Programmed Death 1 and Cytotoxic T-Lymphocyte-Associated Protein 4 Gene Expression in Peripheral Blood Mononuclear Cells Can Serve as Prognostic Biomarkers for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer with poor prognosis. The lack of reliable biomarkers for early detection and accurate diagnosis and prognosis poses a significant challenge to its effective clinical management. In this study, we investigated the diagnostic and prognostic potential of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression in peripheral blood mononuclear cells (PBMCs) in HCC. PD-1 and CTLA-4 gene expression was analyzed comparatively using PBMCs collected from HCC patients and healthy individuals. The results revealed higher PD-1 gene expression levels in patients with multifocal tumors, lymphatic invasion, or distant metastasis than those in their control counterparts. However, conventional serum biomarkers of liver function do not exhibit similar correlations. In conclusion, PD-1 gene expression is associated with OS and PFS and CTLA-4 gene expression is associated with OS, whereas the serum biomarkers analyzed in this study show no significant correlation with survival in HCC. Hence, PD-1 and CTLA-4 expressed in PBMCs are considered potential prognostic biomarkers for patients with HCC that can facilitate prediction of malignancy, response to currently available HCC treatments, and overall survival.

Prognostic Value of Erythroblastic Leukemia Viral Oncogene Homolog 2 and Neuregulin 4 in Hepatocellular Carcinoma.

Although the roles of erythroblastic leukemia viral oncogene homolog 2 (ERBB2), neuregulin 4 (NRG4), and mitogen-inducible gene 6 (MIG6) in epidermal growth factor receptor signaling in hepatocellular carcinoma (HCC) and other malignancies have been previously investigated, the prognostic value of their serum levels in HCC remains undetermined. In the present study, correlations between serum levels and tumor characteristics, overall survival, and tumor recurrence were analyzed. Furthermore, the prognostic potential of the serum levels of these biomarkers was evaluated relative to that of alpha-fetoprotein. Both ERBB2 and NRG4 correlated with the Barcelona Clinic Liver Cancer stage, ERBB2 correlated with the tumor-maximal diameter, and NRG4 correlated with a tumor number. Cox proportional hazards regression analysis revealed that ERBB2 (hazard ratio [HR], 2.719; p = 0.007) was an independent prognostic factor for overall survival. Furthermore, ERBB2 (HR, 2.338; p = 0.002) and NRG4 (HR, 431.763; p = 0.001) were independent prognostic factors for tumor recurrence. The products of ERBB2 and NRG4 had a better area under the curve than alpha-fetoprotein for predicting 6-month, 1-year, 3-year, and 5-year mortality. Therefore, these factors could be used to evaluate prognosis and monitor treatment response in patients with HCC.

CT-based Hounsfield unit values reflect the degree of steatohepatitis in patients with low-grade fatty liver disease.

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Ultrasound, the most used tool for diagnosing NAFLD, is operator-dependent and shows suboptimal performance in patients with mild steatosis. However, few studies have been conducted on whether alternative noninvasive methods are useful for diagnosing mild hepatic steatosis. Also, little is known about whether noninvasive tests are useful for grading the severity of hepatic steatosis or the degree of intrahepatic inflammation. Therefore, we aimed to evaluate whether the HSI, the FLI and HU values in CT could be used to discriminate mild hepatic steatosis and to evaluate the severity of hepatic steatosis or the degree of intrahepatic inflammation in patients with low-grade fatty liver disease using liver biopsy as a reference standard. METHODS: Demographic, laboratory, CT imaging, and histological data of patients who underwent liver resection or biopsy were analyzed. The performance of the HSI, HU values and the FLI for diagnosing mild hepatic steatosis was evaluated by calculating the area under the receiver operating characteristic curve. Whether the degree of hepatic steatosis and intrahepatic inflammation could be predicted using the HSI, HU values or the FLI was also analyzed. Moreover, we validate the results using magnetic resonance imaging proton density fat fraction as an another reference standard. RESULTS: The AUROC for diagnosing mild hepatic steatosis was 0.810 (p < 0.001) for the HSI, 0.732 (p < 0.001) for liver HU value, 0.802 (p < 0.001) for the difference between liver and spleen HU value (L-S HU value) and 0.813 (p < 0.001) for the FLI. Liver HU and L-S HU values were negatively correlated with the percentage of hepatic steatosis and NAFLD activity score (NAS) and significantly different between steatosis grades and between NAS grades. The L-S HU value was demonstrated the good performance for grading the severity of hepatic steatosis and the degree of intrahepatic inflammation. CONCLUSIONS: The HU values on CT are feasible for stratifying hepatic fat content and evaluating the degree of intrahepatic inflammation, and the HSI and the FLI demonstrated good performance with high sensitivity and specificity in diagnosing mild hepatic steatosis.

