Journal of the American Heart Association, Jan 22, 2017
Data are limited regarding outcomes of deferred lesions in patients with angiographically insigni... more Data are limited regarding outcomes of deferred lesions in patients with angiographically insignificant stenosis but low fractional flow reserve (FFR). We investigated the natural history of angiographically insignificant stenosis with low FFR among patients who underwent routine 3-vessel FFR measurement. From December 2011 to March 2014, 1136 patients with 3298 vessels underwent routine 3-vessel FFR measurement (3V FFR-FRIENDS study, ClinicalTrials.gov identifier NCT01621438), and this study analyzed the 2-year clinical outcomes of 1024 patients with 2124 lesions with angiographically insignificant stenosis (percentage of diameter stenosis <50%), in which revascularization was deferred. All lesions were classified according to FFR values, using a cutoff of 0.80 (high FFR >0.80 versus low FFR ≤0.80). The primary end point was outcome of major adverse cardiovascular events (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) at 2 years. M...
Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarctio... more Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarction, paradoxically causes a wide variety of injuries. The opening of the mitochondrial permeability pore and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. Objectives: Necrosis, the main mechanism of cell death during I/R injury to the myocardium, is an uncontrolled cell death, a pathologic condition accompanying inflammatory responses. We aimed to examine the protective role of this novel necrosis inhibitor against myocardial I/R injury using in vitro and in vivo models through anti-necrosis pathway. Methods and Results: Rat cardiomyocytes were exposed to hypoxia-reoxygenation injury after pretreatment with dimethyl sulfoxide (vehicle), necrosis inhibitor (NecX), antioxidant (vitamin C) or apoptosis inhibitor (Z-VAD-fmk). NecX-treated cells, compared with vehicle, showed fewer necrosis (Annexin-V/PI) (13.5±1.9% versus 44.1±3.1%; P=0.049) and more viable cells (...
Objectives: We investigated the risk factors for contrast-induced acute kidney injury (CIAKI) aft... more Objectives: We investigated the risk factors for contrast-induced acute kidney injury (CIAKI) after coronary angiography (CAG) in patients with acute heart failure (AHF), especially with regard to the volume status. Background: Heart failure is a well-known risk factor for CIAKI after CAG. In HF patients, renal perfusion decreases with systemic congestion. Thus, the standard prevention strategy with isotonic solution infusion may be inappropriate while decongestion may be beneficiary in AHF patients undergoing CAG. Deviation from dry body weight suggests imbalanced volume status. Methods: A total of 199 AHF patients who underwent CAG were eligible for the analysis. Absolute deviation of body weight (
Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically cau... more Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically causes a wide variety of injuries. Opening of mitochondrial permeability transition pore (mPTP) and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. We aimed to investigate the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial I/R injury, using in vitro and in vivo models. Methods and Results: In H9C2 rat cardiomyoblasts exposed to hypoxia-reoxygenation stress, the main mechanism of cell death was not apoptosis but necrosis, which was prevented mainly by NecX, the necrosis inhibitor, but not by Z-VAD-fmk, the apoptosis inhibitor. The protective effect of NecX was based on its potent ROS scavenging activity, especially on mitochondrial ROS which is one of the major inducers of mPTP opening. NecX preserved mitochondrial membrane potential, mitochondrial structure, through prevention of Ca 2+ influx and inhibition of the opening of mPTP...
Objective: The optimal treatment option for in-stent restenosis (ISR) is not established. We perf... more Objective: The optimal treatment option for in-stent restenosis (ISR) is not established. We performed a Bayesian network meta-analysis comparing the efficacy and safety of drug-eluting balloon (DEB), drug-eluting stent (DES) or plain old balloon angioplasty (POBA) for treatment of ISR. Design: Systemic review and Bayesian network meta-analysis using random-effects model. The primary outcome was target lesion revascularization (TLR). The secondary outcomes were myocardial infarction (MI), all-cause mortality or major adverse cardiovascular events (MACE). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. Data Sources: PubMed, EMBASE, BioMed Central, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, conference proceedings through February 2014. Eligibility Criteria for Selecting Studies: Randomized controlled trials (RCTs) comparing DEB, DES, or POBA for treatment of ISR. Results: This analysis included 2,059 patie...
ABSTRACTConvolutional neural networks (CNNs) are revolutionizing digital pathology by enabling ma... more ABSTRACTConvolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture), which we show can be construed as abstract morphological genes (“mones”) with strong independent associations to biological phenotypes. We observe that many mones are specific to individual cancer types, while others are found in multiple cancers especially from related tissue types. We also observe...
