Stemness markers in hepatocellular carcinoma of Eastern vs. Western population: Etiology matters?

Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. HCC development is associated with its underlying etiologies, mostly caused by infection of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol, non-alcoholic fatty liver disease, and exposure to aflatoxins. These variables, together with human genetic susceptibility, contribute to HCC molecular heterogeneity, including at the cellular level. HCC initiation, tumor recurrence, and drug resistance rates have been attributed to the presence of liver cancer stem cells (CSC). This review summarizes available data regarding whether various HCC etiologies may be associated to the appearance of CSC biomarkers. It also described the genetic variations of tumoral tissues obtained from Western and Eastern populations, in particular to the oncogenic effect of HBV in the human genome.

Identifying Predictors of Mortality in Sepsis Patients with Malignancy: A Retrospective Cohort Study.

BACKGROUND: Sepsis is a major problem that contributes to a high mortality rate. Its mortality is especially high in patients with malignancy. One study reported that sepsis patients with malignancy have a 2.32 times higher risk of mortality compared to patients without malignancy. For this reason, factors that influence mortality in sepsis patients with malignancy become especially important to provide effective and efficient therapy. This study aims to identify factors that influence mortality in sepsis patients with malignancy. METHODS: This study is a retrospective cohort study using medical records of sepsis patients with malignancy who were treated at Cipto Mangunkusumo Hospital from 2020 to 2022. A bivariate analysis was carried out and followed by a logistic regression analysis on variables with p-value<0.25 on the bivariate analysis. RESULTS: Among the 350 eligible sepsis subjects with malignancy, there was an 82% mortality rate (287 subjects). Bivariate and multivariate analyses revealed significant associations between mortality and both SOFA score (adjusted Odds Ratio of 5.833, 95%CI 3.214-10.587) and ECOG performance status (adjusted Odds Ratio of 3.490, 95%CI 1.690-7.208). CONCLUSION: SOFA score and ECOG performance status are significantly associated with sepsis patient mortality in malignancy cases.

The correlation of anxiety and depression with C3 and C4 Levels and systemic lupus erythematosus activity.

BACKGROUND: Anxiety and depression are psychosomatic disorders that are frequently observed in chronic conditions such as systemic lupus erythematosus (SLE). Anxiety and depression can be induced by immunological and neurotransmitter dysregulation, which is characterized by hypothalamic-pituitary-adrenal (HPA) axis dysfunction, production of proinflammatory cytokines, and activation of complement in the blood, such as C3 and C4. The causes of anxiety and depression in SLE are complex, ranging from neuropsychiatric involvement to drug adverse effects. Detecting anxiety and depression symptoms in SLE patients is critical to preventing disability from impacting quality of life. OBJECTIVE: To assess the relationship between anxiety and depression symptomatology, SLE disease activity with levels of C3 and C4 in Cipto Mangunkusumo National Hospital. METHODS: This study used a cross-sectional design. The study included 120 SLE patients from Cipto Mangunkusumo National Hospital, aged 18 to 60 years. All patients were requested to complete a Hospital Anxiety and Depression Scale (HADS) questionnaire to assess their anxiety and depression symptoms. Subjects with anxiety and depression were assessed for disease activity using the Mexican Systemic Lupus Erythematosus Systemic Disease Activity (Mex-SLEDAI), and blood samples were collected to test complement C3 and C4 levels. Spearman's correlation test was used to examine the relationship between HADS scores, Mex-SLEDAI, and C3 and C4 levels. RESULTS: The results of the study showed a very weak statistically significant negative correlation between anxiety symptoms based on HADS and C3 levels (r = -0.189; p = 0.038) and a weak correlation between anxiety symptoms and C4 levels (r = -204; p = 0.026). Depressive symptoms based on HADS revealed a very poor connection and no statistical significance with levels of C3 (r = -0.056; p = 0.546) and C4 (r = -0.068; p = 0.461). Anxiety (r = 0.06; p = 0.173) and depression (r = 0.031; p = 0.753) symptoms have a weak and insignificant positive connection with SLE activity. CONCLUSION: C3 and C4 serum levels appeared to decrease when the presence of anxious symptoms increased. There was no significant correlation in SLE disease activity between anxious and depressed patients.