Outcomes of laparoscopic radiofrequency ablation versus percutaneous radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Few studies have compared the therapeutic outcomes in patients with HCC who underwent laparoscopic radiofrequency ablation (LRFA) versus percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC). Therefore, this study compared the recurrence and survival outcomes of the two RFA methods in patients with HCC. METHODS: Recurrence and overall survival outcomes were evaluated in 307 patients who underwent LRFA (n = 151) or PRFA (n = 156) as a treatment method for de novo HCC. Inverse probability of treatment weighting (IPTW) analysis was performed to reduce the impact of treatment selection bias. RESULTS: There were no significant differences in major baseline characteristics between the LRFA and PRFA groups. However, the proportion of cirrhotic patients was higher in the LRFA group, whereas the LRFA group had more tumors and a more advanced tumor-node-metastasis stage. Moreover, the mean tumor size was significantly larger in the LRFA group than in the PRFA group. In a multivariate analysis, serum albumin level, more than three tumors, and the RFA method were identified as significant predictors of recurrence-free survival. Moreover, for the overall survival of HCC patients, serum albumin levels, days of hospital stay during RFA, and the RFA method were independent predictors. In the IPTW-adjusted analysis, the LRFA group showed significantly higher recurrence-free survival and overall survival. CONCLUSIONS: Our study revealed that compared with PRFA, LRFA was associated with longer recurrence-free survival and favorable overall survival in patients with HCC. Therefore, LRFA should be considered the primary therapy in patients with HCC eligible for RFA.

Comparison of Gene Expression Profiles of Signet Ring Cell Carcinoma and Poorly Cohesive Carcinoma in Early Gastric Cancer.

Introduction: Although signet ring cell carcinoma (SRC) is a subtype of poorly cohesive carcinoma (PC), the differences in the biological behavior between the 2 morphologically similar carcinomas have not been fully studied. Therefore, we performed transcriptome analysis to evaluate the differences of genetic expressions between SRC and PC. Methods: The study group consisted of patients with SRC or PC pathology from patients with early gastric cancer (EGC) whose depth of invasion was localized in the mucosal layer. A total of 18 patients were enrolled. The patients were divided into 3 groups based on their histologic type and lymph node (LN) status. Group 1 consisted of patients with PC and positive LN metastasis, Group 2 consisted of patients with PC without LN metastasis, and Group 3 consisted of patients with SRC without LN metastasis. Transcriptome analysis was performed using the nCounter PanCancer Progression Panel Kit. Results: The expression of 77 genes in Group 1 was altered compared to that in normal tissues. The expression of 49 and 13 genes in Groups 2 and 3, respectively, was altered when compared to that in normal tissues. Groups 1 and 2 showed similar genetic expressions. However, Group 3 showed numerous differences in gene expression including Roundabout4 (Robo4) compared to the other groups, especially Group 1. Conclusion: Our data suggest that gene expression patterns were different between SRC and PC and expression of ROBO4 may play an important role in the prognosis of SRC and PC type of EGC.

Typhoid fever presenting with gastric ulcer bleeding.

BACKGROUND: Enteric fever is a systemic disease caused by Salmonella enterica serovar Typhi or Salmonella enterica serovar Paratyphi, characterized by high fever and abdominal pain. Most patients with enteric fever improve within a few days after antibiotic treatment. However, some patients do not recover as easily and develop fatal life-threatening complications, including intestinal hemorrhage. Lower gastrointestinal bleeding has been reported in 10% of cases. However, upper gastrointestinal bleeding has rarely been reported in patients with enteric fever. We present a case of gastric ulcer hemorrhage caused by enteric fever. CASE PRESENTATION: A 32-year-old woman, complaining of fever lasting four days and right upper quadrant pain and melena that started one day before admission, consulted our hospital. Abdominal computed tomography revealed mild hepatomegaly and gastroscopy revealed multiple active gastric ulcers with flat black hemorrhagic spots. The melena of the patient stopped on the third day. On the fifth admission day, she developed hematochezia. At that time, Salmonella enterica serovar Typhi was isolated from the blood culture. The antibiotic regimen was switched to ceftriaxone. Her hematochezia spontaneously resolved the following day. Finally, the patient was discharged on the 12th admission day without clinical symptoms. However, her fever recurred one month after discharge, and she was readmitted and Salmonella enterica serovar Typhi was confirmed again via blood culture. She was treated with ceftriaxone for one month, and was discharged without complications. CONCLUSION: Our case showed that although rare, active gastric ulcers can develop in patients with enteric fever. Therefore, upper and lower gastrointestinal bleeding should be suspected in patients with enteric fever, especially showing relapsing bacteremia.

Which scoring system should be used for non-variceal upper gastrointestinal bleeding? Old or new?

