Orofacial fascial space abscess disguised as temporomandibular disorder: a report of 3 cases and literature review.

Fascial space abscess is a condition in which infections spread into fascial spaces. It is a severe and life-threatening disease unless treated at an early stage. Due to the similarity of clinical symptoms, fascial space abscesses in the orofacial area are often disguised as other diseases, such as temporomandibular disorder (TMD). In this case series, we report three cases of fascial space abscesses disguised as TMD. In all cases, patients complained of severely limited mouth opening and pain in the temporomandibular joint (TMJ) and masseter muscles, which led clinicians to diagnose them with TMD. After two patients showed facial swelling and the third complained of dyspnea, clinicians realized the possibility of an orofacial fascial space abscess. On further evaluation, all patients showed increased C-reactive protein in blood tests, and the location of the fascial space abscess was confirmed by enhanced computed tomography images. Moreover, all patients had suspicious sources of odontogenic infections in panoramic images, periapical abscess on maxillary molars and periodontal disease on maxillary and mandibular molars, which were not appropriately evaluated at the first visit. This case series emphasizes the need for clinicians to realize the possibility of orofacial fascial space abscesses based on: clinical symptoms of severely limited mouth opening (< 15 mm) with pain in the facial area, including TMJ or masseter muscle, and possible sources of infection such as odontogenic infection, other infectious lesions, trauma, or invasive treatments. These clinical insights will enable the early detection of fascial space abscesses.

The effect of donor against recipient one-way HLA mismatch on liver transplantation outcomes from a multicenter registry analysis.

Donor against recipient one-way Human leukocyte antigen (HLA) mismatch (D → R one-way HLA MM) seemed strongly associated with graft-versus-host disease (GVHD). The aim of this study is to investigate the relevance of D → R one-way HLA MM in outcome of liver transplantation (LT). We retrospectively analyzed 2670 patients in Korean Organ Transplantation Registry database between April 2014 and December 2020. The patients were categorized into two groups whether D → R one-way HLA MM or not and evaluated the outcomes of LT between the two groups. 18 patients were found to be D → R one-way HLA MM. The incidence of GVHD (0.3% vs. 22.2%, p < 0.001) and mortality rate (11.6% vs. 38.9%, p = 0.003) was much higher in D → R one-way HLA MM group. D → R one-way HLA MM at 3 loci was seemed to be strongly associated with the incidence of GVHD (OR 163.3, p < 0.001), and found to be the strongest risk factor for patient death (HR 12.75, p < 0.001). Patients with D → R one-way HLA MM at 3 loci showed significantly lower overall survival (p < 0.001) but there were no significant differences in rejection-free survival and death-censored graft survival. D → R one-way HLA MM at 3 loci not only affects the overall survival of LT patients but also the incidence of GVHD.

Outcomes and Risk Factors for Liver Transplantation Using graft-to-Recipient Weight Ratio Less than 0.8 Graft from Living Donors: Multicentric Cohort Study.

OBJECTIVE: To compare graft survival after LDLT in patients receiving GRWR<0.8 versus GRWR≥0.8 grafts and identify risk factors for graft loss using GRWR<0.8 grafts. SUMMARY BACKGROUND DATA: Favorable outcomes after living donor liver transplantation (LDLT) using graft-to-recipient weight ratio (GRWR)<0.8 grafts were recently reported; however, these results have not been validated using multicenter data. METHODS: This multicentric cohort study included 3450 LDLT patients. Graft survival was compared between 1:3 propensity score-matched groups and evaluated using various Cox models in the entire population. Risk factors for graft loss with GRWR<0.8 versus GRWR≥0.8 grafts were explored within various subgroups using interaction analyses, and outcomes were stratified according to the number of risk factors. RESULTS: In total, 368 patients (10.7%) received GRWR<0.8 grafts (GRWR<0.8 group), whereas 3082 (89.3%) received GRWR≥0.8 grafts (GRWR≥0.8 group). The 5-y graft survival rate was significantly lower with GRWR<0.8 grafts than with GRWR≥0.8 grafts (85.2% vs. 90.1%, P=0.013). Adjusted hazard ratio (HR) for graft loss using GRWR<0.8 grafts in the entire population was 1.66 (95% confidence interval [CI] 1.17-2.35, P=0.004). Risk factors exhibiting significant interactions with GRWR<0.8 for graft survival were age ≥60 y, MELD score ≥15, and male donor. When ≥2 risk factors were present, GRWR<0.8 grafts showed higher risk of graft loss compared to GRWR≥0.8 graft in LDLT (HR 2.98, 95% CI 1.79-4.88, P<0.001). CONCLUSIONS: GRWR<0.8 graft showed inferior graft survival than controls (85.2% vs. 90.1%), especially when ≥2 risk factors for graft loss (among age ≥60 y, MELD score ≥15, or male donor) were present.

