Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Vaccinia-based oncolytic immunotherapy Pexastimogene Devacirepvec in patients with advanced hepatocellular carcinoma after sorafenib failure: a randomized multicenter Phase IIb trial (TRAVERSE).

Pexastimogene devacirepvec (Pexa-Vec) is a vaccinia virus-based oncolytic immunotherapy designed to preferentially replicate in and destroy tumor cells while stimulating anti-tumor immunity by expressing GM-CSF. An earlier randomized Phase IIa trial in predominantly sorafenib-naïve hepatocellular carcinoma (HCC) demonstrated an overall survival (OS) benefit. This randomized, open-label Phase IIb trial investigated whether Pexa-Vec plus Best Supportive Care (BSC) improved OS over BSC alone in HCC patients who failed sorafenib therapy (TRAVERSE). 129 patients were randomly assigned 2:1 to Pexa-Vec plus BSC vs. BSC alone. Pexa-Vec was given as a single intravenous (IV) infusion followed by up to 5 IT injections. The primary endpoint was OS. Secondary endpoints included overall response rate (RR), time to progression (TTP) and safety. A high drop-out rate in the control arm (63%) confounded assessment of response-based endpoints. Median OS (ITT) for Pexa-Vec plus BSC vs. BSC alone was 4.2 and 4.4 months, respectively (HR, 1.19, 95% CI: 0.78-1.80; p = .428). There was no difference between the two treatment arms in RR or TTP. Pexa-Vec was generally well-tolerated. The most frequent Grade 3 included pyrexia (8%) and hypotension (8%). Induction of immune responses to vaccinia antigens and HCC associated antigens were observed. Despite a tolerable safety profile and induction of T cell responses, Pexa-Vec did not improve OS as second-line therapy after sorafenib failure. The true potential of oncolytic viruses may lie in the treatment of patients with earlier disease stages which should be addressed in future studies. ClinicalTrials.gov: NCT01387555.

Early complications after percutaneous radiofrequency ablation for hepatocellular carcinoma: an analysis of 1,843 ablations in 1,211 patients in a single centre: experience over 10 years.

AIM: To evaluate the incidence of adverse events and associated factors after radiofrequency ablation (RFA) in patients with hepatocellular carcinoma within 30 days. MATERIALS AND METHODS: The early complications that occurred within 30 days after RFA at a single institution from January 2000 to July 2010 were reviewed in order to evaluate the morbidity, mortality, and risk factors associated with the complications. In total, 1,211 patients (845 men, 70.5%) with a mean age of 68 years (range, 27-88 years) underwent 1,843 RFA procedures. RESULTS: The overall incidence rate of complications was 6.8% (125 cases). Major complications (n=36, 2%) included liver abscess (n=15, 0.8%), intraperitoneal bleeding (n=8, 0.4%), liver failure (n=5, 0.3%), variceal bleeding (n=3, 0.2%), haemothorax (n=2, 0.1%), cholecystitis (n=2, 0.1%), and bowel perforation (n=1, 0.1%). Among the minor complications (n=89, 4.8%), the most common was the post RFA syndrome accompanied by pain and fever (n=75, 4.1%). Other minor complications included significant pleural effusion (n=7, 0.4%), skin wound infection (n=4, 0.2%), and thermal injuries to the skin (n=3, 0.2%). Procedural infections significantly increased with tumour size (OR=1.379; 95% confidence interval [CI], 1.191-1.579; p<0.001), and multiple overlapping ablations (OR=1.118; 95% CI, 1.019-1.227, p=0.018). Thrombocytopenia (<50,000/µl), prothrombin time, and serum albumin level were significantly associated with post-RFA bleeding episodes (p=0.041, p=0.021, and p=0.003, respectively). The overall mortality rate was 0.3% (three cases of hepatic failure, two case of sepsis, and one case of renal failure). CONCLUSIONS: RFA is a safe and effective local treatment for hepatocellular carcinoma. Careful selection of patients and appropriate RFA planning could decrease procedural mortality and morbidity.

Predictors of response to tenofovir disoproxil fumarate plus peginterferon alfa-2a combination therapy for chronic hepatitis B.