Diagnostic Performance of Mac-2-Binding Protein Glycosylation Isomer (M2BPGi), compared to Transient Elastography to Assess Liver Stiffness in Treatment Naïve Chronic Hepatitis C Patients.

BACKGROUND: Liver fibrosis is an essential factor in the management of Hepatitis C virus infection. Its assessment is crucial in decision-making regarding the therapeutic decisions, and the patients' follow up. However, the established liver measurement methods have several limitations. Therefore, this study aims to assess the role of Mac-2-Binding Protein Glycosylation Isomer (M2BPGi) as a novel biomarker to measure liver stiffness in treatment naïve Chronic Hepatitis C Indonesian patients. METHODS: This study used a cross-sectional design to determine the correlation between serum M2BPGi and the degree of liver stiffness, Transient Elastrography, and differences in serum M2BPGi levels in chronic hepatitis C patients. Serum M2BPGi level and Transient Elastography results were evaluated in 56 Chronic Hepatitis C patients and 48 healthy controls. Pearson correlation analysis was conducted to find the correlation between the level of M2BPGi and Transient Elastography result. ROC analysis was conducted to find the optimum cut-off to assess fibrosis's degree among Chronic Hepatitis C Patients. RESULTS: The level of serum M2BPGi and Transient Elastography result was strongly correlated with the median level of serum M2BPGi. It was also significantly higher among Chronic Hepatitis C Patients than among healthy controls (r: 0.708, p<0.001; 0.590 COI vs. 4.130 COI, p<0.001). Among the Chronic Hepatitis C patients, the median serum of M2BPGi increased according to the degree of liver fibrosis: 1.500 COI (F0-F1), 2.985 COI (F2-F3) and 8.785 COI (≥F4). The optimum cut-off value for diagnosing significant fibrosis (F2-F3) was 1.820 COI (AUC: 90.8%) and for diagnosing cirrhosis (≥F4) was 3.770 COI (AUC: 89.3%). CONCLUSION: Serum M2BPGi was a reliable diagnostic tool for identifying liver fibrosis in Indonesian patients with Chronic Hepatitis C.

The alpha-fetoprotein serum is still reliable as a biomarker for the surveillance of hepatocellular carcinoma in Indonesia.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC), the most common type of liver cancer, is one of the leading causes of cancer-related death worldwide with an inferior prognosis. In Indonesia, the average life expectancy is less than 5 months, with most patients being in an advanced stage wherein the survival rate is very low. Early detection through surveillance program is very crucial. HCC guidelines worldwide have provided surveillance recommendation through the examination of α-fetoprotein (AFP) and ultrasound for patients at risk in developing HCC. However, there have been some controversies regarding the usage of AFP concerning its low sensitivity and specificity in detecting HCC. Therefore, the effectiveness of AFP in the surveillance of HCC patients and identifying the parameters most associated with the increase of AFP ≥ 10 ng/ml in Indonesia should be evaluated. METHODS: We analyzed medical records of HCC patients and those at high risk of developing HCC through cross-sectional study, including patients with cirrhosis and hepatitis B and C, from 2015 to 2017 who underwent treatment at the Cipto Mangunkusumo National General Hospital and Dharmais National Cancer Hospital, Indonesia. RESULTS: The sensitivity and specificity of AFP in the surveillance of HCC in Indonesia with a cut-off of 10 ng/ml were 82.6 and 71.2%, respectively. The parameters most associated with the increase of AFP ≥10 ng/ml according to multivariate analysis were the etiology of hepatitis B, the stage of Barcelona Clinic Liver Cancer (BCLC) B and C, and the presence of cirrhosis, respectively. CONCLUSION: AFP can still be used in the surveillance of HCC in Indonesia for its high sensitivity value.

Evaluation of Acoustic Radiation Force Impulse (ARFI) for Fibrosis Staging in Chronic Liver Diseases.