Diagnostic Role of Bile Pigment Components in Biliary Tract Cancer.

Bile pigment, bilirubin, and biliverdin concentrations may change as a results of biliary tract cancer (BTC) altering the mechanisms of radical oxidation and heme breakdown. We explored whether changes in bile pigment components could help distinguish BTC from benign biliary illness by evaluating alterations in patients with BTC. We collected bile fluid from 15 patients with a common bile duct stone (CBD group) and 63 individuals with BTC (BTC group). We examined the bile fluid's bilirubin, biliverdin reductase (BVR), heme oxygenase (HO-1), and bacterial taxonomic abundance. Serum bilirubin levels had no impact on the amounts of bile HO-1, BVR, or bilirubin. In comparison to the control group, the BTC group had considerably higher amounts of HO-1, BVR, and bilirubin in the bile. The areas under the curve for the receiver operating characteristic curve analyses of the BVR and HO-1 were 0.832 (p<0.001) and 0.891 (p<0.001), respectively. Firmicutes was the most prevalent phylum in both CBD and BTC, according to a taxonomic abundance analysis, however the Firmicutes/Bacteroidetes ratio was substantially greater in the BTC group than in the CBD group. The findings of this study showed that, regardless of the existence of obstructive jaundice, biliary carcinogenesis impacts heme degradation and bile pigmentation, and that the bile pigment components HO-1, BVR, and bilirubin in bile fluid have a diagnostic significance in BTC. In tissue biopsies for the diagnosis of BTC, particularly for distinguishing BTC from benign biliary strictures, bile pigment components can be used as additional biomarkers.

Comparative Effectiveness of Long-Term Maintenance Beta-Blocker Therapy After Acute Myocardial Infarction in Stable, Optimally Treated Patients Undergoing Percutaneous Coronary Intervention.

Background The benefits of long-term maintenance beta-blocker (BB) therapy in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) have not been well established. Methods and Results Using the Korean nationwide registry, a total of 7159 patients with AMI treated with PCI who received BBs at discharge and were free from death or cardiovascular events for 3 months after PCI were included in the analysis. Patients were divided into 4 groups according to BB maintenance duration: <12 months, 12 to <24 months, 24 to <36 months, and ≥36 months. The primary outcome was the composite of all-cause death, recurrent MI, heart failure, or hospitalization for unstable angina. During a mean 5.0±2.8 years of follow-up, over half of patients with AMI (52.5%) continued BB therapy beyond 3 years following PCI. After propensity score matching and propensity score marginal mean weighting through stratification, a stepwise inverse correlation was noted between BB duration and risk of the primary outcome (<12 months: hazard ratio [HR], 2.19 [95% CI, 1.95-2.46]; 12 to <24 months: HR, 2.10 [95% CI, 1.81-2.43];, and 24 to <36 months: HR, 1.68 [95%CI, 1.45-1.94]; reference: ≥36 months). In a 3-year landmark analysis, BB use for <36 months was associated with an increased risk of the primary outcome (adjusted HR, 1.59 [95% CI, 1.37-1.85]) compared with BB use for ≥36 months. Conclusions Among stabilized patients with AMI following PCI, longer maintenance BB therapy, especially for >36 months, was associated with better clinical outcomes. These findings might imply that a better prognosis can be expected if patients with AMI maintain BB therapy for ≥36 months after PCI. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02806102.