BACKGROUND: In patients with chronic hepatitis B, tenofovir disoproxil fumarate (TDF) plus pegylated interferon (PEG-IFN) for 48-weeks results in higher rates of hepatitis B surface antigen (HBsAg) loss than either monotherapy. AIM: To identify baseline and on-treatment factors associated with HBsAg loss at Week 72 and provide a model for predicting HBsAg loss in patients receiving combination therapy for 48 weeks. METHODS: A secondary analysis of data from an open-label study where patients were randomised to TDF (300 mg/day, oral) plus PEG-IFN (PI, 180 µg/week, subcutaneous) for 48 weeks (TDF/PI-48w); TDF plus PEG-IFN for 16 weeks, TDF for 32 weeks (TDF/PI-16w+TDF-32w); TDF for 120 weeks (TDF-120w) or PEG-IFN for 48 weeks (PI-48w). Logistic regression methods were used to identify models that best predicted HBsAg loss at Week 72. RESULTS: Rates of HBsAg loss at Week 72 were significantly higher in the TDF/PI-48w group (6.5%) than in the TDF/PI-16w+TDF-32w (0.5%), TDF-120w (0%) and PI-48w (2.2%) groups (P = 0.09). The only baseline factor associated with response was genotype A. HBsAg decline at Week 12 or 24 of treatment was associated with HBsAg loss at Week 72 (P < 0.001). HBsAg decline >3.5 log10 IU/mL at Week 24 in the TDF/PI-48w group resulted in a positive predictive value of 85% and a negative predictive value of 99% for HBsAg loss at Week 72. CONCLUSIONS: HBsAg decline at Week 24 of TDF plus PEG-IFN combination therapy may identify patients who, after completing 48 weeks of treatment, have a better chance of achieving HBsAg loss at Week 72.

A phase 3b study of sofosbuvir plus ribavirin in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 2 hepatitis C virus.

In Korea, patients with chronic hepatitis C virus (HCV) infection are typically treated with pegylated interferon-alpha plus ribavirin, but interferons are contraindicated in many patients and are often poorly tolerated, particularly by the elderly and those with advanced liver disease. No interferon-free treatment regimens are approved in Korea. Sofosbuvir is an oral nucleotide analog inhibitor of the HCV nonstructural 5B RNA polymerase. It is approved in the USA, European Union and Japan for treating a number of HCV genotypes, including genotype 2. Genotype 2 has a seroprevalence of 38-46% in Korea. This single-arm, phase 3b study (NCT02021643) examined the efficacy and safety of sofosbuvir plus ribavirin (12-week duration) in chronic genotype 2 HCV-infected treatment-naive and treatment-experienced Korean patients with and without cirrhosis. The proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12) was 97% (125/129), with 96% (101/105) of treatment-naive and 100% (24/24) of treatment-experienced patients achieving SVR12. Two patients experienced virologic failure (n = 1, on-treatment failure; n = 1, relapse). No patient discontinued study treatment due to an adverse event (AE). The most common treatment-emergent AEs were headache (18%, 23/129) and pruritus (15%, 19/129). Few patients had grade 3 AEs (5%, 6/129) or grade 3 laboratory abnormalities (12%, 15/129). No grade 4 AE was reported. These data suggest that 12 weeks of treatment with the all-oral, interferon-free regimen of sofosbuvir plus ribavirin is effective and well tolerated in Korean patients with chronic genotype 2 HCV infection.

The feasibility of endoscopic submucosal dissection for rectal carcinoid tumors: comparison with endoscopic mucosal resection.

BACKGROUND AND STUDY AIMS: Rectal carcinoid tumors are often found incidentally during screening colonoscopy and can be resected using various endoscopic techniques. This study aimed to compare the safety and efficacy of endoscopic submucosal dissection (ESD) with endoscopic mucosal resection (EMR) for rectal carcinoid tumors. PATIENTS AND METHODS: Between January 2003 and June 2009, 74 patients (74 lesions) underwent either EMR (n = 28) or ESD (n = 46) for rectal carcinoid tumors. The rate of endoscopic complete resection, pathological complete resection, procedure complications, and tumor recurrence were analyzed retrospectively. RESULTS: The endoscopic complete resection rate was significantly higher in the ESD group (46 lesions, 100 %) compared with the EMR group (25 lesions, 89.3 %) ( P = 0.049). The pathological complete resection rate was higher in the ESD group (38 lesions, 82.6 %) compared with the EMR group (18 lesions, 64.3 %); however, this difference was borderline significant ( P = 0.067). Overall complication rate was not significantly different between the EMR group (3.6 %) and the ESD group (6.3 %). There was one case of remnant lesion in the EMR group, which was managed by ESD, and no recurrence has been detected in either the EMR or ESD groups. CONCLUSION: This study suggests that ESD might be a feasible treatment technique for small rectal carcinoid tumors. It showed superior efficacy and comparable safety to EMR.

Where has the tumor gone? The characteristics of cases of negative pathologic diagnosis after endoscopic mucosal resection.