BACKGROUND AND AIM: Several scoring systems for predicting outcomes in patients with non-variceal upper gastrointestinal bleeding (NVUGIB) have recently been devised, but not sufficiently validated. We compared the predictive accuracy of several scoring systems and assessed the usefulness of new scoring systems. METHODS: The medical records of 1048 patients with NVUGIB were reviewed to collect demographic, clinical, laboratory, and endoscopic data. The areas under the receiver operating characteristic curve (AUROCs) were calculated for the ABC, new Japanese scoring system, Progetto Nazionale Emorrhagia Digestiva (PNED), and other scores to compare their predictive accuracy for 30-day mortality, therapeutic intervention, rebleeding, and prolonged hospital stay (≥ 10 days). Outcome predictors were identified by multivariate analysis. RESULTS: The ABC, new Japanese scoring system, and PNED scores best predicted 30-day mortality (AUROC 0.907), need for therapeutic intervention (AUROC 0.707), and rebleeding (AUROC 0.874), respectively (all P < 0.001). The ABC and PNED scores were similarly better at predicting prolonged hospital stay (ABC AUROC: 0.765; PNED AUROC: 0.790; both P < 0.001). Thirty-day mortality was related to sex, systolic blood pressure (SBP), syncope, estimated glomerular filtration rate (eGFR), albumin, heart failure, disseminated malignancy, chronic obstructive pulmonary disease (COPD), and liver cirrhosis. Sex, age, SBP, hematemesis, blood urea nitrogen, and eGFR independently predicted the need for therapeutic intervention. Sex, SBP, pulse, albumin level, heart failure, disseminated malignancy, and COPD predicted rebleeding. CONCLUSION: The outcomes of patients with NVUGIB were better predicted by newly developed than by old scoring systems.

Outcomes of end-stage renal disease patients on the waiting list for deceased donor kidney transplantation: A single-center study.

BACKGROUND: Kidney transplantation is an effective renal replacement therapy for patients with end-stage renal disease (ESRD). In this study, we assessed the impact of the baseline characteristics and comorbidities of ESRD patients on the probability of deceased donor kidney transplantation (DDKT) and evaluated the morbidity and mortality during the time spent waiting. METHODS: The study population consisted of 544 ESRD patients on the waiting list for DDKT at Chungnam National University Hospital in South Korea between February 2000 and October 2015. The patients were observed from the date of transplantation list registration to the date of transplantation. Baseline characteristics and comorbidities were investigated together with new-onset comorbidities that occurred during the waiting time. RESULTS: Diabetes mellitus (39.0%), hypertension (25.2%), and glomerulonephritis (21.3%) were the three most common causes of ESRD in this study, and coronary artery disease (9.4%) was the most common comorbidity. The 115 patients (19.3%) who underwent DDKT had a mean waiting time of 1,711 days (768-2,654 days or 4.68 years [2.10-7.27]). Blood groups other than type O, peritoneal dialysis, and nondiabetic ESRD were significantly associated with a higher likelihood of DDKT. Infection was the leading cause of death and the most common comorbidity that arose during the waiting time. Patients who experienced cardiovascular events during the waiting time showed a lower transplant rate compared with those who did not. CONCLUSION: The prevalence of comorbidities was high in renal transplantation candidates. During the often-long waiting time, new comorbidities may occur, with long-term sequelae limiting access to kidney transplantation or resulting in death.

Rhabdomyolysis in a patient taking nebivolol.

ß Blockers such as propranolol and labetalol are known to induce toxic myopathy because of their partial ß2 adrenoceptor agonistic effect. Nebivolol has the highest ß1 receptor affinity among ß blockers, and it has never been reported to induce rhabdomyolysis until now. We report a patient who developed rhabdomyolysis after changing medication to nebivolol. A 75-year-old woman was admitted to our hospital because of generalized weakness originating 2 weeks before visiting. Approximately 1 month before her admission, her medication was changed from carvedilol 12.5 mg to nebivolol 5 mg. Over this time span, she had no other lifestyle changes causing rhabdomyolysis. Her blood chemistry and whole body bone scan indicated rhabdomyolysis. We considered newly prescribed nebivolol as a causal agent. She was prescribed carvedilol 12.5 mg, which she was previously taking, instead of nebivolol. She was treated by hydration and urine alkalization. She had fully recovered and was discharged.

Clinical Characteristics of Overhydration in Patients with Idiopathic Edema.