Sphingosine-1-phosphate Treatment Improves Cryopreservation Efficiency in Human Mesenchymal Stem Cells.

The actin cytoskeleton plays a crucial role not only in maintaining cell shape and viability but also in homing/engraftment properties of mesenchymal stem cells (MSCs), a valuable source of cell therapy. Therefore, during the cryopreservation process of MSCs, protecting the actin cytoskeleton from the freezing/thawing stress is critical in maintaining their functionality and therapeutic potential. In this study, the safety and cryoprotective potential of sphingosine-1-phosphate (S1P), which has a stabilizing effect on actin cytoskeleton, on dental pulp-derived MSCs (DP-MSCs) was investigated. Our results demonstrated that S1P treatment did not adversely affect viability and stemness of DP-MSCs. Furthermore, S1P pretreatment enhanced cell viability and proliferation properties of post-freeze/thaw DP-MSCs, protecting them against damage to the actin cytoskeleton and adhesion ability as well. These findings suggest that a new cryopreservation method using S1P pretreatment can enhance the overall quality of cryopreserved MSCs by stabilizing the actin cytoskeleton and making them more suitable for various applications in regenerative medicine and cell therapy.

Strategic multimodal non-invasive assessment of cardiac performance in patients with heart failure.

AIMS: Although various non-invasive cardiac examinations are known to be predictive of long-term outcomes in patients with heart failure (HF), combining them properly would provide synergism. We aimed to show that non-invasive cardiac assessments targeting left ventricular filling pressure (LVFP), left atrial remodelling, and exercise capacity would provide better prognostication in combination. METHODS AND RESULTS: This prospective observational study included consecutive hospitalized stage A-C HF patients evaluated with N-terminal pro-B-type natriuretic peptide (NT-proBNP), echocardiography including two-dimensional speckle tracking, and cardiopulmonary exercise testing. According to NT-proBNP and echocardiographic semi-quantitative LVFP grading (Echo-LVFP), patients were classified into three LVFP groups: normal range of both Echo-LVFP and NT-proBNP (Group 1), normal range of Echo-LVFP but elevated NT-proBNP (Group 2), and elevated Echo-LVFP and NT-proBNP (Group 3). The adverse outcome was defined as a composite of cardiovascular death, non-fatal acute coronary syndrome, acute stroke, or HF-related hospitalization. Among 224 HF patients (mean age of 63.8 ± 11.6 years, 158 men) analysed, 160 (71.4%) had ischaemic aetiology. During the follow-up of 18.6 ± 9.8 months, event-free survival in Group 2 (n = 56, age of 65.4 ± 12.4) was better than that in Group 3 (n = 45, age of 68.5 ± 11.5) but worse than that in Group 1 (n = 123, mean age of 61.4 ± 10.5) (log-rank P < 0.001). Mechanical left atrial dysfunction (peak longitudinal strain <28%) (adjusted hazard ratio 5.69, 95% confidence interval 1.06-4.48) and limited exercise capacity (peak VO2 per +5 mL/kg/min) (adjusted hazard ratio 0.63, 95% confidence interval 0.46-0.87) were also predictable adverse outcomes. Serial addition of peak VO2 and left atrial strain to the model incrementally enhanced the predictive power of LVFP-based risk stratification for adverse outcomes. CONCLUSIONS: The combination of NT-proBNP and Echo-LVFP could be used to predict adverse outcomes in patients with HF of various stages. Left atrial mechanics and exercise capacity are incremental to prognostication. Non-invasive test findings could be strategically combined to provide an integrative profile of cardiac performance.

Survival outcome of surgical resection compared to non-resection for Bismuth type IV perihilar cholangiocarcinoma.