BACKGROUND AND STUDY AIMS: Discrepancies can occur between the histopathological findings from forceps biopsy and endoscopic mucosal resection (EMR), and occasionally in embarrassing cases tumorous tissue is not found at EMR. The aim of the present study was to evaluate the clinical, endoscopic, and histological features of gastric tumors in patients with pathololgically negative findings at EMR. PATIENTS AND METHODS: We retrospectively reviewed data from all patients with gastric tumor treated with EMR or endoscopic submucosal dissection (ESD) between August 1999 and April 2007 at our institution, and enrolled into the study patients with no tumor tissue found at mucosal resection. Their biopsy and EMR specimen slides were reviewed by a single pathologist. Patient characteristics, including demographic and clinical features, and the endoscopic appearance of mucosal lesions were evaluated. RESULTS: Out of 633 patients treated with EMR or ESD, 20 patients (3.2 %) were included. The mean +/- SD maximal dimension of the mucosal lesions was 6.40 +/- 2.19 mm (range 3 - 10). Mean number of forceps biopsy fragments was 3.80 +/- 1.96 and mean sampling ratio was 2.08 +/- 1.07 mm/fragment. Before resection, histological findings from forceps biopsy were: 13 low grade dysplasias (65.0 %), 2 high grade dysplasias (10.0 %), and 5 intramucosal carcinomas (25.0 %). CONCLUSIONS: In the case of pathologically negative findings at EMR, tumors might have been small enough to have been removed by the previous forceps biopsy. However, the possibility of sampling error or of a different location should be considered. Furthermore, appropriate communication between endoscopists and pathologists is essential.

Hyperglycaemia, hypercholesterolaemia and the risk for developing gastric dysplasia.

BACKGROUND/GOALS: Gastric dysplasia is believed to be the penultimate stage of gastric carcinogenesis. Few studies have evaluated whether there is a relationship between such risk factors and gastric dysplasia. This case-control study was conducted to investigate the associations between obesity, serum glucose, lipids and gastric dysplasia. STUDY: Endoscopic findings and pathology specimens were reviewed from 1 July 1997 to 31 December 2006 in the Health Promotion Center. One hundred thirty patients have the dysplasia in the stomach during screening endoscopy. The same number of controls was evaluated and matched to the gastric dysplasia group for age and gender. RESULT: The univariate analysis showed that the dysplasia risk was slightly increased among persons with a higher low-density lipoprotein, lower high-density lipoprotein, impaired fasting glucose and higher total cholesterol. However, a higher body mass index and higher triglyceride level were not associated with the diagnosis of gastric dysplasia. In the multivariate-adjusted model, a higher low-density lipoprotein cholesterol and glucose were strongly associated with an increased risk of dysplasia compared to the controls. However, the body mass index, triglyceride and total cholesterol were not associated with the risk for dysplasia. CONCLUSION: Hyperglycaemia and low-density lipoprotein cholesterol appear to be associated with the risk for gastric dysplasia. Further epidemiologic studies including a large cohort of patients with gastric dysplasia and adenocarcinoma are needed to clarify the association of low-density lipoprotein cholesterol, serum glucose and gastric carcinogenesis.

Factors related to lymph node metastasis and the feasibility of endoscopic mucosal resection for treating poorly differentiated adenocarcinoma of the stomach.

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) is currently not accepted as an alternative treatment to surgery in early gastric cancer (EGC) of the undifferentiated histologic type. The present retrospective analysis examined the correlation of various histologic factors with the presence of lymph node metastasis (LNM). PATIENTS AND METHODS: A retrospective analysis on 234 patients with poorly differentiated EGC who underwent radical gastrectomy with D2 lymph node dissection was undertaken. Several clinicopathologic factors were investigated to identify predictive factors for LNM: age, sex, type of operation, tumor location, tumor size, gross type, ulceration, lymphatic invasion, and depth of invasion. RESULTS: Of the 234 lesions with poorly differentiated EGC, half (n = 116) already showed submucosal invasion in the resection specimen; 25.9 % of those (30/116) were limited to the upper third (SM1). Of the lesions confined to the mucosa, LNM was found in 3.4 % (4/118). With minor submucosal infiltration (SM1), the LNM rate was lower (0/30) in our patient population. Only with SM2/3 infiltration did the LNM rate sharply rise to around 30 %. The cut-off for submucosal infiltration depth was 500 microm (0/32 LNM), above which LNM rates were substantial (31.2 %; 24/77). There was limited correlation between the SM1-3 classification and actual measurement of submucosal infiltration depth. In a multivariate analysis, tumor size ( P = 0.033), depth of invasion ( P = 0.004), and lymphatic invasion ( P < 0.001) were associated with LNM. CONCLUSION: Poorly differentiated EGC confined to the mucosa or with minimal submucosal infiltration (

Gastric lymphangioma.

Gastric lymphangioma is a rare benign gastric tumor composed of unilocular or multilocular lymphatic spaces. On gastrofiberscopy a submucosal tumor covered with smooth transparent normal mucosa is revealed in the stomach with or without a stalk. Endoscopic ultrasonography has become an indispensable tool for differentiating these gastric tumors. Treatment of lymphangioma depends on its size, location, and presence of complications. Endoscopic resection is safe and easy and plays an important role in confirming the diagnosis and treatment of the tumors especially of small-sized ones. We report a case of gastric lymphangioma in a 68-yr-old woman who presented with nausea and vague epigastric discomfort for two months. She was diagnosed by gastrofiberscopy with endoscopic ultrasonography and treated successfully with endoscopic resection by strip biopsy method.