Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

An algorithm for simplified hepatitis C virus treatment with non-specialist care based on nation-wide data from Taiwan.

BACKGROUND: Both European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) guidelines recommend simplified hepatitis C virus (HCV) treatment with pan-genotypic sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for eligible patients. This observational study used real-world data to assess these regimens' safety in eligible patients and develop an algorithm to identify patients suitable for simplified treatment by non-specialists. METHODS: 7,677 HCV-infected patients from Taiwan Hepatitis C Registry (TACR) who received at least one dose of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, and fulfilled the EASL/AASLD-IDSA criteria for simplified treatment were analyzed. Multivariate analysis was conducted on patient characteristics and safety data. RESULTS: Overall, 92.8% (7,128/7,677) of patients achieved sustained virological response and only 1.9% (146/7,677) experienced Grades 2-4 laboratory abnormalities in key liver function parameters (alanine aminotransferase, aspartate aminotransferase, and total bilirubin), with only 18 patients (0.23%) experiencing Grades 3-4 abnormalities. Age > 70 years old, presence of hepatocellular carcinoma, total bilirubin > 1.2 mg/dL, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and Fibrosis-4 > 3.25 were associated with higher risks of Grades 2-4 abnormalities. Patients with any of these had an odds of 4.53 times than that of those without in developing Grades 2-4 abnormalities (p < 0.01). CONCLUSIONS: Real-world data from Taiwan confirmed that simplified HCV treatment for eligible patients with pan-genotypic regimens is effective and well tolerated. The TACR algorithm, developed based on this study's results, can further identify patients who can be safely managed by non-specialist care.

Artificial intelligence predicts direct-acting antivirals failure among hepatitis C virus patients: A nationwide hepatitis C virus registry program.

BACKGROUND/AIMS: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1-3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. METHODS: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. RESULTS: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. CONCLUSION: Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Factors predicting long-term outcomes of early-stage hepatocellular carcinoma after primary curative treatment: the role of surgical or nonsurgical methods.

BACKGROUND: We quantified the elusive effects of putative factors on the clinical course of early hepatocellular carcinoma (HCC) after primary surgical or nonsurgical curative treatment. METHODS: Patients with newly diagnosed early HCC who received surgical resection (SR) or percutaneous radiofrequency ablation (RFA) with or without transcatheter arterial chemoembolization (TACE) from January 2003 to December 2016 were enrolled. The cumulative overall survival (OS) and disease-free survival (DFS) rates were compared. A polytomous logistic regression was used to estimate factors for early and late recurrence. Independent predictors of OS were identified using Cox proportional hazard regression. RESULTS: One hundred twenty-five patients underwent SR, and 176 patients underwent RFA, of whom 72 were treated with TACE followed by RFA. Neither match analysis based on propensity score nor multiple adjustment regression yielded a significant difference in DFS and OS between the two groups. Multivariate analysis showed high AFP (> 20 ng/mL), and multinodularity significantly increased risk of early recurrence (< 1 year). In contrast, hepatitis B virus, hepatitis C virus and multinodularity were significantly associated with late recurrence (> 1 year). Multivariate Cox regression with recurrent events as time-varying covariates identified older age (HR = 1.55, 95% CI:1.01-2.36), clinically significant portal hypertension (CSPH) (HR = 1.97, 95% CI:1.26-3.08), early recurrence (HR = 6.62, 95% CI:3.79-11.6) and late recurrence (HR = 3.75, 95% CI:1.99-7.08) as independent risk factors of mortality. A simple risk score showed fair calibration and discrimination in early HCC patients after primary curative treatment. In the Barcelona Clinic Liver Cancer (BCLC) stage A subgroup, SR significantly improved DFS compared to RFA with or without TACE. CONCLUSION: Host and tumor factors rather than the initial treatment modalities determine the outcomes of early HCC after primary curative treatment. Statistical models based on recurrence types can predict early HCC prognosis but further external validation is necessary.

Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: A real-world nationwide hepatitis C virus registry programme in Taiwan.

BACKGROUND/AIMS: Direct-acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)-infected patients. The real-world treatment outcome in Taiwanese patients on a nationwide basis is elusive. METHODS: The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end-of-treatment). RESULTS: A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype-1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment-naïve noncirrhotic, treatment-naïve cirrhotic, treatment-experienced noncirrhotic and treatment-experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment-experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment-naïve noncirrhotic patients (94.8%) and treatment-experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio [aOR]/95% confidence interval [CI]: 117.1/52.4-261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25-14.9, P = .0003 and aOR/CI: 1.55/1.05-2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57-7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67-3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94-5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20-5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57-2.97, P < .001). CONCLUSIONS: DAAs are highly effective in treating Taiwanese HCV patients in the real-world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.

Acoustic Radiation Force Impulse Elastography with APRI and FIB-4 to Identify Significant Liver Fibrosis in Chronic Hepatitis B Patients.

INTRODUCTION AND AIM: In chronic hepatitis B (CHB) patients with equivocal indication for antiviral therapy, therapeutic decision currently depends on histopathology of the liver. We aimed to evaluate if acoustic radiation force impulse (ARFI) in conjunction with aspartate transaminase to platelet ratio index (APRI) and fibrosis-4 (FIB-4) score could replace liver biopsy to indicate treatment for CHB. MATERIAL AND METHODS: We prospectively enrolled 101 clinically non-cirrhotic patients whose serum alanine aminotransferase was mildly elevated (1-2 folds above the upper normal limit) despite a high viral load (HBV DNA > 2,000 IU/mL). All participants underwent liver biopsy, and measurement of ARFI, APRI and FIB-4. The ability of the markers to distinguish fibrosis ≥ METAVIR F2 was evaluated. RESULTS: According to histopathology, liver fibrosis was METAVIR F0 in 2 (2.0%), F1 in 43 (42.6%), F2 in 34 (33.7%), F3 in 16 (15.8%), and F4 in 6 (5.9%) patients, and was correlated with ARFI (p = 0.0001), APRI (p = 0.012), and FIB-4 (p = 0.004). The six patients with cirrhosis were included for analysis, and received antiviral therapy. The C statistics of ARFI, APRI, and FIB-4 for fibrosis ≥ F2 were 0.70 (95% confidence interval [CI], 0.59-0.80), 0.62 (95% CI, 0.51-0.73), and 0.64 (0.53- 0.75), respectively. The cut-off values for 95% sensitivity and 95% specificity to identify significant fibrosis were 0.97 m/sec and 1.36 m/sec for ARFI, 0.36 and 1.0 for APRI, 0.63 and 2.22 for FIB-4, respectively. Using a combination of these 3 indices, 44 patients (43.6%) could be spared a liver biopsy procedure. CONCLUSIONS: A combination of ARFI, APRI, and FIB-4 may spare some CHB patients with equivocal indication for antiviral treatment a liver biopsy.

Role of computed tomography angiography on the management of overt obscure gastrointestinal bleeding.

BACKGROUND AND AIM: The role of computed tomography angiography (CTA) on the management of acute overt obscure gastrointestinal bleeding (OGIB) remains unclear. We designed a study to evaluate the impact of CTA before enteroscopy for acute overt OGIB. METHODS: All patients undergoing CTA followed by enteroscopy for acute overt OGIB were enrolled in this retrospective study. Clinical characteristics and diagnosis were compared between patients with positive and negative CTA findings. We evaluated the impact of CTA on subsequent enteroscopy. RESULTS: From February 2008 to March 2015, 71 patients including 25 patients with positive CTA findings and 46 patients with negative CTA findings, were enrolled. All 25 patients with positive CTA findings were confirmed to have mid GI lesions, a significantly higher proportion than among patients with negative CTA findings (100% vs. 52.2%, respectively; P <0.001). CTA had a higher diagnostic yield for bleeding from tumor origin than from non-tumor origin (80.0% vs. 23.7%, respectively; P <0.001). The diagnostic yield of CTA and enteroscopy was 35.2% and 73.2%, respectively. The lesions could be identified by the initial route of enteroscopy in more patients with positive CTA findings than in those with negative CTA findings (92.0% vs. 47.8%, respectively; P <0.001). Lesions could be identified in seven of the 25 patients (28.0%) with positive CTA findings by using only push enteroscopy instead of single-balloon enteroscopy (SBE), but all 46 patients with negative CTA findings needed SBE for deep small-bowel examination. CONCLUSIONS: CTA is useful in the diagnosis of acute overt OGIB, especially in patients with bleeding from tumors. In addition, it also can show the precise location of bleeding, and guide subsequent enteroscopic management.