Background: Understanding of biological processes associated with irAEs for patients treated with... more Background: Understanding of biological processes associated with irAEs for patients treated with immune checkpoint inhibitors (ICI) is limited. We used serum-based, proteomic scores at baseline and after treatment initiation to explore mechanisms of irAEs for patients with non-small cell lung cancer (NSCLC) treated with ICI. Methods: Under an ongoing clinical protocol, 43 patients with advanced NSCLC were consented and serum samples were prospectively collected at two timepoints: baseline and approximately 3 weeks after treatment initiation with ICI (median 22 [IQR, 21 - 26] days). Samples were analyzed, blinded to clinical data, using MALDI-ToF mass spectrometry. Protein Set Enrichment Analysis (PSEA) approach applied to mass-spectral data was used to assign biological scores characterizing activation of 10 processes of interest (e.g., Type 1 immunity, complement, interferon (IFN)-gamma). irAEs after initiation of ICI with or without chemotherapy were classified per standard definitions. Patients were classified into two groups based on irAEs of any grade: irAE positive and negative. Results: Of the 43 participants, 28 received ICI with chemotherapy and 15 received monotherapy. 18 of 43 patients (42%) were determined to have irAEs. These included the following: 9 pneumonitis, 3 thyroiditis, 3 adrenal insufficiency, 1 arthritis, 1 flare of pre-existing psoriasis, 1 mucositis, 1 colitis, 1 myocarditis, and 1 hepatitis (2 patients had both thyroiditis and adrenal insufficiency, 1 patient had both mucositis and pneumonitis). The median timeframe between treatment initiation and development of irAEs was 105 days [IQR, 42 - 169 days]. PSEA scores measured at 3 weeks after initiation of systemic therapy showed significant differences between irAE positive and negative groups in the following processes: extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance (P Conclusions: Our findings demonstrate that serum-based, proteomic scores can provide insight into understanding early mechanisms for the development of irAEs in patients treated with ICI. In particular, we identified several mechanisms associated with the development of irAEs, including extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance. These associations were not present at baseline and were only observed after treatment initiation, suggesting that early changes in the blood may provide insight into prediction of irAEs. Citation Format: Andrew A. Davis, Jonghanne Park, Leeseul Kim, Gahyun Gim, Wade T. Iams, Michael S. Oh, Robert W. Lentz, Heinrich Roder, Joanna Roder, Senait Asmellash, Lelia Net, Julia Grigorieva, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae. Serum proteomic scores for understanding the mechanisms of immune-related adverse events (irAEs) in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5527.
Background: Lung cancer has the highest mortality rate among tumor entities in the United States.... more Background: Lung cancer has the highest mortality rate among tumor entities in the United States. Patients with lung cancer may require transfusions due to blood loss during surgery or bone marrow suppression caused by chemoradiation. Despite common use in practice, however, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. There have been long-standing concerns on the associated risk, including possible contamination by undetected malignant cells. The concept of transfusion-related immunomodulation (TRIM) has also been highlighted, which hypothesizes that transfusions may suppress the anti-tumor immune surveillance and promote growth of cancer cells. In spite of these concerns, scholarly efforts elucidating the relationship between transfusions and cancer recurrence have focused primarily on other cancers such as colorectal cancer. We thus performed an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients. Methods: We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to 11/28/2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I2 test. Publication bias was explored via funnel plot and trim-and-fill analyses. Results: We identified 843 citations initially and four studies were added after reviewing references of the searched articles. By assessing titles and abstracts, we excluded 393 duplicates and 414 irrelevant articles. 16 studies were removed given that they were review or correspondence articles or lacked the outcome of interest. As a result, 24 cohort studies with 13,036 patients (3,098 cases and 9,938 controls) were included for meta-analysis. Among these records, 23 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.36, 95% CI=1.14-1.62, P=0.0005, I2=0%) and DFS (HR=1.46, 95% CI=1.16-1.84, P=0.0013, I2=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI=1.07-1.48, P=0.0052; DFS: HR=1.36, 95% CI=1.10-1.69, P=0.0053). Conclusion: Blood transfusions were associated with decreased survival of lung cancer patients. Citation Format: Sukjoo Cho, Jonghanne Park, Misuk Lee, Dongyup Lee, Horyun Choi, Gahyun Gim, Leeseul Kim, Cyra Y. Kang, Young Kwang Chae. Blood transfusions may adversely affect survival outcomes of patients with lung cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5791.
3120 Background: Discovery of predictive biomarker to enrich the responder of immune checkpoint i... more 3120 Background: Discovery of predictive biomarker to enrich the responder of immune checkpoint inhibitor (ICI) in PD-L1-low ( < 50%) non-small cell lung cancer (NSCLC) is still challenging. Recent study showed that loss of heterozygosity (LOH) of HLA led to immune evasion. In the current study, we hypothesized that 3 immune phenotype (3IP): inflamed, excluded and desert would be reliably classified by deep-learning algorithm of H&E image, called Lunit-SCOPE, which would dictate the responder in PD-L1-low NSCLC patients and discover a unique resistance pathway in excluded phenotype. Methods: Lunit-SCOPE was trained with 1,824 H&E Whole-Slide Image (WSI) of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches (~10 high-power fields) which was classified for 3IP, based on both quantity and localization of immune cells. The 3IP was trained and optimized by considering clinical outcome of 119 NSCLC patients with PD-(L)1 inhibitor (training cohort, patches = 25,897), ...
