCFA (25.8%); OCT-fibrous plaque (34.0%); attenuation due to calcium (23.2%); attenuation due to macrophage (10.3%); no significant attenuation (6.7%). There was a notable discordance in the diagnostic assessment of TCFA between RF-IVUS and OCT. The majority of RF-derived TCFA were not categorized as fibroatheroma using OCT, while all OCT-TCFA were classified as TCFA by RF-IVUS. ClinicalTrials.gov Identifier NCT00962416. Show less
Thondapu, V.; Mamon, C.; Poon, E.K.W.; Kurihara, O.; Kim, H.O.; Russo, M.; ... ; Jang, I.K. 2021
Aims To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion.Methods and results Intracoronary optical coherence tomography performed in 37 patients with... Show moreAims To investigate local haemodynamics in the setting of acute coronary plaque rupture and erosion.Methods and results Intracoronary optical coherence tomography performed in 37 patients with acute coronary syndromes caused by plaque rupture (n=19) or plaque erosion (n=18) was used for three-dimensional reconstruction and computational fluid dynamics simulation. Endothelial shear stress (ESS), spatial ESS gradient (ESSG), and oscillatory shear index (OSI) were compared between plaque rupture and erosion through mixed-effects logistic regression. Lipid, calcium, macrophages, layered plaque, and cholesterol crystals were also analysed. By multivariable analysis, only high ESSG [odds ratio (OR) 5.29, 95% confidence interval (CI) 2.57-10.89, P<0.001], lipid (OR 12.98, 95% CI 6.57-25.67, P<0.001), and layered plaque (OR 3.17, 95% CI 1.82-5.50, P<0.001) were independently associated with plaque rupture. High ESSG (OR 13.28, 95% CI 6.88-25.64, P<0.001), ESS (OR 2.70, 95% CI 1.34-5.42, P=0.005), and OSI (OR 2.18, 95% CI 1.33-3.54, P=0.002) independently associated with plaque erosion. ESSG was higher at rupture sites than erosion sites [median (interquartile range): 5.78 (2.47-21.15) vs. 2.62 (1.44-6.18) Pa/mm, P=0.009], OSI was higher at erosion sites than rupture sites [1.04 x 10(-2) (2.3 x 10(-3)-4.74 x 10(-2)) vs. 1.29 x 10(-3) (9.39 x 10(-5)-3.0 x 10(-2)), P<0.001], but ESS was similar (P=0.29).Conclusions High ESSG is independently associated with plaque rupture while high ESSG, ESS, and OSI associate with plaque erosion. While ESSG is higher at rupture sites than erosion sites, OSI is higher at erosion sites and ESS was similar. These results suggest that ESSG and OSI may play critical roles in acute plaque rupture and erosion, respectively. Show less
In this thesis we studied the feasibility of three optical imaging techniques to differentiate tumor tissue from its surrounding tissue for various clinical purposes. Our main research question... Show moreIn this thesis we studied the feasibility of three optical imaging techniques to differentiate tumor tissue from its surrounding tissue for various clinical purposes. Our main research question hereby was: Is it feasible to differentiate tumor tissue from surrounding tissue using optical imaging techniques; and which technique can be of added value for clinicians in which clinical situation?We concluded that both full field optical coherence tomography and single fiber reflectance spectroscopy could either with help of pathologists or by signal analysis differentiate tumor tissue from its surrounding tissue. Although FF-OCT is especially useful in imaging ovarian tissue, endogenous contrast in breast and pancreatic tissue is not yet sufficient. Using fluorescence lifetime we were able to demonstrate differences between tracer bound to tumor cells and tracer not bound to tumor cells. However, this technique is still much more experimental and with the current technique, differentiating tumor tissue from its directly surrounding tissue is not yet possible. Show less
We aimed to assess a possible difference of the neointimal coverage status and its quality after implantation of the current-generation metallic stents in patients with acute coronary syndrome (ACS... Show moreWe aimed to assess a possible difference of the neointimal coverage status and its quality after implantation of the current-generation metallic stents in patients with acute coronary syndrome (ACS) vs. stable coronary lesions (non-ACS). We comprehensively analyzed three prospective single-center observational studies RESTORE (UMIN000033009), HEAL-BioFreedom (UMIN000029692), and HEAL-BioFreedom ACS (UMIN000034769). All patients who received successful optical coherence tomography (OCT) examination at planned 3-month follow-up after stent implantation were analyzed. Study population was divided into two groups, ACS vs. non-ACS groups. We evaluated standard OCT variables, coverage percent, and the quantitative light property values including light intensity, attenuation, and backscatter of neointima. A total of 177 lesions from 154 patients (ACS 44 lesions vs. non-ACS 133 lesions) were analyzed. At 3-month follow-up, coverage percent (ACS 91.5 +/- 9.5% vs. non-ACS 91.8 +/- 9.0%, P = 0.722) and neointimal thickness (ACS 59.5 +/- 32.3 mu m vs. non-ACS 58.2 +/- 32.3 mu m, P = 0.760) did not significantly differ. Light property values were similar between both groups (light intensity 159.29 +/- 72.20 vs. 159.45 +/- 63.78, P = 0.654; light attenuation 0.88 +/- 0.26 vs. 0.87 +/- 0.24 m(-1), P = 0.988; backscatter 4.86 +/- 0.58 vs. 4.83 +/- 0.57, P = 0.812). The similarity of the neointimal quality in ACS and non-ACS patients was consistent across the 6 different types of current-generation metallic stents (P for interaction > 0.05). Our findings suggested the comparable neointimal characteristics 3 months after implantation of the current-generation metallic stents in patients with ACS and stable coronary lesions by quantitative OCT methodology. Show less