A case series on the use of circumferential radiofrequency ablation for early esophageal squamous neoplasias in patients with esophageal varices.

BACKGROUND AND AIMS: Endoscopic radiofrequency ablation (RFA) is a rapidly evolving therapeutic modality for early esophageal squamous cell neoplasias (ESCNs). However, the feasibility of RFA for ESCNs in the setting of esophageal varices has not been reported. METHODS: We retrospectively enrolled 8 consecutive patients with cirrhosis (Child-Pugh score ≤6) with early flat-type ESCNs (high-grade intraepithelial neoplasia/intramucosal cancer, and Lugol unstained lesion [USL] length ≥3 cm extending ≥1/2 the circumference) on or adjacent to esophageal varices, for which circumferential RFA was applied as the initial treatment. The primary endpoint was a complete response at 12 months, and the secondary endpoints were adverse events and procedure-related mortality. RESULTS: The mean USL length was 5.3 cm (range, 3-10 cm), and the average length of the treatment area was 7.5 cm (range, 5-12 cm), with an average procedure time of 31.9 min (range, 25-40 min). After circumferential RFA, 3 adverse events were recorded, including 2 intramucosal hematomas and 1 mucosal laceration, all of which spontaneously resolved without further management. No massive bleeding, perforation, stricture, or hepatic failure occurred after the procedure. Six of the 8 patients achieved a complete response after single circumferential RFA, but 2 had residual squamous neoplasias. After additional focal-type RFA treatment, all achieved a complete response at 12 months. No neoplastic progression or recurrence occurred during a median follow-up period of 21.6 months (range, 13-42 months). CONCLUSIONS: RFA was associated with good treatment results, no neoplastic progression, and an acceptable adverse event profile for the treatment of early ESCNs in patients with well-compensated cirrhosis and esophageal varices.

Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients.

BACKGROUND & AIMS: Oral antiviral therapy may reduce the disease progression of chronic hepatitis B (CHB) patients. We aimed to further investigate the efficacy of long-term entecavir therapy in reduction of the risk of hepatocellular carcinoma (HCC), cirrhotic events and mortality in a large group of CHB-related cirrhosis patients. METHODS: The C-TEAM (Cirrhosis-Taiwanese EntecAvir Multicenter) study was a nationwide, multicenter, retrospective-prospective cohort study in Taiwan. We enrolled treatment-naïve patients with CHB-related cirrhosis and baseline HBV-DNA≥2000 IU/mL receiving long-term entecavir therapy and compared the development of HCC, cirrhotic events and mortality with that of a historical untreated cohort. RESULTS: In total, 1315 entecavir-treated and 503 untreated patients with cirrhosis were enrolled, with median treatment and follow-up durations of 4 and 6 years respectively. Compared with the untreated cohort, entecavir therapy was associated with a 60% HCC risk reduction [hazard ratio (HR): 0.40, 95% confidence interval (CI): 0.28-0.57]. Additionally, an older age, the male gender, HBeAg positivity, alpha-fetoprotein (AFP)≥7 ng/mL before therapy were independent predictors of HCC development. Further analysis showed that entecavir therapy significantly reduced risks of variceal bleeding, spontaneous bacterial peritonitis, and liver-related and all-cause mortality. These findings were confirmed by propensity score-matched cohorts in sensitivity analysis. In patients under entecavir therapy, an older age, the male gender, HBeAg positivity, AFP level ≥7 ng/mL before therapy, and 1-year virological response were predictive of HCC development. CONCLUSIONS: Four-year entecavir therapy significantly reduces the risk of HCC, cirrhotic events and mortality in patients with CHB-related cirrhosis.