Background Resistive reserve ratio is a thermodilution‐based index which integrates both coronary... more Background Resistive reserve ratio is a thermodilution‐based index which integrates both coronary flow and pressure. Resistive reserve ratio represents the vasodilatory capacity of interrogated vessels including both epicardial coronary artery and microvascular circulation. We evaluated the prognostic potential of resistive reserve ratio compared with pressure‐derived index (fractional flow reserve [ FFR ]) or flow‐derived index (coronary flow reserve [ CFR ]). Methods and Results A total of 1245 patients underwent coronary pressure and flow measurement using pressure‐temperature wire. Resistive reserve ratio was calculated by CFR adjusted using the ratio between resting and hyperemic distal coronary pressure ([resting mean transit time/hyperemic mean transit time]×[resting distal coronary pressure/hyperemic distal coronary pressure]). Clinical outcome was assessed by patient‐oriented composite outcome ( POCO ), a composite of any death, myocardial infarction, and revascularization ...
Background Sex‐specific differences may influence prognosis after deferred revascularization foll... more Background Sex‐specific differences may influence prognosis after deferred revascularization following fractional flow reserve ( FFR ) measurement. This study sought to investigate the sex differences in long‐term prognosis of patients with deferred revascularization following FFR assessment. Methods and Results A total of 879 patients (879 vessels) with deferred revascularization with FFR >0.75 who underwent FFR and coronary flow reserve measurements were enrolled from 3 countries (Korea, Japan, and Spain). Long‐term outcomes were assessed in 649 men and 230 women by the patient‐oriented composite outcome ( POCO , a composite of any death, any myocardial infarction, and any revascularization). We applied inverse‐probability weighting based on propensity scores to account for differences at baseline between women and men (age, hyperlipidemia, diabetes mellitus, diameter stenosis, lesion length, multivessel disease, FFR , coronary flow reserve. The median follow‐up duration was 18...
BACKGROUND The prognostic impact of diabetes mellitus (DM) with or without coronary microvascular... more BACKGROUND The prognostic impact of diabetes mellitus (DM) with or without coronary microvascular dysfunction (CMD) in patients undergoing fractional flow reserve (FFR)-guided revascularization has not been clarified. We sought to investigate the clinical outcomes of patients undergoing FFR-guided revascularization according to the existence of DM and CMD. METHODS A total of 283 patients with available FFR data as well as index of microcirculatory resistance (IMR) were selected from the 3 V FFR-FRIENDS study. CMD was defined as an IMR ≥25U. Patients were grouped according to the presence of DM and CMD into group A (DM-, CMD-), group B (DM-, CMD+), group C (DM+, CMD-), and group D (DM+, CMD+). The primary outcome was a major adverse cardiac event (MACE, a composite of myocardial infarction, ischemia-driven revascularization, and cardiac death) at 2 years. RESULTS DM patients displayed a notably higher risk of MACEs in comparison with non-DM patients (HR 4.88, 95% CI 1.54-15.48, p = 0.003). MACEs at 2 years among the four groups were 2.2%, 2.0%, 7.0%, and 18.5%, respectively. Group D exhibited a significantly higher risk of MACEs as compared to group A (HR 8.98, 95% CI 2.15-37.41, p = 0.003). Multivariable regression analysis showed that the presence of DM and CMD was an independent predictor of a 2-year MACE (HR 11.24, 95% CI 2.53-49.88, p = 0.002), and integrating CMD into a model with DM increased discriminant ability (C-index 0.683 vs. 0.710, p = 0.010, integrated discrimination improvement 0.015, p = 0.040). CONCLUSION Among the patients undergoing FFR-guided revascularization, those with DM and CMD were correlated with an augmented risk of MACEs. Integration of CMD improved risk stratification in predicting the occurrence of a MACE.