BACKGROUND/OBJECTIVES: Bismuth type IV perihilar cholangiocarcinoma has been considered an unresectable disease. The aim of the study was to assess whether the surgical resection of type IV perihilar cholangiocarcinoma was associated with better survival rates. METHODS: The data of 117 patients diagnosed with type IV perihilar cholangiocarcinoma at Keimyung University Dongsan Hospital from 2005 to 2020 were retrospectively reviewed. The Bismuth type was assigned based on the patient's radiological imaging findings. The primary outcomes were the surgical results and median overall survival. RESULTS: The demographic characteristics of the 117 patients with type IV perihilar cholangiocarcinoma were comparable between the surgical resection and non-resection groups. Thirty-two (27.4%) patients underwent surgical resections. A left hepatectomy was performed in 16 patients, right hepatectomy in 13 patients, and a central bi-sectionectomy in three patients. The remaining 85 patients received non-surgical treatments. Thirteen (10.9%) received palliative chemotherapy, and 72 (60.5%) patients received conservative treatment including biliary drainage. The patients in the resection group showed significantly longer median overall survival than the patients in the non-resection group (32.4 vs 16.0 months; P = 0.002), even though the positive resection margin rate was high (62.5%). Surgical complications occurred in 15 (46.9%) patients. Complications of Clavien-Dindo classification grade III or higher occurred in 13 (40.6%) patients and grade V in two patients (6.3%). CONCLUSION: Surgical resection for Bismuth type IV perihilar cholangiocarcinoma is technically demanding. The survival of the resection group was significantly better than that of the non-resection group. The resection of selected patients achieved a curative goal with acceptable postoperative morbidity, although the microscopically positive resection margin rate was high.

Effect of anatomical liver resection for hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Despite retrospective studies comparing anatomical liver resection (AR) and non-anatomical liver resection (NAR), the efficacy and benefits of AR for hepatocellular carcinoma remain unclear. MATERIALS AND METHODS: The authors systemically reviewed MEDLINE, Embase, and Cochrane Library for propensity score matched cohort studies that compared AR and NAR for hepatocellular carcinoma. Primary outcomes were overall survival (OS) and recurrence-free survival (RFS). Secondary outcomes were recurrence patterns and perioperative outcomes. RESULTS: Overall, 22 propensity score matched studies (AR, n =2,496; NAR, n =2590) were included. AR including systemic segmentectomy was superior to NAR regarding the 3-year and 5-year OS. AR showed significantly better 1-year, 3-year, and 5-year RFS than NAR, with low local and multiple intrahepatic recurrence rates. In the subgroup analyses of tumour diameter less than or equal to 5 cm and tumours with microscopic spread, the RFS in the AR group was significantly better than that in the NAR group. Patients with cirrhotic liver in the AR group showed comparable 3-year and 5-year RFS with the NAR group. Postoperative overall complications were comparable between AR and NAR. CONCLUSIONS: This meta-analysis demonstrated that AR showed better OS and RFS with a low local and multiple intra-hepatic recurrence rate than NAR, especially in patients with tumour diameter less than or equal to 5 cm and non-cirrhotic liver.

The prognostic value of cardiopulmonary exercise testing and HFA-PEFF in patients with unexplained dyspnea and preserved left ventricular ejection fraction.

BACKGROUND: HFA-PEFF and cardiopulmonary exercise testing (CPET) are comprehensive diagnostic tools for heart failure with preserved ejection fraction (HFpEF). We aimed to investigate the incremental prognostic value of CPET for the HFA-PEFF score among patients with unexplained dyspnea with preserved ejection fraction (EF). METHODS: Consecutive patients with dyspnea and preserved EF (n = 292) were enrolled between August 2019 and July 2021. All patients underwent CPET and comprehensive echocardiography, including two-dimensional speckle tracking echocardiography in the left ventricle, left atrium and right ventricle. The primary outcome was defined as a composite cardiovascular event including cardiovascular-related mortality, acute recurrent heart failure hospitalization, urgent repeat revascularization/myocardial infarction or any hospitalization due to cardiovascular events. RESULTS: The mean age was 58 ± 14.5 years, and 166 (56.8%) participants were male. The study population was divided into three groups based on the HFA-PEFF score: < 2 (n = 81), 2-4 (n = 159), and ≥ 5 (n = 52). HFA-PEFF score ≥ 5, VE/VCO2 slope, peak systolic strain rate of the left atrium and resting diastolic blood pressure were independently associated with composite cardiovascular events. Furthermore, the addition of VE/VCO2 and HFA-PEFF to the base model showed incremental prognostic value for predicting composite cardiovascular events (C-statistic 0.898; integrated discrimination improvement 0.129, p = 0.032; net reclassification improvement 1.043, p ≤ 0.001). CONCLUSIONS: CPET could be exploited for the HFA-PEFF approach in terms of incremental prognostic value and diagnosis among patients with unexplained dyspnea with preserved EF.