BACKGROUND: Idiopathic edema (IE) is a common clinical syndrome. Designing treatment plans for IE is problematic because of the difficulty in assessing volume status. We aimed to evaluate volume status, measured by bioimpedance spectroscopy (BIS), and investigated clinical parameters associated with volume overload (VO) in patients with IE. METHODS: Patients with IE were defined as those with symptomatic edema and without abnormal renal function or any other apparent cause of edema. A total of 124 patients were included. Overhydration (OH) and extracellular water (ECW) were calculated using BIS. Relative hydration status (x0394;HS) was defined as OH/ECW. Patients were classified into 2 groups: overhydrated group (OG; x0394;HS ≥7%) and non-OG (NOG; x0394;HS <7). Simple and multiple logistic regression analyses were used to assess the influence of several variables on the incidence of VO. RESULTS: Of 124 patients, 37 (29.8%) were in the OG. The proportion of men in the OG was higher than that in the NOG (p = 0.020). Patients in the OG showed more frequent pretibial pitting edema (PTPE, p < 0.001) and had lower hemoglobin (p = 0.008) and serum albumin levels (p < 0.001). The multivariate analysis showed that the presence of PTPE (OR 10.62, 95% CI 1.98-57.1), low serum albumin level (OR 0.01, 95% CI 0.00-0.25) and lower fat tissue index (OR 0.78, 95% CI 0.63-0.97) were independent risk factors for the presence of VO. CONCLUSIONS: BIS helps to identify volume status and body composition in patients with IE.

Comparison of treatment delay associated with tunneled hemodialysis catheter placement between interventionists.

BACKGROUND/AIMS: Fragmented care in nephrology can cause treatment delays. Nephrologists are qualified to perform vascular access-related procedures because they understand the pathophysiology of renal disease and perform physical examination for vascular access. We compared treatment delays associated with tunneled hemodialysis catheter (TDC) placement between interventional radiologists and nephrologists. METHODS: We collected data by radiologists from January 1, 2011 through December 31, 2011 and by nephrologists from since July 1, 2012 through June 30, 2013. We compared the duration from the hemodialysis decision to TDC placement (D-P duration) and hemodialysis initiation (D-H duration), catheter success and the complication rate, and the frequency and the usage time of non-tunneled hemodialysis catheters (NDCs) before TDC placement. RESULTS: The study analyzed 483 placed TDCs: 280 TDCs placed by radiologists and 203 by nephrologists. The D-P durations were 319 minutes (interquartile range [IQR], 180 to 1,057) in the radiologist group and 140 minutes (IQR, 0 to 792) in the nephrologist group. Additionally, the D-H durations were 415 minutes (IQR,260 to 1,091) and 275 minutes (IQR, 123 to 598), respectively. These differences were statistically significant (p = 0.00). The TDC success rate (95.3% vs. 94.5%, respectively; p = 0.32) and complication rate (16.2% vs. 11%, respectively; p = 0.11) did not differ between the groups. The frequency (24.5 vs. 26%, respectively; p = 0.72) and the usage time of NDC (8,451 vs. 8,416 minutes, respectively; p = 0.91) before TDC placement were not statistically significant. CONCLUSIONS: Trained interventional nephrologists could perform TDC placement safely, minimizing treatment delays.

Overhydration measured by bioimpedance analysis and the survival of patients on maintenance hemodialysis: a single-center study.

BACKGROUND: Bioimpedance analysis (BIA) helps measuring the constituents of the body noninvasively. Prior studies suggest that BIA-guided fluid assessment helps to predict survival in dialysis patients. We aimed to evaluate the clinical usefulness of BIA for predicting the survival rate of hemodialysis patients in Korea. METHODS: We conducted a single-center retrospective study. All patients were diagnosed with end-stage renal disorder and started maintenance hemodialysis between June 2009 and April 2014. BIA was performed within the 1(st) week from the start of hemodialysis. The patients were classified into 2 groups based on volume status measured by the body composition monitor (BCM; Fresenius): an overhydrated group [OG; overhydration/extracellular water (OH/ECW) >15%] and a nonoverhydrated group (NOG; OH/ECW ≤15%). RESULTS: A total of 344 patients met the inclusion criteria. Of these, 252 patients (73.3%) were categorized into the OG and 92 patients (26.7%) into the NOG. Age- and sex-matching patients were selected with a rate of 2:1. Finally, 160 overhydrated patients and 80 nonoverhydrated patients were analyzed. Initial levels of hemoglobin and serum albumin were significantly lower in the OG. During follow-up, 43 patients from the OG and 7 patients from the NOG died (median follow-up duration, 24.0 months). The multivariate-adjusted all-cause mortality was significantly increased in the OG (odds ratio, 2.569; P = 0.033) and older patients (odds ratio, 1.072/y; P < 0.001). No significant difference of all-cause or disease-specific admission rate was observed between the 2 groups. CONCLUSION: The ratio of OH/ECW volume measured with body composition monitor is related to the overall survival of end-stage renal disorder patients who started maintenance hemodialysis.