OBJECTIVES The study evaluated the physiologic characteristics of discordant lesions between inst... more OBJECTIVES The study evaluated the physiologic characteristics of discordant lesions between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) and the prognosis at 5 years. BACKGROUND FFR or iFR have been standard methods for assessing the functional significance of coronary artery stenosis. However, limited data exist about the physiologic characteristics of discordant lesions and the prognostic implications resulting from these lesions. METHODS A total of 840 vessels from 596 patients were classified according to iFR and FFR; high iFR-high FFR (n = 580), low iFR-high FFR (n = 40), high iFR-low FFR (n = 69), and low iFR-low FFR (n = 128) groups, which were compared with a control group (n = 23). The differences in coronary circulatory indices including the coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and resistance reserve ratio (RRR) (resting distal arterial pressure × mean transit time / hyperemic distal arterial pressure × hyperemic mean transit time), which reflect the vasodilatory capacity of coronary microcirculation, were compared. Patient-oriented composite outcomes (POCO) at 5 years including all-cause death, any myocardial infarction, and any revascularization were compared among patients with deferred lesions. RESULTS In the low iFR-high FFR group, CFR, RRR, and IMR measurements were similar to the low iFR-low FFR group: CFR 2.71 versus 2.43 (p = 0.144), RRR 3.36 versus 3.68 (p = 0.241), and IMR 18.51 versus 17.38 (p = 0.476). In the high iFR-low FFR group, the CFR, RRR, and IMR measurements were similar to the control group: CFR 2.95 versus 3.29 (p = 0.160), RRR 4.28 versus 4.00 (p = 0.414), and IMR 17.44 versus 17.06 (p = 0.818). Among the 4 groups, classified by iFR and FFR, CFR and RRR were all significantly different, except for IMR. However, there were no significant differences in the rates of POCO, regardless of discordance between the iFR and FFR. Only the low iFR-low FFR group had a higher POCO rate compared with the high iFR-high FFR group (adjusted hazard ratio: 2.46; 95% confidence interval: 1.17 to 5.16; p = 0.018). CONCLUSIONS Differences in coronary circulatory function were found, especially in the vasodilatory capacity between the low iFR-high FFR and high iFR-low FFR groups. FFR-iFR discordance was not related to an increased risk of POCO among patients with deferred lesions at 5 years. (Clinical, Physiological and Prognostic Implication of Microvascular Status;NCT02186093; Physiologic Assessment of Microvascular Function in Heart Transplant Patients; NCT02798731).
Background In patients with ST‐segment–elevation myocardial infarction, timely reperfusion therap... more Background In patients with ST‐segment–elevation myocardial infarction, timely reperfusion therapy with door‐to‐balloon (D2B) time <90 minutes is recommended by the current guidelines. However, whether further shortening of symptom onset‐to‐door (O2D) time or D2B time would enhance survival of patients with ST‐segment–elevation myocardial infarction remains unclear. Therefore, the current study aimed to evaluate the prognostic impact of O2D or D2B time in patients with ST‐segment–elevation myocardial infarction who underwent primary percutaneous coronary intervention. Methods and Results We analyzed 5243 patients with ST‐segment–elevation myocardial infarction were treated at 20 tertiary hospitals capable of primary percutaneous coronary intervention in Korea. The association between O2D or D2B time with all‐cause mortality at 1 year was evaluated. The median O2D time was 2.0 hours, and the median D2B time was 59 minutes. A total of 92.2% of the total population showed D2B time ≤...
Background Quantitative flow ratio ( QFR ) has a high diagnostic accuracy in assessing functional... more Background Quantitative flow ratio ( QFR ) has a high diagnostic accuracy in assessing functional stenoses relevance, as judged by fractional flow reserve ( FFR ). However, its diagnostic performance has not been thoroughly evaluated using instantaneous wave‐free ratio ( iFR ) or coronary flow reserve as the reference standard. This study sought to evaluate the diagnostic performance of QFR using other reference standards beyond FFR . Methods and Results We analyzed 182 patients (253 vessels) with stable ischemic heart disease and 82 patients (105 nonculprit vessels) with acute myocardial infarction in whom coronary stenoses were assessed with FFR , iFR, and coronary flow reserve. Contrast QFR analysis of interrogated vessels was performed in blinded fashion by a core laboratory, and its diagnostic performance was evaluated with respect to the other invasive physiological indices. Mean percentage diameter stenosis, FFR , iFR , coronary flow reserve, and QFR were 53.1±19.0%, 0.80±0.1...
Journal of the American Heart Association, Jan 22, 2017
Data are limited regarding outcomes of deferred lesions in patients with angiographically insigni... more Data are limited regarding outcomes of deferred lesions in patients with angiographically insignificant stenosis but low fractional flow reserve (FFR). We investigated the natural history of angiographically insignificant stenosis with low FFR among patients who underwent routine 3-vessel FFR measurement. From December 2011 to March 2014, 1136 patients with 3298 vessels underwent routine 3-vessel FFR measurement (3V FFR-FRIENDS study, ClinicalTrials.gov identifier NCT01621438), and this study analyzed the 2-year clinical outcomes of 1024 patients with 2124 lesions with angiographically insignificant stenosis (percentage of diameter stenosis <50%), in which revascularization was deferred. All lesions were classified according to FFR values, using a cutoff of 0.80 (high FFR >0.80 versus low FFR ≤0.80). The primary end point was outcome of major adverse cardiovascular events (a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization) at 2 years. M...
Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarctio... more Background: Reperfusion, although essential for salvage of myocardium in the myocardial infarction, paradoxically causes a wide variety of injuries. The opening of the mitochondrial permeability pore and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. Objectives: Necrosis, the main mechanism of cell death during I/R injury to the myocardium, is an uncontrolled cell death, a pathologic condition accompanying inflammatory responses. We aimed to examine the protective role of this novel necrosis inhibitor against myocardial I/R injury using in vitro and in vivo models through anti-necrosis pathway. Methods and Results: Rat cardiomyocytes were exposed to hypoxia-reoxygenation injury after pretreatment with dimethyl sulfoxide (vehicle), necrosis inhibitor (NecX), antioxidant (vitamin C) or apoptosis inhibitor (Z-VAD-fmk). NecX-treated cells, compared with vehicle, showed fewer necrosis (Annexin-V/PI) (13.5±1.9% versus 44.1±3.1%; P=0.049) and more viable cells (...
Objectives: We investigated the risk factors for contrast-induced acute kidney injury (CIAKI) aft... more Objectives: We investigated the risk factors for contrast-induced acute kidney injury (CIAKI) after coronary angiography (CAG) in patients with acute heart failure (AHF), especially with regard to the volume status. Background: Heart failure is a well-known risk factor for CIAKI after CAG. In HF patients, renal perfusion decreases with systemic congestion. Thus, the standard prevention strategy with isotonic solution infusion may be inappropriate while decongestion may be beneficiary in AHF patients undergoing CAG. Deviation from dry body weight suggests imbalanced volume status. Methods: A total of 199 AHF patients who underwent CAG were eligible for the analysis. Absolute deviation of body weight (
Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically cau... more Background: Reperfusion, although essential for salvage of ischemic myocardium, paradoxically causes a wide variety of injuries. Opening of mitochondrial permeability transition pore (mPTP) and Ca 2+ overload contribute to myocardial ischemia-reperfusion (I/R) injury. We aimed to investigate the protective role of a novel necrosis inhibitor (NecroX-7; NecX) against myocardial I/R injury, using in vitro and in vivo models. Methods and Results: In H9C2 rat cardiomyoblasts exposed to hypoxia-reoxygenation stress, the main mechanism of cell death was not apoptosis but necrosis, which was prevented mainly by NecX, the necrosis inhibitor, but not by Z-VAD-fmk, the apoptosis inhibitor. The protective effect of NecX was based on its potent ROS scavenging activity, especially on mitochondrial ROS which is one of the major inducers of mPTP opening. NecX preserved mitochondrial membrane potential, mitochondrial structure, through prevention of Ca 2+ influx and inhibition of the opening of mPTP...
Objective: The optimal treatment option for in-stent restenosis (ISR) is not established. We perf... more Objective: The optimal treatment option for in-stent restenosis (ISR) is not established. We performed a Bayesian network meta-analysis comparing the efficacy and safety of drug-eluting balloon (DEB), drug-eluting stent (DES) or plain old balloon angioplasty (POBA) for treatment of ISR. Design: Systemic review and Bayesian network meta-analysis using random-effects model. The primary outcome was target lesion revascularization (TLR). The secondary outcomes were myocardial infarction (MI), all-cause mortality or major adverse cardiovascular events (MACE). The pairwise posterior median odds ratio (OR) with 95% credible interval (CrI) was the effect measure. Data Sources: PubMed, EMBASE, BioMed Central, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, conference proceedings through February 2014. Eligibility Criteria for Selecting Studies: Randomized controlled trials (RCTs) comparing DEB, DES, or POBA for treatment of ISR. Results: This analysis included 2,059 patie...
ABSTRACTConvolutional neural networks (CNNs) are revolutionizing digital pathology by enabling ma... more ABSTRACTConvolutional neural networks (CNNs) are revolutionizing digital pathology by enabling machine learning-based classification of a variety of phenotypes from hematoxylin and eosin (H&E) whole slide images (WSIs), but the interpretation of CNNs remains difficult. Most studies have considered interpretability in a post hoc fashion, e.g. by presenting example regions with strongly predicted class labels. However, such an approach does not explain the biological features that contribute to correct predictions. To address this problem, here we investigate the interpretability of H&E-derived CNN features (the feature weights in the final layer of a transfer-learning-based architecture), which we show can be construed as abstract morphological genes (“mones”) with strong independent associations to biological phenotypes. We observe that many mones are specific to individual cancer types, while others are found in multiple cancers especially from related tissue types. We also observe...