Non-Renal Risk Factors for Chronic Kidney Disease in Liver Recipients with Functionally Intact Kidneys at 1 Month.

Chronic kidney disease (CKD) is a critical complication of liver transplants, of which non-renal risk factors are not fully understood yet. This study aimed to reveal pre- and post-transplant risk factors for CKD (<60 mL/min/1.73 m2), examining liver recipients with functionally intact kidneys one month after grafting using nationwide cohort data. Baseline risk factors were analyzed with multivariable Cox regression analyses and post-transplant risk factors were investigated with the time-dependent Cox model and matched analyses of time-conditional propensity scores. Of the 2274 recipients with a one-month eGFR ≥ 60 mL/min/1.73 m2, 494 (22.3%) developed CKD during a mean follow-up of 36.6 ± 14.4 months. Age, female sex, lower body mass index, pre-transplant diabetes mellitus, and lower performance status emerged as baseline risk factors for CKD. Time-dependent Cox analyses revealed that recurrent hepatocellular carcinoma (HR = 1.93, 95% CI 1.06−3.53) and infection (HR = 1.44, 95% CI 1.12−1.60) were significant post-transplant risk factors for CKD. Patients who experienced one of those factors showed a significantly higher risk of subsequent CKD compared with the matched controls who lacked these features (p = 0.013 for recurrent hepatocellular carcinoma, and p = 0.003 for infection, respectively). This study clarifies pre- and post-transplant non-renal risk factors, which lead to renal impairment after LT independently from patients' renal functional reserve.

XaMINA: A Real-World, Prospective, Observational Study of Treatment-Naïve Patients Treated with Rivaroxaban for Stroke Prevention in Atrial Fibrillation in Asia.

INTRODUCTION: The efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism have been demonstrated in Asian and non-Asian patients with non-valvular atrial fibrillation (NVAF) in multiple studies. However, limited published data exist on its use specifically in treatment-naïve patients from the Asia region. Patients in South Korea and Taiwan can now receive rivaroxaban as first-line therapy, allowing for data generation in this patient group. METHODS: XaMINA was a prospective, real-world, multicenter, single-arm, observational cohort study of patients with NVAF in South Korea and Taiwan naïve to anticoagulation and initiating rivaroxaban. The primary outcome was major bleeding; secondary outcomes included all-cause mortality, symptomatic thromboembolic events, and treatment persistence. RESULTS: In total, 1094 patients were included and the follow-up was 1 year. The baseline mean CHADS2 score was 1.63 ± 0.98, mean CHA2DS2-VASc score was 2.92 ± 1.42, and mean HAS-BLED score was 1.00 ± 0.75. The primary outcome occurred in 20 (1.8%) patients [incidence rate 2.1 events per 100 patient-years (95% CI 1.35-3.25)]. Thromboembolic events occurred in 9 (0.8%) patients, of whom 5 (0.5%) had stroke, 3 (0.3%) myocardial infarction, and 1 (0.1%) a transient ischemic attack. There were no cases of non-central nervous system systemic embolism, and 735 (67.2%) patients persisted with rivaroxaban treatment for 1 year. CONCLUSION: XaMINA demonstrated low incidence rates of major bleeding events and thromboembolic events in patients with NVAF newly initiating rivaroxaban in South Korea and Taiwan, consistent with previous real-world studies reconfirming the results of the ROCKET AF study. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (identifier NCT03284762) on 15 September 2017.