Introduction Coronary angiography (CAG) is the standard modality for assessment of coronary stenoses and intraprocedural guidance of percutaneous coronary interventions (PCI). However, the... Show moreIntroduction Coronary angiography (CAG) is the standard modality for assessment of coronary stenoses and intraprocedural guidance of percutaneous coronary interventions (PCI). However, the limitations of CAG are well recognized. Intracoronary imaging (ICI) can potentially overcome these limitations. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) are the main ICI techniques utilized in clinical practice. Aim This narrative literature review addresses the current clinical applications of OCT in relation to IVUS and CAG in patients with coronary artery disease (CAD). Items reviewed are: technical implications of OCT and IVUS, lesion characterization and decision-making, stent optimization criteria, post-stenting results, safety in terms of procedural complications, clinical outcomes, and indications. Main Findings OCT is able to reveal more detail than IVUS due to its higher resolution. However, this higher resolution comes at the cost of a lower penetration depth. Pre-stenting OCT results in procedural change in more than 50% of the cases in terms of stent length and diameter. Post-stenting OCT resulting in stent optimization is reported in at least 27% of the cases. Malapposition and under-expansion are treated with post-dilatations, while edge dissections are treated with additional stent placement. Stent expansion, stent apposition, distal stent edge dissections, and reference lumen areas seem to be the most important stent optimization criteria for both decision-making and for reducing the risk of adverse events during follow-up. Both OCT and IVUS are superior in terms of post-stenting results compared with CAG alone. However, there is no consensus about whether OCT guidance results in better stent expansion than IVUS guidance. OCT, IVUS, and CAG are safe procedures with few reported procedural complications. In general, OCT guidance seems to contribute to favorable clinical outcomes compared with CAG guidance only. However, OCT guidance results in similar clinical outcomes as with IVUS guidance. OCT could be considered for lumen assessment and stent-related morphology in more complex cases in which CAG interpretation remains uncertain. Since OCT and IVUS have distinct characteristics, these techniques are complementary and should be considered carefully for each patient case based on the benefits and limitations of both techniques. Show less
Heterogeneous neointimal response has been observed after implantation of all generations of coronary stents. Our aim was assessing local factors of shear stress (SS) and plaque characteristics in... Show moreHeterogeneous neointimal response has been observed after implantation of all generations of coronary stents. Our aim was assessing local factors of shear stress (SS) and plaque characteristics in neointimal response after implantation of bioresorbable scaffolds (BRS) in bifurcations. Ten patients from the BIFSORB pilot study were analysed. Follow-up optical frequency domain imaging (OFDI) was performed at 1 month and 2 years. Coronary lumen and BRS structure were reconstructed by fusion of OFDI and angiography and were used for subsequent flow simulation. Plaque arc degree and SS were quantified using post-procedural OFDI data and were matched with follow-up OFDI using anatomical landmarks. Strut-level and segment-level analysis were performed for 1-month and 2-year follow-up respectively. A total of 444 struts (54 jailing struts) were included at 1-month follow-up. Time-average SS (TASS) was significantly lower for covered struts than for uncovered struts in non-bifurcation segments (TASS: 1.81 +/- 1.87 vs. 3.88 +/- 3.72 Pa, p < 0.001). The trend remained the same for jailing struts, although statistically insignificant (TASS: 10.85 +/- 13.12 vs. 13.64 +/- 14.48 Pa, p = 0.328). For 2-year follow-up, a total of 66 sub-regions were analysed. Neointimal hyperplasia area (NTA) was negatively correlated with TASS in core-segments (rho = - 0.389, p = 0.037) and positively correlated with plaque arc degree in non-core segments (rho = 0.387, p = 0.018). Slightly stronger correlations with NTA were observed when combining TASS and plaque arc degree in both core segments (rho = - 0.412, p = 0.026) and non-core segments (rho = - 0.395, p = 0.015). Hemodynamic microenvironment and baseline plaque characteristics may regulate neointimal response after BRS implantation in bifurcation. These findings underline the combined role of plaque characteristics and local hemodynamics in vessel healing after stent implantation. Show less
Purpose: Improve mapping and registration of longitudinal view on histopathology vessels in a three-dimensional alignment procedure for postmortem quantitative coronary plaque analyses. This new... Show morePurpose: Improve mapping and registration of longitudinal view on histopathology vessels in a three-dimensional alignment procedure for postmortem quantitative coronary plaque analyses. This new procedure is applied and results shown using calcified coronary plaque analyses within post-mortem computed tomography angiography (PMCTA), optical coherence tomography (OCT) and the gold standard of histopathology.Results: In total, 338 annotated histopathology images were included, 166 PMCTA transversal images and 285 OCT images were aligned in the comparison. The results from the comparison using the alignment procedure showed overall that the calcified plaques seem to be overestimated by PMCTA and underestimated by OCT.Conclusions: The 3D fusion approach, aligning the images of PMCTA, OCT and histopathology as gold standard allowed for a slice-based comparison of the different modalities. The results showed that PMCTA overestimates the calcified plaques while OCT underestimates these, compared to histopathology. (C) 2018 Elsevier Inc. All rights reserved. Show less