Background: Understanding of biological processes associated with irAEs for patients treated with... more Background: Understanding of biological processes associated with irAEs for patients treated with immune checkpoint inhibitors (ICI) is limited. We used serum-based, proteomic scores at baseline and after treatment initiation to explore mechanisms of irAEs for patients with non-small cell lung cancer (NSCLC) treated with ICI. Methods: Under an ongoing clinical protocol, 43 patients with advanced NSCLC were consented and serum samples were prospectively collected at two timepoints: baseline and approximately 3 weeks after treatment initiation with ICI (median 22 [IQR, 21 - 26] days). Samples were analyzed, blinded to clinical data, using MALDI-ToF mass spectrometry. Protein Set Enrichment Analysis (PSEA) approach applied to mass-spectral data was used to assign biological scores characterizing activation of 10 processes of interest (e.g., Type 1 immunity, complement, interferon (IFN)-gamma). irAEs after initiation of ICI with or without chemotherapy were classified per standard definitions. Patients were classified into two groups based on irAEs of any grade: irAE positive and negative. Results: Of the 43 participants, 28 received ICI with chemotherapy and 15 received monotherapy. 18 of 43 patients (42%) were determined to have irAEs. These included the following: 9 pneumonitis, 3 thyroiditis, 3 adrenal insufficiency, 1 arthritis, 1 flare of pre-existing psoriasis, 1 mucositis, 1 colitis, 1 myocarditis, and 1 hepatitis (2 patients had both thyroiditis and adrenal insufficiency, 1 patient had both mucositis and pneumonitis). The median timeframe between treatment initiation and development of irAEs was 105 days [IQR, 42 - 169 days]. PSEA scores measured at 3 weeks after initiation of systemic therapy showed significant differences between irAE positive and negative groups in the following processes: extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance (P Conclusions: Our findings demonstrate that serum-based, proteomic scores can provide insight into understanding early mechanisms for the development of irAEs in patients treated with ICI. In particular, we identified several mechanisms associated with the development of irAEs, including extracellular matrix remodeling, complement activation, IFN-gamma signaling, and immune tolerance. These associations were not present at baseline and were only observed after treatment initiation, suggesting that early changes in the blood may provide insight into prediction of irAEs. Citation Format: Andrew A. Davis, Jonghanne Park, Leeseul Kim, Gahyun Gim, Wade T. Iams, Michael S. Oh, Robert W. Lentz, Heinrich Roder, Joanna Roder, Senait Asmellash, Lelia Net, Julia Grigorieva, Nisha Mohindra, Victoria Villaflor, Young Kwang Chae. Serum proteomic scores for understanding the mechanisms of immune-related adverse events (irAEs) in non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5527.
Background: Lung cancer has the highest mortality rate among tumor entities in the United States.... more Background: Lung cancer has the highest mortality rate among tumor entities in the United States. Patients with lung cancer may require transfusions due to blood loss during surgery or bone marrow suppression caused by chemoradiation. Despite common use in practice, however, the impact of blood transfusions on prognosis among patients with lung cancer remains unclear. There have been long-standing concerns on the associated risk, including possible contamination by undetected malignant cells. The concept of transfusion-related immunomodulation (TRIM) has also been highlighted, which hypothesizes that transfusions may suppress the anti-tumor immune surveillance and promote growth of cancer cells. In spite of these concerns, scholarly efforts elucidating the relationship between transfusions and cancer recurrence have focused primarily on other cancers such as colorectal cancer. We thus performed an updated systematic review and meta-analysis to evaluate the influence of blood transfusions on survival outcomes of lung cancer patients. Methods: We searched PubMed, Embase, Cochrane Library, and Ovid MEDLINE for publications illustrating the association between blood transfusions and prognosis among people with lung cancer from inception to 11/28/2019. Overall survival (OS) and disease-free survival (DFS) were the outcomes of interest. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were computed using the random-effects model. Study heterogeneity was evaluated with the I2 test. Publication bias was explored via funnel plot and trim-and-fill analyses. Results: We identified 843 citations initially and four studies were added after reviewing references of the searched articles. By assessing titles and abstracts, we excluded 393 duplicates and 414 irrelevant articles. 16 studies were removed given that they were review or correspondence articles or lacked the outcome of interest. As a result, 24 cohort studies with 13,036 patients (3,098 cases and 9,938 controls) were included for meta-analysis. Among these records, 23 studies investigated the effect of perioperative transfusions, while one examined that of transfusions during chemotherapy. Two studies suggested the possible dose-dependent effect in accordance with the number of transfused units. In pooled analyses, blood transfusions deleteriously influenced both OS (HR=1.36, 95% CI=1.14-1.62, P=0.0005, I2=0%) and DFS (HR=1.46, 95% CI=1.16-1.84, P=0.0013, I2=0%) of people with lung cancer. No evidence of significant publication bias was detected in funnel plot and trim-and-fill analyses (OS: HR=1.26, 95% CI=1.07-1.48, P=0.0052; DFS: HR=1.36, 95% CI=1.10-1.69, P=0.0053). Conclusion: Blood transfusions were associated with decreased survival of lung cancer patients. Citation Format: Sukjoo Cho, Jonghanne Park, Misuk Lee, Dongyup Lee, Horyun Choi, Gahyun Gim, Leeseul Kim, Cyra Y. Kang, Young Kwang Chae. Blood transfusions may adversely affect survival outcomes of patients with lung cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5791.