Safety of Tacrolimus Monotherapy within 12 Months after Liver Transplantation in the Era of Reduced Tacrolimus and Mycophenolate Mofetil: National Registry Study.

Tacrolimus monotherapy is accepted as a feasible option during early post-liver transplantation as per current international consensus guidelines. However, its effects in the recent era of reduced tacrolimus (TAC) and mycophenolate mofetil (MMF) remain unclear. Liver recipients who either received TAC monotherapy from the treatment onset or switched from TAC/MMF to TAC-mono within 12 months (TAC-mono group; n = 991) were chronologically matched to patients who continued to receive TAC/MMF (TAC/MMF group; n = 991) at the corresponding time points on time-conditional propensity scores. Outcomes within 12 months after matched time points were compared. Biopsy-proven rejection (TAC/MMF: 3.5% vs. TAC-mono: 2.6%; p = 0.381) and graft failure (0.2% vs. 0.7%; p = 0.082) were similar in both groups. However, the decline in eGFR was 3.1 mL/min/1.73 m2 (95% CI: 0.8-5.3) greater at six months (p = 0.008) and 2.4 mL/min/1.73 m2 (95% CI: -0.05-4.9) greater at 12 months (p = 0.048) after the matched time points in TAC-mono group than that in TAC/MMF group. TAC trough levels were also higher in the TAC-mono group throughout the study period. TAC-mono within 12 months after liver transplantation is immunologically safe. However, it can increase the required TAC dose and the decline in renal function than that in TAC/MMF combination therapy.

Relationship of Serial High-Sensitivity C-Reactive Protein Changes to Long-term Clinical Outcomes in Stabilised Patients After Myocardial Infarction.

BACKGROUND: Little is known about the association between serial high-sensitivity C-reactive protein (hsCRP) measurements and long-term outcomes in post-myocardial infarction (MI) patients. We aimed to investigate the usefulness of serial hsCRP measurements for risk stratification in stabilised post-MI patients after percutaneous coronary intervention (PCI). METHODS: A total of 1018 patients who had hsCRP values at both baseline and 1 year after MI were included. High inflammatory status was defined as hsCRP > 2 mg/L. Patients were classified into 4 groups: persistently low, falling (first high then low hsCRP), rising (first low then high hsCRP), and persistently high hsCRP. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE: a composite of all-cause of death, MI, and cerebrovascular accident) within 4 years after the second hsCRP measurement. RESULTS: At 1 year after MI, the numbers of patients in the persistently low, falling, rising, and persistently high hsCRP groups were 394 (38.7%), 358 (35.2%), 69 (6.8%), and 197 (19.4%), respectively. The incidence of MACCE was progressively elevated from the persistently low to the falling, rising, and persistently high hsCRP groups (4.8%, 8.1%, 10.1%, and 13.2%, respectively; P = 0.004). Persistently high hsCRP was an independent predictor of MACCE (adjusted hazard ratio 2.55; 95% confidence interval 1.35-4.81; P = 0.004) and provided incremental prognostic value beyond that of the baseline clinical risk model (net reclassification improvement = 0.397; integrated discrimination improvement = 0.025; all P < 0.001). CONCLUSIONS: Among stabilised post-MI patients who underwent PCI, persistently high hsCRP was frequently seen 1 year after MI and was strongly associated with long-term adverse clinical outcomes. Serial measurements of hsCRP during clinical follow-up after MI may help to identify patients at higher risk for mortality and morbidity.

Single direct oral anticoagulant therapy in stable patients with atrial fibrillation beyond 1 year after coronary stent implantation.