BACKGROUND: acoustic radiation force impulse (ARFI) is a new proposed noninvasive method for liver fibrosis staging. Integrated with B-mode ultrasonography, ARFI can be used to assess liver tissue condition. However its diagnostic accuracy is still being continuously evaluated. Also, there is lack of data regarding the utilization of ARFI in our population. This study aimed to evaluate the diagnostic value of ARFI as an alternative noninvasive modality for fibrosis staging in chronic hepatitis B and hepatitis C patients in our population. METHODS: we conducted cross-sectional comparison of ARFI imaging and transient elastography on patients who underwent liver biopsy at Cipto Mangunkusumo Hospital. Fibrosis staging using METAVIR scoring system presented as standard reference. A total of 43 patients underwent liver biopsy was evaluated by ARFI imaging and transient elastography. Cut-off values were determined using receiver-operating characteristic (ROC). RESULTS: both liver stiffness determined by ARFI and transient elastography (TE) were moderately correlated with METAVIR score with value of 0.581 and 0.613, respectively (both P<0.01). Diagnostic accuracy of ARFI predicted significant fibrosis (F≥2) with area under receiver operating characteristic curve (AUROC) of 0.773 (95% CI 0.616-0.930) and even better for cirrhosis (F4 fibrosis), expressed as AUROC of 0.856 (95% CI 0.736-0.975). Transient elastography was better for significant fibrosis with AUROC of 0.761 (95% CI 0.601-0.920) and was best for prediction of cirrhosis, expressed as AUROC of 0.845 (95% CI 0.722-0.968). CONCLUSION: ARFI is provided with more convenient evaluation of liver tissue condition, and its diagnostic accuracy is not significantly different from TE for staging liver fibrosis.

The Correlation of Short-Chain Fatty Acids with Peripheral Arterial Disease in Diabetes Mellitus Patients.

Diabetes mellitus (DM) is a significant risk factor for peripheral arterial disease (PAD). PAD affects 20% of DM patients over 40 and has increased by 29% in the last 50 years. The gut microbiota produces short-chain fatty acids (SCFAs) that affect atherosclerosis. SCFA inhibits inflammation, which contributes to atherosclerosis. This study tried to link feces SCFA levels to atherosclerosis in people with diabetes with peripheral arterial disease (PAD). The study included 53 people with diabetes and PAD: gas chromatography-mass spectrometry measured acetate, butyrate, and propionate levels in feces samples (GC-MS). There was a positive correlation between random blood glucose (RBG) levels, peak systolic velocity (PSV), volume flow (VF), plaque, relative and absolute acetate, relative valerate, butyrate, and propionate. This supports the idea that elevated SCFA levels in type 2 diabetic (T2D) patients reduce adipose tissue inflammation and cholesterol metabolism, contributing to atherosclerosis pathogenesis. We conclude that increased fecal SCFA excretion is linked to cardiovascular disease. To determine the causal effect correlation of the SCFA with clinical and laboratory parameters for PAD in DM patients, compare the SCFA in plasma and feces, and account for confounding variables, a specific method with larger sample sizes and more extended follow-up periods is required.

Factors Influenced the Endoscopic Services Volume during the COVID-19 Pandemic at National Tertiary Referral Hospital in Indonesia: Dr. Cipto Mangunkusumo Hospital.

The impact of the COVID-19 pandemic caused a decrease in healthcare services, the intervention of non-surgical procedures, and endoscopy. This study examined the volume of endoscopy at Dr. Cipto Mangukusumo Hospital, the highest referral hospital in Indonesia. A cross-sectional mixed method was used to assess the relationship between endoscopy volume, age, gender, number of COVID-19 cases, type of patient's case, the origin of treatment, and the kind of endoscopic procedure before and during the pandemic. The secondary data were collected through the hospital's Electronic Health Record (EHR) System and "Kawal COVID-19" Websites, while the primary data were collected through observation, document reviews, and in-depth online interviews with doctors at endoscopic units. This study period was divided into six intervals of three months, respectively, from January 2020 to September 2021, and 5030 endoscopic procedures were collected. The data were analyzed both quantitatively through the SPSS statistics and qualitatively. The quantitative data presented as descriptive and bivariate results in an Independent T-Test and a Chi-Square test. The results showed there was a significant difference (p = 0.004) in the volume of endoscopes before (the highest volume) and during the pandemic (the lowest volume during April-June 2020 period). The mean age of the patients was higher before the pandemic. There was a significant difference between patient admissions from outpatient and emergency procedures before and during the pandemic. There are changes in the flow of outpatient to do endoscopies which were different from the flow of emergency patients during the pandemic, which focused on the long waiting list for inward entry queues, the mandatory COVID-19 PCR swab, and the criteria of emergency cases for fast-track procedures, the reduced bed capacity, and the expired date of laboratory examinations. The decreased volume was also caused by the limitation of patient intervention by the doctors. However, the duration of the action procedure was accelerated without reducing its quality. Furthermore, there was a high wave of Delta Variant cases from May to July 2021. In addition, the factors of age, type of patient's case, origin, and treatment showed significant differences before and during the COVID-19 pandemic. Finally, changes in the flow of services also influenced various impacts on endoscopy and service costs. Therefore, further study is required to calculate the unit costs.