3120 Background: Discovery of predictive biomarker to enrich the responder of immune checkpoint i... more 3120 Background: Discovery of predictive biomarker to enrich the responder of immune checkpoint inhibitor (ICI) in PD-L1-low ( < 50%) non-small cell lung cancer (NSCLC) is still challenging. Recent study showed that loss of heterozygosity (LOH) of HLA led to immune evasion. In the current study, we hypothesized that 3 immune phenotype (3IP): inflamed, excluded and desert would be reliably classified by deep-learning algorithm of H&E image, called Lunit-SCOPE, which would dictate the responder in PD-L1-low NSCLC patients and discover a unique resistance pathway in excluded phenotype. Methods: Lunit-SCOPE was trained with 1,824 H&E Whole-Slide Image (WSI) of NSCLC from Samsung Medical Center (SMC). WSI was divided into patches (~10 high-power fields) which was classified for 3IP, based on both quantity and localization of immune cells. The 3IP was trained and optimized by considering clinical outcome of 119 NSCLC patients with PD-(L)1 inhibitor (training cohort, patches = 25,897), ...
Background Resistive reserve ratio is a thermodilution‐based index which integrates both coronary... more Background Resistive reserve ratio is a thermodilution‐based index which integrates both coronary flow and pressure. Resistive reserve ratio represents the vasodilatory capacity of interrogated vessels including both epicardial coronary artery and microvascular circulation. We evaluated the prognostic potential of resistive reserve ratio compared with pressure‐derived index (fractional flow reserve [ FFR ]) or flow‐derived index (coronary flow reserve [ CFR ]). Methods and Results A total of 1245 patients underwent coronary pressure and flow measurement using pressure‐temperature wire. Resistive reserve ratio was calculated by CFR adjusted using the ratio between resting and hyperemic distal coronary pressure ([resting mean transit time/hyperemic mean transit time]×[resting distal coronary pressure/hyperemic distal coronary pressure]). Clinical outcome was assessed by patient‐oriented composite outcome ( POCO ), a composite of any death, myocardial infarction, and revascularization ...
Background Sex‐specific differences may influence prognosis after deferred revascularization foll... more Background Sex‐specific differences may influence prognosis after deferred revascularization following fractional flow reserve ( FFR ) measurement. This study sought to investigate the sex differences in long‐term prognosis of patients with deferred revascularization following FFR assessment. Methods and Results A total of 879 patients (879 vessels) with deferred revascularization with FFR >0.75 who underwent FFR and coronary flow reserve measurements were enrolled from 3 countries (Korea, Japan, and Spain). Long‐term outcomes were assessed in 649 men and 230 women by the patient‐oriented composite outcome ( POCO , a composite of any death, any myocardial infarction, and any revascularization). We applied inverse‐probability weighting based on propensity scores to account for differences at baseline between women and men (age, hyperlipidemia, diabetes mellitus, diameter stenosis, lesion length, multivessel disease, FFR , coronary flow reserve. The median follow‐up duration was 18...
BACKGROUND The prognostic impact of diabetes mellitus (DM) with or without coronary microvascular... more BACKGROUND The prognostic impact of diabetes mellitus (DM) with or without coronary microvascular dysfunction (CMD) in patients undergoing fractional flow reserve (FFR)-guided revascularization has not been clarified. We sought to investigate the clinical outcomes of patients undergoing FFR-guided revascularization according to the existence of DM and CMD. METHODS A total of 283 patients with available FFR data as well as index of microcirculatory resistance (IMR) were selected from the 3 V FFR-FRIENDS study. CMD was defined as an IMR ≥25U. Patients were grouped according to the presence of DM and CMD into group A (DM-, CMD-), group B (DM-, CMD+), group C (DM+, CMD-), and group D (DM+, CMD+). The primary outcome was a major adverse cardiac event (MACE, a composite of myocardial infarction, ischemia-driven revascularization, and cardiac death) at 2 years. RESULTS DM patients displayed a notably higher risk of MACEs in comparison with non-DM patients (HR 4.88, 95% CI 1.54-15.48, p = 0.003). MACEs at 2 years among the four groups were 2.2%, 2.0%, 7.0%, and 18.5%, respectively. Group D exhibited a significantly higher risk of MACEs as compared to group A (HR 8.98, 95% CI 2.15-37.41, p = 0.003). Multivariable regression analysis showed that the presence of DM and CMD was an independent predictor of a 2-year MACE (HR 11.24, 95% CI 2.53-49.88, p = 0.002), and integrating CMD into a model with DM increased discriminant ability (C-index 0.683 vs. 0.710, p = 0.010, integrated discrimination improvement 0.015, p = 0.040). CONCLUSION Among the patients undergoing FFR-guided revascularization, those with DM and CMD were correlated with an augmented risk of MACEs. Integration of CMD improved risk stratification in predicting the occurrence of a MACE.