OBJECTIVE: Optimal antithrombotic therapy in patients with atrial fibrillation (AF) beyond 1 year after coronary stent implantation has not been well established in the era of direct oral anticoagulant (DOAC). METHODS: Using Korean National Health Insurance Service data, we analysed 4294 patients with AF who were prescribed DOAC beyond 1 year after coronary stent implantation. Subjects were classified into the monotherapy group (DOAC single therapy, n=1221) or the combination therapy group (DOAC with an antiplatelet agent, n=3073). The primary ischaemic endpoint was defined as a composite of cardiovascular death, myocardial infarction, stroke or systemic thromboembolism. The secondary endpoints were all-cause death, major bleeding defined as a bleeding event requiring hospitalisation and net adverse clinical events. Propensity score matching was performed to balance baseline covariates. RESULTS: Among included patients, 94% had drug-eluting coronary stents. During a median follow-up of 19 (7-32) months, the monotherapy group had a similar risk of the primary ischaemic endpoint (HR 0.828, 95% CI 0.660 to 1.038) and all-cause death (HR 1.076, 95% CI 0.895 to 1.294) compared with the combination therapy group. Risk of major bleeding was lower in the monotherapy group (HR 0.690, 95% CI 0.481 to 0.989), which was mostly driven by reduced gastrointestinal bleeding (HR 0.562, 95% CI 0.358 to 0.883). There was no significant difference in net adverse clinical events between the two groups. CONCLUSIONS: DOAC monotherapy showed similar efficacy in preventing ischaemic events and was associated with lower major bleeding events compared with combination therapy in patients with AF beyond 1 year after coronary stent implantation.

Associations of Serum Tumor Biomarkers with Integrated Genomic and Clinical Characteristics of Hepatocellular Carcinoma.

INTRODUCTION: Serum α-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP (AFP-L3), and des-γ-carboxy-pro-thrombin (DCP) are useful biomarkers of hepatocellular carcinoma (HCC). However, associations among molecular characteristics and serum biomarkers are unclear. We analyzed RNA expression and DNA variant data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) to examine their associations with serum biomarker levels and clinical data. METHODS: From 371 TCGA-LIHC patients, we selected 91 seen at 3 institutions in Korea and the USA and measured AFP, AFP-L3, and DCP from preoperatively obtained serum. We conducted an integrative clinical and molecular analysis, focusing on biomarkers, and validated the findings with the remaining 280 patients in the TCGA-LIHC cohort. RESULTS: Patients were categorized into 4 subgroups: elevated AFP or AFP-L3 alone (↑AFP&L3), elevated DCP alone (↑DCP), elevation of all 3 biomarkers (elevated levels of all 3 biomarkers [↑All]), and reference range values for all biomarkers (RR). CTNNB1 variants were frequently observed in ↑DCP patients (53.8%) and RR patients (38.5%), but ↑DCP patients with a CTNNB1 variant had worse survival than RR patients. TP53 sequence variants were associated with ↑AFP (30.8%) and ↑DCP (30.8%). The Wnt-ß-catenin signaling pathway was activated in the ↑AFP&L3, whereas liver-related Wnt signaling was activated in the RR. TGF-ß and VEGF signaling were activated in ↑AFP&L3, whereas dysregulated bile acid and fatty acid metabolism were dominant in ↑DCP. We validated these findings by showing similar results between the test cohort and the remainder of the TCGA-LIHC cohort. CONCLUSIONS: Serum AFP, AFP-L3, and DCP levels can help predict variants in the genetic profile of HCC, especially for TP53 and CTNNB1. These findings may facilitate development of an evidence-based approach to treatment.

Liquid Biopsy from Bile-Circulating Tumor DNA in Patients with Biliary Tract Cancer.

