Clinical findings, viral load, and outcomes of COVID-19: Comparison of patients with negative and positive initial chest computed tomography.

Reports detailing the clinical characteristics, viral load, and outcomes of patients with normal initial chest CT findings are lacking. We sought to compare the differences in clinical findings, viral loads, and outcomes between patients with confirmed COVID-19 who initially tested negative on chest CT (CT negative) with patients who tested initially positive on chest CT (CT positive). The clinical data, viral loads, and outcomes of initial CT-positive and CT-negative patients examined between January 2020 and April 2020 were retrospectively compared. The efficacy of viral load (cyclic threshold value [Ct value]) in predicting pneumonia was evaluated using receiver operating characteristic (ROC) curve and area under the curve (AUC). In total, 128 patients underwent initial chest CT (mean age, 54.3 ± 19.0 years, 50% male). Of those, 36 were initially CT negative, and 92 were CT positive. The CT-positive patients were significantly older (P < .001) than the CT-negative patients. Only age was significantly associated with the initial presence of pneumonia (odds ratio, 1.060; confidence interval (CI), 1.020-1-102; P = .003). In addition, age (OR, 1.062; CI, 1.014-1.112; P = .011), fever at diagnosis (OR, 6.689; CI, 1.715-26.096; P = .006), and CRP level (OR, 1.393; CI, 1.150-1.687; P = .001) were significantly associated with the need for O2 therapy. Viral load was significantly higher in the CT-positive group than in the CT-negative group (P = .017). The cutoff Ct value for predicting the presence of pneumonia was 27.71. Outcomes including the mean hospital stay, intensive care unit admission, and O2 therapy were significantly worse in the CT-positive group than in the CT-negative group (all P < .05). In conclusion, initially CT-negative patients showed better outcomes than initially CT-positive patients. Age was significantly associated with the initial presence of pneumonia, and viral load may help in predicting the initial presence of pneumonia.

Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein improves diagnostic accuracy for hepatocellular carcinoma.

BACKGROUND: Diagnostic accuracy of various tumor markers and their combinations for hepatocellular carcinoma (HCC) was not fully investigated. AIM: To evaluate the diagnostic accuracy of alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II) and their combination for HCC diagnosis. METHODS: Patients with newly detected liver mass or elevated serum AFP levels were considered eligible. Serum AFP level, AFP-L3 fraction, and PIVKA-II level were measured at the first visit. RESULTS: In total, 622 patients were included; 355 patients (57.1%) had chronic liver disease, and 208 (33.4%) had liver cirrhosis. HCC was diagnosed in 160 patients (25.7%). The area under the receiver operating characteristics curves (AUROCs) of the serum AFP, AFP-L3 fraction, AFP-L3, and PIVKA-II levels for the diagnosis of HCC were 0.775, 0.792, 0.814, and 0.834, respectively. A novel diagnostic model was developed by classifying patients in a 1:1 ratio into training and validation sets. Using the binary regression analysis of the training cohort, the AFP, AFP-L3 fraction, and PIVKA-II (ALPs) score was calculated as follows: ALPs score = 3.8 × [serum AFP level (ng/mL) × AFP-L3 fraction (%) × 0.01] + 0.2 × PIVKA-II level (mAU/mL). The AUROC of the ALPs score for diagnosis of HCC was 0.878, significantly higher than that of serum AFP level (P < 0.001), AFP-L3 fraction (P < 0.001), PIVKA-II level (P = 0.036), and AFP-L3 level (P = 0.006). The optimal ALPs score cut-off was 5.3 (sensitivity, 85.0%, specificity 80.1%). The validation cohort showed similar results. CONCLUSION: The ALPs score calculated using serum AFP level, AFP-L3 fraction, and PIVKA-II level showed improved accuracy in HCC diagnosis.

How Should We Assign Large Infiltrative Hepatocellular Carcinomas for Staging?

Infiltrative gross morphology of hepatocellular carcinoma (HCC) is known to be associated with poor prognosis, but this is not considered for staging. A total of 774 HCC patients who underwent curative liver resection were retrospectively reviewed and the prognostic significance of infiltrative type HCC was assessed using the American Joint Committee on Cancer (AJCC) and Barcelona Clinic Liver Cancer (BCLC) staging systems. Seventy-four patients (9.6%) had infiltrative HCCs with a higher proportion of multifocal tumors, larger tumors, vessel invasion, increased tumor marker levels, and advanced T-stages than those with nodular HCC (all, p < 0.01). Infiltrative morphology was independently associated with lower overall survival (OS), but its impact was significant when the tumor size was ≥ 4 cm (p < 0.001). Under current AJCC and BCLC staging criteria, these large infiltrative HCCs were associated with significantly worse OS in early AJCC T-stages (T1b/T2, p < 0.001) and BCLC stage A/B (both, p < 0.01) but not in late AJCC (T3/T4) and BCLC C. The reassignment of this subtype to T3 and T4 increased the discriminatory ability of AJCC T-staging with lower AIC values (3090 and 3088 vs. 3109) and higher c-index (0.69 and 0.69 vs. 0.67), respectively (both, p < 0.001). Similarly, the reassignment of large infiltrative HCC to BCLC stages B and C also improved the prognostic performance. Large infiltrative HCCs should be assigned to more advanced stages in current staging systems for their prognostic impact.