Comparative effectiveness of nucleos(t)ide analogues in chronic hepatitis B patients undergoing cytotoxic chemotherapy.

BACKGROUND: Comparative effectiveness of different nucleos(t)ide analogues for preventing hepatitis B virus reactivation induced by cytotoxic chemotherapy has not been elucidated. The prophylactic drug of choice remains controversial. AIM: Our objective was to compare the effectiveness of tenofovir, telbivudine and entecavir with lamivudine in preventing the reactivation of hepatitis B virus caused by chemotherapy. METHODS: This retrospective cohort study consecutively screened all patients who were positive for hepatitis B virus surface antigen and received chemotherapy for malignant diseases in a teaching hospital in Taiwan. Eligible patients were grouped according to whether they received nucleos(t)ide analogues before (prophylactic group) or during chemotherapy (historical control). Those who received antiviral prophylaxis were further classified by the medications that included lamivudine, telbivudine, entecavir and tenofovir. The incidence of hepatitis, liver decompensation and interruption of chemotherapy were audited. RESULTS: A total of 212 consecutive patients were enrolled into analysis. Those who prophylactically used nucleos(t)ide analogues (n = 177) had significantly lower rates of liver decompensation (0.6% vs 20%, P < 0.01), interruption of chemotherapy (0% vs 40%, P < 0.01) and incidence of hepatitis (4.5% vs 100%, P < 0.01), as compared with their historical control (n = 35). In the prophylactic group, there was no difference among tenofovir, telbivudine, entecavir and lamivudine users in the incidence of hepatitis, liver decompensation and interruption of chemotherapy. CONCLUSION: Lamivudine, telbivudine, entecavir and tenofovir are all effective as the prophylactic antiviral therapy to prevent reactivation of hepatitis B induced by chemotherapy.

Doxorubicin-modified magnetic nanoparticles as a drug delivery system for magnetic resonance imaging-monitoring magnet-enhancing tumor chemotherapy.

In this study, we developed functionalized superparamagnetic iron oxide (SPIO) nanoparticles consisting of a magnetic Fe3O4 core and a shell of aqueous stable polyethylene glycol (PEG) conjugated with doxorubicin (Dox) (SPIO-PEG-D) for tumor magnetic resonance imaging (MRI) enhancement and chemotherapy. The size of SPIO nanoparticles was ~10 nm, which was visualized by transmission electron microscope. The hysteresis curve, generated with vibrating-sample magnetometer, showed that SPIO-PEG-D was superparamagnetic with an insignificant hysteresis. The transverse relaxivity (r 2) for SPIO-PEG-D was significantly higher than the longitudinal relaxivity (r 1) (r 2/r 1 >10). The half-life of Dox in blood circulation was prolonged by conjugating Dox on the surface of SPIO with PEG to reduce its degradation. The in vitro experiment showed that SPIO-PEG-D could cause DNA crosslink more serious, resulting in a lower DNA expression and a higher cell apoptosis for HT-29 cancer cells. The Prussian blue staining study showed that the tumors treated with SPIO-PEG-D under a magnetic field had a much higher intratumoral iron density than the tumors treated with SPIO-PEG-D alone. The in vivo MRI study showed that the T2-weighted signal enhancement was stronger for the group under a magnetic field, indicating that it had a better accumulation of SPIO-PEG-D in tumor tissues. In the anticancer efficiency study for SPIO-PEG-D, the results showed that there was a significantly smaller tumor size for the group with a magnetic field than the group without. The in vivo experiments also showed that this drug delivery system combined with a local magnetic field could reduce the side effects of cardiotoxicity and hepatotoxicity. The results showed that the developed SPIO-PEG-D nanoparticles own a great potential for MRI-monitoring magnet-enhancing tumor chemotherapy.