OBJECTIVES The study evaluated the physiologic characteristics of discordant lesions between inst... more OBJECTIVES The study evaluated the physiologic characteristics of discordant lesions between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) and the prognosis at 5 years. BACKGROUND FFR or iFR have been standard methods for assessing the functional significance of coronary artery stenosis. However, limited data exist about the physiologic characteristics of discordant lesions and the prognostic implications resulting from these lesions. METHODS A total of 840 vessels from 596 patients were classified according to iFR and FFR; high iFR-high FFR (n = 580), low iFR-high FFR (n = 40), high iFR-low FFR (n = 69), and low iFR-low FFR (n = 128) groups, which were compared with a control group (n = 23). The differences in coronary circulatory indices including the coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and resistance reserve ratio (RRR) (resting distal arterial pressure × mean transit time / hyperemic distal arterial pressure × hyperemic mean transit time), which reflect the vasodilatory capacity of coronary microcirculation, were compared. Patient-oriented composite outcomes (POCO) at 5 years including all-cause death, any myocardial infarction, and any revascularization were compared among patients with deferred lesions. RESULTS In the low iFR-high FFR group, CFR, RRR, and IMR measurements were similar to the low iFR-low FFR group: CFR 2.71 versus 2.43 (p = 0.144), RRR 3.36 versus 3.68 (p = 0.241), and IMR 18.51 versus 17.38 (p = 0.476). In the high iFR-low FFR group, the CFR, RRR, and IMR measurements were similar to the control group: CFR 2.95 versus 3.29 (p = 0.160), RRR 4.28 versus 4.00 (p = 0.414), and IMR 17.44 versus 17.06 (p = 0.818). Among the 4 groups, classified by iFR and FFR, CFR and RRR were all significantly different, except for IMR. However, there were no significant differences in the rates of POCO, regardless of discordance between the iFR and FFR. Only the low iFR-low FFR group had a higher POCO rate compared with the high iFR-high FFR group (adjusted hazard ratio: 2.46; 95% confidence interval: 1.17 to 5.16; p = 0.018). CONCLUSIONS Differences in coronary circulatory function were found, especially in the vasodilatory capacity between the low iFR-high FFR and high iFR-low FFR groups. FFR-iFR discordance was not related to an increased risk of POCO among patients with deferred lesions at 5 years. (Clinical, Physiological and Prognostic Implication of Microvascular Status;NCT02186093; Physiologic Assessment of Microvascular Function in Heart Transplant Patients; NCT02798731).
Background In patients with ST‐segment–elevation myocardial infarction, timely reperfusion therap... more Background In patients with ST‐segment–elevation myocardial infarction, timely reperfusion therapy with door‐to‐balloon (D2B) time <90 minutes is recommended by the current guidelines. However, whether further shortening of symptom onset‐to‐door (O2D) time or D2B time would enhance survival of patients with ST‐segment–elevation myocardial infarction remains unclear. Therefore, the current study aimed to evaluate the prognostic impact of O2D or D2B time in patients with ST‐segment–elevation myocardial infarction who underwent primary percutaneous coronary intervention. Methods and Results We analyzed 5243 patients with ST‐segment–elevation myocardial infarction were treated at 20 tertiary hospitals capable of primary percutaneous coronary intervention in Korea. The association between O2D or D2B time with all‐cause mortality at 1 year was evaluated. The median O2D time was 2.0 hours, and the median D2B time was 59 minutes. A total of 92.2% of the total population showed D2B time ≤...
Background Quantitative flow ratio ( QFR ) has a high diagnostic accuracy in assessing functional... more Background Quantitative flow ratio ( QFR ) has a high diagnostic accuracy in assessing functional stenoses relevance, as judged by fractional flow reserve ( FFR ). However, its diagnostic performance has not been thoroughly evaluated using instantaneous wave‐free ratio ( iFR ) or coronary flow reserve as the reference standard. This study sought to evaluate the diagnostic performance of QFR using other reference standards beyond FFR . Methods and Results We analyzed 182 patients (253 vessels) with stable ischemic heart disease and 82 patients (105 nonculprit vessels) with acute myocardial infarction in whom coronary stenoses were assessed with FFR , iFR, and coronary flow reserve. Contrast QFR analysis of interrogated vessels was performed in blinded fashion by a core laboratory, and its diagnostic performance was evaluated with respect to the other invasive physiological indices. Mean percentage diameter stenosis, FFR , iFR , coronary flow reserve, and QFR were 53.1±19.0%, 0.80±0.1...
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