Although liquid biopsy of blood is useful for cancer diagnosis and prediction of prognosis, diagnostic and prognostic value of ctDNA in bile fluid for BTCs are not clear yet. To determine whether liquid biopsy for circulating tumor DNA (ctDNA) can replace tissue biopsy when assessing somatic mutations in biliary tract cancers (BTCs). Bile samples were obtained from 42 patients with BTC. Matched formalin-fixed paraffin-embedded (FFPE) samples were obtained from 20 of these patients and matched plasma samples from 16 of them. Droplet digital PCR (ddPCR) was used for detection KRAS somatic mutation. KRAS mutations were identified in the bile ctDNA of 20 of 42 (48%) patients. Patients with mutant KRAS showed significantly worse survival than those with wild-type KRAS (2-year survival rates: 0% vs. 55.5%, respectively; p = 0.018). There was 80.0% mutational concordance between the paired bile ctDNA and FFPE samples, and 42.9% between the plasma and FFPE samples. On transcriptomic sequencing of one set of paired bile and FFPE samples, expression level of KRAS-associated signaling oncogenes in the bile and tissue samples showed a strong positive correlation (r = 0.991, p < 0.001). Liquid biopsy of bile reliably detect mutational variants within the bile ctDNA of BTC patients. These results suggest that bile is an effective biopsy fluid for ctDNA analysis.

Circulating microRNAs as biomarkers in bile-derived exosomes of cholangiocarcinoma.

PURPOSE: In this pilot study, using next-generation sequencing and integrated messenger RNA (mRNA) sequencing, we investigated circulating microRNA (miRNA) expression profiling from bile-derived exosomes to identify dysregulated miRNA signatures and oncogenic pathways and determine their effects on targeted mRNAs in cholangiocarcinoma (CCA). Moreover, we explored the possibility that genetic analysis using bile-derived exosomes may replace gene analysis using tissue. METHODS: Bile was collected from a patient with perihilar CCA before curative resection. As a control, bile was collected from a patient with a common bile duct stone. Exosomes were isolated from the bile, and we performed next-generation miRNA sequencing using isolated exosomes. To evaluate miRNA-mRNA interactions, mRNA sequencing was performed using bile fluid in both patients. RESULTS: We identified 22 differentially expressed miRNAs. More than 65% of the predicted mRNA targets of those miRNAs were actually differentially expressed between control and CCA bile samples. In functional pathway analysis, targets of 22 miRNAs were primarily enriched in mitogen-activated protein kinase, platelet derived growth factor, vascular endothelial growth factor, epidermal growth factor receptor, and p53 signaling. In particular, in the functional assessment of miRNA-mRNA interactions, RAS pathways, including downstream pathways (PI3K-AKT-mTOR and RAS-RAF-MEK-ERK), were determined to be enriched. CONCLUSION: Circulating miRNAs in bile-derived exosomes provide new information for the development of miRNA analysis in CCA. These miRNAs may represent the oncogenic characteristics of CCA tissue, enabling them to be used instead of tissue samples for the diagnosis of CCA. Further research investigating circulating miRNAs in bile exosomes may lead to more rational, targeted approaches to treatment.

Liver Resection Versus Local Ablation Therapies for Hepatocellular Carcinoma Within the Milan Criteria: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the oncologic outcomes of liver resection (LR) and local ablation therapies for HCC. SUMMARY OF BACKGROUND DATA: Although several studies have compared LR and local ablation therapies, the optimal treatment of choice for HCC within the Milan criteria remains controversial. METHODS: We systemically searched the MEDLINE, Embase, and Cochrane Library databases for randomized control trials (RCTs) and matched nonrandomized trials (NRTs) that compared LR and local ablation therapies for HCC within the Milan criteria. The primary outcome was overall survival (OS). Secondary outcomes were recurrence free survival (RFS) and recurrence pattern. RESULTS: A total of 7 RCTs and 18 matched NRTs, involving 2865 patients in the LR group and 2764 patients in the local ablation therapy group [RFA, MWA, RFA plus trans-arterial chemoembolization (TACE)], were included. Although there was no significant difference in OS between LR and RFA, LR showed a significantly better 5-year RFS than RFA in the analysis of RCTs (hazards ratio: 0.75; 95% confidence interval: 0.62-0.92; P = 0.006). The RFA group showed a significantly higher local recurrence than the LR group in both analyses of RCTs and NRTs. Additionally, the LR group showed better OS and RFS than the MWA or RFA plus TACE groups. CONCLUSION: Our meta-analysis showed that LR was superior to RFA in terms of RFS and incidence of local recurrence. Moreover, LR showed better oncologic outcomes than MWA or RFA plus TACE.