The Spatial Predilection for Early Esophageal Squamous Cell Neoplasia: A "Hot Zone" for Endoscopic Screening and Surveillance.

Early esophageal squamous cell neoplasias (ESCNs) are easily missed with conventional white-light endoscopy. This study aimed to assess whether early ESCNs have a spatial predilection and the patterns of recurrence after endoscopic treatment. We analyzed the circumferential and longitudinal location of early ESCNs, as well as their correlations with exposure to carcinogens in a cohort of 162 subjects with 248 early ESCNs; 219 of which were identified by screening and 29 by surveillance endoscopy. The circumferential location was identified using a clock-face orientation, and the longitudinal location was identified according to the distance from the incisor. The most common circumferential and longitudinal distributions of the early ESCNs were found in the 6 to 9 o'clock quadrant (38.5%) and at 26 to 30 cm from the incisor (41.3%), respectively. A total of 163 lesions (75%) were located in the lower hemisphere arc, and 149 (68.4%) were located at 26 to 35 cm from the incisor. One hundred eleven (51%) early ESCNs were centered within the "hot zone" (i.e., lower hemisphere arc of the esophagus at 26 to 35 cm from the incisor), which comprised 20% of the esophageal area. Exposure to alcohol, betel nut, or cigarette was risk factors for the development of early ESCNs in the lower hemisphere. After complete endoscopic treatment, the mean annual incidence of metachronous tumors was 10%. In addition, 43% of the metachronous recurrent neoplasias developed within the "hot zone." Cox regression analysis revealed that the index tumor within the hot zone (hazard ratio [HR]: 3.19; 95% confidence interval [CI]: 1.17-8.68; P = 0.02) and the presence of numerous Lugol-voiding lesions in the esophageal background mucosa were independent predictors for metachronous recurrence (HR: 4.61; 95% CI: 1.36-15.56; P = 0.01). We identified a hot zone that may be used to enhance the detection of early ESCNs during endoscopic screening and surveillance, especially in areas that lack resources and have a high prevalence of ESCNs.

Human papillomavirus infection on initiating synchronous esophageal neoplasia in patients with head and neck cancer.

OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV) is a risk factor for head and neck squamous cell carcinoma (HNSCC) as well as esophageal squamous cell carcinoma (ESCC). We aimed to investigate whether HPV infection underlies the field cancerization phenomenon over upper aerodigestive tract to develop synchronous multiple cancers. STUDY DESIGN: A case control study. METHODS: The presence and subtype of HPV-DNA sequence in cancers were examined by polymerase chain reaction and sequencing in a prospective cohort with 100 HNSCCs, 50 of which had synchronous ESCCs. The clinicopathologic characteristics were further analyzed according to the presence of HPV. RESULTS: Twelve patients were HPV-positive, of which 11 were positive for HPV-16. The prevalence of HPV infection were not different between the synchronous and HNSCC alone groups (P = 0.357). Testing for HPV in paired HNSCC and ESCC tissues from the same patient revealed that none were concomitantly HPV-positive. Multivariate logistic regression showed drinking alcohol (odds ratio [OR], 18.75; P = 0.030), alcohol flushing (OR, 2.53; P = 0.041), and body mass index (OR, 0.77; P = 0.001) but not HPV infection were independent risk factors for synchronous phenotype. The patients with synchronous ESCCs had significantly poorer survival than those with HNSCC alone (5-year overall survival: 30% vs. 70%; log-rank P < 0.001). However, patients with HPV-positive HNSCC tend to have favorable outcome than those with HPV-negative HNSCC. CONCLUSIONS: HPV infection plays little role in field cancerization phenomenon to initiate synchronous SCC. The synchronous HNSCC and ESCC from the same patients had no clonal relationship. Routine endoscopic examination of the esophagus should be recommended for patients with risk factors identified. LEVELS OF EVIDENCE: NA. Laryngoscope, 126:1097-1102, 2016.