Survival according to recurrence patterns after resection for transplantable hepatocellular carcinoma in HBV endemic area: Appraisal of liver transplantation strategy.

BACKGROUND AND AIMS: Since there is a shortage of liver donors, we investigated recurrence patterns and outcomes after liver resection (LR) to determine the feasibility of salvage liver transplantation (SLT). METHODS: We analyzed 468 patients with hepatocellular carcinoma (HCC) within the Milan criteria (MC) who were mainly associated with Hepatitis B virus infection (76.3%) and had undergone curative LR as an initial treatment. RESULTS: The overall survival (OS) rates were 86.6% and 67.4% at 5 and 10 years after LR, respectively. During a median follow-up of 59 months, 211 patients experienced recurrences including 175 (37.4%) within MC and 36 (7.7%) beyond MC. Survival was lowest in patients with beyond MC-recurrence followed by within MC- and no-recurrence groups (26.5%, 86.6%, and 94.7% at 5 years, respectively, P<0.001). Independent pathologic predictors of recurrence beyond MC were the presence of satellite nodules, microvascular invasion, and unfavorable gross findings (multinodular confluent and infiltrative) (all, P<0.05). Patients with all three risk factors experienced recurrence with the highest cumulative incidence of mortality. Among 173 patients with recurrence within MC, the cumulative incidence of HCC progression beyond MC despite resection and locoregional treatment (LRT) was 29% and 60% at 5 and 10 years after recurrence, respectively, and their 10-year OS rate was 25.8%. CONCLUSION: Curative LR achieved a 5-year survival of>85% in patients with transplantable HCC, but early SLT after recurrence within MC is advocated because of poor survival and high risk of progression thereafter. Further, prophylactic LT could be considered for those with high risk of recurrence.

Comparison of 2 curative treatment options for very early hepatocellular carcinoma: Efficacy, recurrence pattern, and retreatment.

Curative treatments for very early-stage hepatocellular carcinoma (HCC), defined as single HCC with a maximum diameter of <2 cm in patients with well-preserved liver function, consist of surgical resection or radiofrequency ablation (RFA). In this retrospective study, we compared the efficacy of both treatments in 154 patients with very early-stage HCCs who underwent resection or RFA as initial therapy and were followed up for a median of 56.8 months. Propensity score matching analysis was also conducted. Overall survival was comparable between treatment groups (median survival time of 143 vs 97 months for resection and RFA, respectively; P = .132). Resection group; however, demonstrated a significantly lower recurrence rate after initial therapy than RFA group (42.3% vs 65.7%; P = .006) with a longer median recurrence-free survival time (66.7 vs 33.8 months; P = .002), which was confirmed even after matching (P = .04). In contrast, the recurrence pattern in advanced-stage (9.6% vs 1.0%; P = .01) or incurable recurrences (19% vs 13%; P = .04) was more frequent following resection than RFA. Recurrent lesions were comparatively more curable in RFA group than in resection group (80% vs 54.5%; P = .02). The recurrence of HCC was independently associated with lower serum albumin level (P = .027), the presence of comorbid diabetes mellitus (P = .010), and RFA (P = .034). In conclusion, in patients with very early-stage HCC, surgical resection has achieved significantly better recurrence-free survival than RFA. A closer follow-up is required after resection.

Prosthetic Joint Infections Caused by Candida Species: A Systematic Review and a Case Series.

The purpose of this study was to evaluate the efficacy of echinocandins in the treatment of Candida prosthetic joint infection (PJI) based on published literature and on patients we examined. A structured literature review of multiple databases was conducted to identify patients who received echinocandins for Candida PJIs. Additionally, we describe here the first cases of PJIs due to C. parapsilosis, successfully treated with prolonged anidulafungin therapy. Out of 17 patients, 12 were female and the mean age at diagnosis was 66.0 years. No risk factors associated with Candida PJIs were found in four patients (23.5%). Infection sites included the knee (n = 10, 62.5%), the hip (n = 6, 35.3%) and the shoulder (n = 1, 5.9%). The most frequently isolated Candida species were C. albicans (n = 7, 41.2%) and C. glabrata (n = 7, 41.2%), followed by C. parapsilosis (n = 2, 11.8%) and C. freyschussii (n = 1, 5.9%). All patients were cured with the combination of systemic antifungal therapy and surgical interventions. Two-stage exchange arthroplasty and resection arthroplasty were performed in five and nine patients, respectively. The most frequently used echinocandins were caspofungin (n = 11, 64.7%), followed by anidulafungin (n = 4, 23.5%) and micafungin (n = 2, 11.8%). The median duration (days) of echinocandin therapy was as follows: caspofungin (25.5, range 8-56), micafungin (14.0, range 4-56) and anidulafungin (58, range 14-90). This study supports the effective role of echinocandins, as well as the potential advantage of surgical intervention in the treatment of Candida PJIs. Furthermore, it provides fundamental data on the safety of long-term echinocandin therapy.

Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-ß-D-glucosaminidase.

BACKGROUND AND AIM: For appropriate management of acute kidney injury (AKI) in cirrhotic patients, accurate differentiation of the types of AKI, prerenal azotemia (PRA), hepatorenal syndrome (HRS), and acute tubular necrosis (ATN) is very important. Urine N-acetyl-ß-D-glucosaminidase (NAG) has been proposed as a good tubular injury marker in many studies, but its efficacy in cirrhosis is unclear. This study was performed to evaluate the usefulness of urine NAG in patients with decompensated cirrhosis. METHODS: In 114 hospitalized patients with decompensated cirrhosis, we assessed serum creatinine, cystatin C, and urine NAG levels as markers for AKI differentiation and development and patient mortality. RESULTS: Thirty patients diagnosed with AKI at baseline had significantly higher serum creatinine and cystatin C levels, urine NAG levels, and Child-Pugh scores than those without AKI. Only urine NAG levels were significantly higher in patients with ATN than those with PRA or HRS (116.1 ± 46.8 U/g vs 39.4 ± 20.2 or 54.0 ± 19.2 U/g urinary creatinine, all P < 0.05). During a median follow up of 6.1 months, AKI developed in 17 of 84 patients: PRA in nine, HRS in six, and ATN in three. Higher serum cystatin C and urine NAG levels were independent predictors of AKI development in patients with decompensated cirrhosis. Survival was significantly associated with low serum cystatin C and urine NAG levels. CONCLUSION: Serum cystatin C and urine NAG levels are useful to differentiate types of AKI and are strong predictors for AKI development and mortality in patients with decompensated cirrhosis.

Identification of novel susceptibility loci associated with hepatitis B surface antigen seroclearance in chronic hepatitis B.

BACKGROUND/AIMS: The seroclearance of hepatitis B virus (HBV) surface antigen (HBsAg) is regarded as a functional cure of chronic hepatitis B (CHB) although it occurs rarely. Recently, several genome-wide association studies (GWASs) revealed various genetic alterations related to the clinical course of HBV infection. However, all of these studies focused on the progression of HBV infection to chronicity and had limited application because of the heterogeneity of HBV genotypes. In the present study, we aimed to determine susceptibility genetic markers for seroclearance of HBsAg in CHB patients with a homogenous viral genotype. METHODS: One hundred patients with CHB who had experienced HBsAg seroclearance before 60 years of age and another 100 with CHB showing high serum levels of HBsAg even after 60 years of age were enrolled. Extreme-phenotype GWAS was conducted using blood samples of participants. RESULTS: We identified three single nucleotide polymorphisms, rs7944135 (P = 4.17 × 10-6, odds ratio [OR] = 4.16, 95% confidence interval [CI] = 2.27-7.63) at 11q12.1, rs171941 (P = 3.52×10-6, OR = 3.69, 95% CI = 2.13-6.42) at 5q14.1, and rs6462008 (P = 3.40×10-6, OR = 0.34, 95% CI = 0.22-0.54) at 7p15.2 as novel susceptibility loci associated with HBsAg seroclearance in patients with CHB. The flanking genes at these loci including MPEG1, DTX4, MTX3, and HOXA13 were suggested to have functional significance. In addition, through functional analysis, CXCL13 was also presumed to be related. CONCLUSIONS: To the best of our knowledge, this study is the first GWAS regarding the seroclearance of HBsAg in CHB patients. We identify new susceptibility loci for cure of CHB, providing new insights into its pathophysiology.

In vitro development of a hemangioblast from a human embryonic stem cell, SNUhES#3.

AIMS: Recent reports demonstrated that a hemangioblast population emerged during hematopoietic development in both mouse and human embryonic stem cell (hESC) differentiation cultures. MAIN METHODS: In this study, a new uncharacterized hESC line, SNUhES#3, was studied for its capacity to proliferate with STO cells and differentiate into hemangioblasts in co-culture with OP9 cells. KEY FINDINGS: We were able to obtain CD34(+)CD45(-) cells from SNUhES#3 cells after 12 days of in vitro culture, and this cell population could be maximized to 12.6% of the total. These cells, derived from SNUhES#3, showed the morphology of hematopoietic precursor cells and endothelial lineage cells with high efficiency. Reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the hematopoietic markers CD34, GATA2, and LMO2 were co-expressed with the endothelial marker CD31 from day 8, whereas ES cell marker OCT4 no longer existed at an early stage. Moreover, we found that the efficacy of colony forming by SNUhES#3 cells is better than that of H9 cells. SIGNIFICANCE: These findings provide evidence that SNUhES#3 cells can be used as an established human ESC line, and co-culture with OP9 can induce SNUhES#3 cells to differentiate into hemangioblasts, the common precursors of the hematopoietic and endothelial lineages.