Overall Survival of Hepatocellular Carcinoma Patients Underwent Radiofrequency Ablation (RFA) Treatment: a Retrospective Cohort Study from Two Referral Hospitals in Indonesia.

BACKGROUND: Radiofrequency ablation (RFA) is one of the curative modality therapies commonly used for the early stage of HCC management. Although numerous studies have reported the outcome of RFA around the world, the data regarding the usage of RFA for the early and intermediate stage of HCC remains limited. Hence, the study aimed to report the survival rate of the early and intermediate stage HCC patients who underwent RFA in two tertiary referral hospitals in Jakarta, Indonesia. METHODS: A retrospective cohort study was conducted in Cipto Mangunkusumo and Medistra multicenter hospital in Jakarta, Indonesia. The patients with HCC BCLC A and B who underwent RFA treatments between January 2015 to December 2017 were recruited for the study. Baseline characteristics of patients were collected from the medical record. Survival analysis was calculated using the Kaplan Meier. p value result was obtained from the log-rank test. Sub-analysis of factors associated with the survival was also included in this study. RESULTS: There were 62 patients enrolled in this study (32.3% were BCLC A and 67.7% were BCLC B). Forty-six out of 62 patients (74.2%) were reported to have RFA as their first line of treatment, while 12 (25.8%) were reported to have a combination of RFA and other therapy modalities. All these patients were follow-up with an average duration of 27 months. The survival rate of liver cancer due to HCC for 12 and 36 months in patients who received RFA was 82.3% and 57.8%, respectively. Moreover, BCLC staging of liver cancer and response after RFA was significantly associated with survival. CONCLUSION: RFA still can be used as initial modality therapy nor combination with another therapy for the early and intermediate stage of HCC. BCLC staging and response after RFA had shown to be the independent factors related to survival.

Correlation of gut Firmicutes/Bacteroidetes ratio with fibrosis and steatosis stratified by body mass index in patients with non-alcoholic fatty liver disease.

We investigated the gut microbiota in patients with non-alcoholic fatty liver disease (NAFLD) and its correlation with fibrosis and steatosis stratified by body mass index, as reflected in the controlled attenuation parameter and transient elastography values. A cross-sectional study was performed on 37 patients with NAFLD at Cipto Mangunkusumo National General Hospital from December 2018 to March 2019. The gut microbiota was investigated in fecal samples with 16S RNA sequencing using the MiSeq next-generation sequencing platform (Illumina). NAFLD was more common in patients with metabolic syndrome. Firmicutes, Bacteroidetes, and Proteobacteria were the predominant phyla. Bacteroides was more dominant than Prevotella, contrary to the results of previous studies on healthy populations in Indonesia. Microbiota dysbiosis was observed in most samples. The gastrointestinal microbiota diversity was significantly decreased in patients with NAFLD, high triglyceride levels, and central obesity. The Firmicutes/Bacteroidetes ratio correlated with steatosis and obesity, whereas some of the other species in lower taxonomy levels were mostly associated with steatosis and obesity without fibrosis. Proteobacteria was the only phylum strongly correlated with fibrosis in patients with an average body mass index. The gut microbiota diversity was decreased in patients with NAFLD, high triglyceride levels, and central obesity, and certain gut microbes were correlated with fibrosis and steatosis.