Radiofrequency Ablation Versus Endoscopic Submucosal Dissection in Treating Large Early Esophageal Squamous Cell Neoplasia.

Radiofrequency ablation (RFA) and endoscopic submucosal dissection (ESD) can potentially be applied for early esophageal squamous cell neoplasia (ESCN); however, no study has directly compared these 2 modalities.We retrospectively enrolled the patients with flat-type "large" (length ≥3 cm extending ≥1/2 of the circumference of esophagus) early ESCNs treated endoscopically. The main outcome measurements were complete response at 12 months, and adverse events.Of a total of 65 patients, 18 were treated with RFA and 47 with ESD. The procedure time of RFA was significantly shorter than that of ESD (126.6 vs 34.8 min; P < 0.001). The complete resection rate of ESD and complete response rate after primary RFA were 89.3% and 77.8%, respectively. Based on the histological evaluation of the post-ESD specimens showed 14 of 47 (29.8%) had histological upstaging compared with the pre-ESD biopsies, and 4 of them had lymphovascular invasion requiring chemoradiation or surgery. After additional therapy for residual lesions, 46 (97.9%) patients in the ESD group and 17 (94.4%) patients in the RFA group achieved a complete response at 12 months. Four patients (8.5%) developed major procedure-related adverse events in the ESD group, but none in the RFA group. In patients with lesions occupying more than 3/4 of the circumference, a significantly higher risk of esophageal stenosis was noted in the ESD group compared with RFA group (83% vs 27%, P = 0.01), which required more sessions of dilatation to resolve the symptoms (median, 13 vs 3, P = 0.04). There were no procedure-related mortality or neoplastic progression in either group; however, 1 patient who received ESD and 1 who received RFA developed local recurrence during a median follow-up period of 32.4 (range, 13-68) and 18.0 (range, 13-41) months, respectively.RFA and ESD are equally effective in the short-term treatment of early flat large ESCNs; however, more adverse events occur with ESD, especially in lesions extending more than 3/4 of the circumference. RFA does not allow for pathology to evaluate the curability after ablation, and thus currently the use for invasive ESCNs should be conservative until longer follow-up studies are available.

Current trends and recent advances in diagnosis, therapy, and prevention of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has been one of the most fatal malignant tumors worldwide and its associated morbidity and mortality remain of significant concern. Based on in-depth reviews of serological diagnosis of HCC, in addition to AFP, there are other biomarkers: Lens culinaris agglutinin-reactive AFP (AFP-L3), des- carboxyprothrombin (DCP), tyrosine kinase with Ig and eprdermal growth factor (EGF) homology domains 2 (TIE2)-espressing monocytes (TEMs), glypican-3 (GPC3), Golgi protein 73 (GP73), interleukin-6 (IL-6), and squamous cell carcinoma antigen (SCCA) have been proposed as biomarkers for the early detection of HCC. The diagnosis of HCC is primarily based on noninvasive standard imaging methods, such as ultrasound (US), dynamic multiphasic multidetector-row CT (MDCT) and magnetic resonance imaging (MRI). Some experts advocate gadolinium diethyl-enetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and contrast-enhanced US as the promising imaging madalities of choice. With regard to recent advancements in tissue markers, many cuting-edge technologies using genome-wide DNA microarrays, qRT-PCR, and proteomic and inmunostaining studies have been implemented in an attempt to identify markers for early diagnosis of HCC. Only less than half of HCC patients at initial diagnosis are at an early stage treatable with curative options: local ablation, surgical resection, or liver transplant. Transarterial chemoembolization (TACE) is considered the standard of care with palliation for intermediate stage HCC. Recent innovative procedures using drug-eluting-beads and radioembolization using Yttrium-90 may exhibit beneficial effects in HCC treatment. During the past few years, several molecular targeted agents have been evaluated in clinical trials in advanced HCC. Sorafenib is currently the only approved systemic treatment for HCC. It has been approved for the therapy of asymptomatic HCC patients with well-preserved liver function who are not candidates for potentially curative treatments, such as surgical resection or liver transplantation. In the USA, Europe and particularly Japan, hepatitis C virus (HCV) related HCC accounts for most liver cancer, as compared with Asia-Pacific regions, where hepatitis B virus (HBV) may play a more important role in HCC development. HBV vaccination, while a vaccine is not yet available against HCV, has been recognized as a best primary prevention method for HBV-related HCC, although in patients already infected with HBV or HCV, secondary prevention with antiviral therapy is still a reasonable strategy. In addition to HBV and HCV, attention should be paid to other relevant HCC risk factors, including nonalcoholic fatty liver disease due to obesity and diabetes, heavy alcohol consumption, and prolonged aflatoxin exposure. Interestingly, coffee and vitamin K2 have been proven to provide protective effects against HCC. Regarding tertiary prevention of HCC recurrence after surgical resection, addition of antiviral treatment has proven to be a rational strategy.

The impact of human papillomavirus infection on the survival and treatment response of patients with esophageal cancers.

OBJECTIVE: This study aimed to investigate the impact of human papillomavirus (HPV) infection on the prognosis and treatment response of esophageal squamous cell carcinoma (ESCC). METHODS: We examined the presence and subtypes of HPV in the tumors by polymerase chain reaction and sequencing in 150 ESCC patients. Their clinicopathological characteristics, treatment response and survival were further analyzed according to the presence of HPV infection. RESULTS: Of 150 ESCC tumor samples, 27 (18.0%) were HPV-positive, of which 22 (81.5%) had HPV-16 infection. The risk of developing multifocal ESCC was not significantly different in the HPV-positive and HPV-negative groups (29.6% vs 28.5%, P = 0.90). In subgroup analysis, patients with HPV-16-positive advanced ESCC had a significantly better survival than those with HPV-negative ESCC (3-year survival: 55% vs 21%, log-rank P = 0.03). Cox proportional hazards model showed that the presence of HPV-16 was associated with a significant reduction in the mortality rate (hazard ratio 0.41, 95% CI 0.18-0.96). Patients with HPV-16 infection had better response to chemoradiotherapy (CRT) than those without HPV-16 infection (P = 0.026). CONCLUSIONS: In patients with advanced ESCC, HPV-16-positive patients had a significantly favorable survival, especially those who received CRT. Larger scale studies are needed to determine the causal relationship.

Determinants of hepatocellular carcinoma in cirrhotic patients treated with nucleos(t)ide analogues for chronic hepatitis B.

OBJECTIVES: We aimed to identify determinants of hepatocellular carcinoma (HCC) in cirrhotic patients who received nucleos(t)ide analogues for chronic hepatitis B (CHB). PATIENTS AND METHODS: This retrospective-prospective study screened all patients (n = 1630) who received antiviral therapy for CHB between 1 September 2007 and 31 March 2013 at the E-Da Hospital and enrolled 210 consecutive cirrhotic patients with pretreatment viral DNA >2000 IU/mL. Those who developed HCC within 3 months of treatment were excluded. All participants were observed until occurrence of HCC, death or 1 January 2014. The incidence and determinants of HCC were estimated using competing risk analyses adjusted for mortality. RESULTS: Thirty-five (16.7%) patients developed HCC during a median follow-up of 25.2 months (IQR, 16.3-37.3 months), with a cumulative incidence of 24.1% (95% CI, 16.3%-32.0%) at 5 years. Multivariate-adjusted analyses identified age >55 years [adjusted hazard ratio (HR), 2.19; 95% CI, 1.03-4.66], male gender (adjusted HR, 3.07; 95% CI, 1.05-9.02), model for end-stage liver disease (MELD) score >12 points (adjusted HR, 2.16; 95% CI, 1.10-4.23) and diabetes mellitus (DM; adjusted HR, 3.49; 95% CI, 1.54-7.91) as independent risk factors after adjusting for multiple covariates, including antidiabetes medication. A scoring formula that used information on age, gender, MELD score, DM and antidiabetes regimen significantly discriminated patients at high or low risk of HCC, with sensitivity and specificity of 82.9% and 62.3%, respectively. CONCLUSIONS: Age, gender, hepatic dysfunction, DM and medication for DM are baseline factors that stratify the risk of HCC in cirrhotic patients who receive nucleos(t)ide analogues for CHB.