Effect of atorvastatin on subclinical atherosclerosis in virally-suppressed HIV-infected patients with CMV seropositivity: a randomized double-blind placebo-controlled trial.

Background: Persistent immune activation and inflammation in HIV-infection are linked to excess cardiovascular risk and other non-communicable diseases. Periodic asymptomatic CMV-reactivity in HIV infected patients over a lifetime may contribute to non-AIDS defining morbidity. Despite undetectable levels of HIV and CMV, these patients continue to have increased levels of biomarkers and immune activations. Statin administration is thought to reduce subclinical atherosclerosis by decreasing LDL-C levels. It may also add beneficial effects against CMV infection. Methods: We are conducting a double-blind placebo-controlled trial in which patients are randomized to receive either atorvastatin or placebo with a ratio of 1:1. This trial aims to study the effect of atorvastatin in statin-naive virally-suppressed HIV-infected patients with stable ART and CMV seropositivity on carotid intima media thickness (CIMT), tool that evaluates subclinical atherosclerosis. The study recruits 80 patients at HIV integrated care unit of Cipto Mangunkusumo hospital. All eligible subjects have CIMT evaluation as primary outcome, along with flow mediated vasodilatation (FMD), liver fibrosis and steatosis evaluation, fasting lipid, neurocognitive test, community periodontal index (CPI), and residual immune activation as secondary outcomes in 48 weeks. Ethics and dissemination: This study has received an ethical approval from Health Research Ethics Commitee-Universitas Indonesia and Cipto Mangunkusumo Hospital. Before joining the study, all participants fill in an informed consent form. At the end of study analysis, the trial results will be published and disseminated in peer-reviewed journals. Discussion: The main purpose of our study is to evaluate the effect of atorvastatin administration on CIMT changes in statin naïve virally suppressed HIV-infected patients with stable ART and CMV seropositivity Registration: ClinicalTrials.gov ID NCT04101136; registered on 24 September 2019.

Risk factors of mortality in the patients with hepatocellular carcinoma: A multicenter study in Indonesia.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is considered a significant burden, and its associated rate of mortality is increasing. Therefore, a population-based cancer registry is considered an essential element in the baseline and comprehensive analysis of the risk factors associated with HCC. We present a multicenter analysis of HCC registry from 2 hospitals in Indonesia. METHODS: We performed a follow-up on patients with HCC who were admitted between January 2015 and November 2017 in Cipto Mangunkusumo National General Hospital and Dharmais Hospital, Jakarta, Indonesia. Patient's death was considered the primary outcome of the study. A multivariate analysis was conducted using logistic regression, and odds ratio (OR) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 282 patients with HCC included. At the last follow-up, 136 (48.2%) patients had died. Mortality rate was not significantly affected by sex, age, etiology, the presence of cirrhosis, nor surveillance of HCC. Based on the Child-Pugh (CP) classification, the OR increased progressively in CP C patients (OR 1.95; 95% CI 1.08-3.53; P = 0.026). The progressive increase was also found in patients with a higher Barcelona Clinic Liver Cancer stage, and the OR for CP C and D patients were 3.50 (95% CI 1.18-10.38; P = 0.024) and 3.41 (95% CI 1.02-11.41; P = 0.047), respectively. Supportive treatment was the most common treatment modality with an OR of 2.17 (95% CI 1.14-4.16; P = 0.019), and it was associated with the mortality rate of HCC. CONCLUSIONS: The CP classification, Barcelona Clinic Liver Cancer staging system, and treatment modality might predict mortality in patients with HCC. Moreover, other parameters must be further evaluated.

The role of gut microbiota in non-alcoholic fatty liver disease: pathways of mechanisms.

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Its prevalence increases with increasing rates of obesity, insulin resistance, and diabetes mellitus. The pathogenesis of NAFLD involves many factors, including the gastrointestinal microbiota. However, there is still debate about the impact of gut dysbiosis in the NAFLD disease progression. Therefore, this paper aims to review the relationship between gut microbiota and other risk factors for NAFLD and how gut dysbiosis plays a role in the pathogenesis of NAFLD. Hopefully, this paper can make an appropriate contribution to the development of NAFLD research in the future.