Effectiveness of intragastric balloon treatment for obese patients: one-year follow-up after balloon removal.

BACKGROUND: The Bioenterics Intragastric Balloon (BIB) is effective for weight loss. However, comparisons of its effectiveness between groups with different body mass index (BMI) are rare. This study compared the effectiveness of BIB treatment in patients with BMI <32 kg/m(2) and those with BMI ≥ 32 kg/m(2) at the time of BIB removal and at 1 year later. METHODS: Between April 2009 and June 2011, 28 obese patients who completed a full course of BIB treatment were enrolled. There are 16 patients with BMI <32 and 12 with BMI ≥ 32. Patients who lost more than 20 % of excess weight (% EWL) were categorized as responders. RESULTS: The BMI significantly fell from 32.4 ± 3.7 to 28.5 ± 3.7 kg/m(2) (P < 0.01) at the time of BIB removal. All biochemical measurements except for cholesterol level were significantly improved. The median value of %EWL of all patients at BIB removal was 40.1, and 20 patients (71.4 %) were responders. Adherence to dietitian counseling was significantly better in responders than in non-responders (85 vs. 25 %, respectively; P < 0.01). The percentage of responders at 1 year after BIB removal was significantly higher among patients with BMI <32 than those with ≥ 32 (62.5 vs. 16.7 %, respectively; P = 0.02). CONCLUSIONS: BIB placement can achieve significant weight loss and improvement of co-morbidities in obese patients. Better adherence to dietitian counseling is associated with better response. Patients with BMI <32 maintain better weight loss at 1 year after BIB removal.

Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis.

BACKGROUND & AIMS: Taiwan has a high prevalence of hepatitis B viral (HBV) infection and hepatocellular carcinoma (HCC) with increasing consumption of alcohol. We investigated the impact of heavy alcohol consumption and HBV infection on HCC in cirrhotic patients. METHODS: 966 cirrhotic patients (132 with HBV infection and alcoholism, 632 with HBV infection, and 202 patients with alcoholism) were enrolled between 2000 and 2009 and followed until 2011. The primary end point was newly developed HCC. RESULTS: Within the three patient groups (cirrhotic patients with HBV infection and alcoholism, HBV infection alone, and alcoholism alone) 38 (28.8%), 100 (15.8%), and 21 (10.4%) showed newly developed HCC, respectively. The 10-year cumulative (52.8% vs. 39.8% vs. 25.6%, p <0.001) and annual incidences (9.9%, 4.1%, and 2.1%) of HCC were significantly higher in cirrhotic patients with HBV infection and alcoholism than those in patients with HBV infection or alcoholism alone. For patients with HBV infection and alcoholism, baseline serum HBV DNA (OR=16.8, p=0.025), antiviral nucleos(t)ides analogues (NUCs) therapy (OR=0.01, p=0.035), and serum α-fetoprotein (OR=1.18, p=0.045) were risk predictors of HCC by multivariate logistic regression models. The cumulative incidence of HCC was higher in patients with higher baseline serum HBV DNA. Antiviral NUCs therapy reduced the incidence of HCC. CONCLUSIONS: Heavy alcohol consumption significantly increased the risk of HCC in HBV-related cirrhotic patients. Elevated baseline serum HBV DNA was a strong risk predictor of HCC and antiviral NUCs therapy reduced the incidence of HCC in cirrhotic patients with HBV infection and alcoholism.