Risk of HBV reactivation during therapies for HCC: A systematic review.

BACKGROUND AND AIMS: Treatment for HCC has evolved rapidly, but the risk of HBV reactivation to new therapies is unclear. We systematically reviewed data on HBV reactivation in patients receiving HCC therapy in relation to use of HBV antiviral prophylaxis. APPROACH AND RESULTS: A literature search was performed to identify all published studies including HBsAg-positive patients with HCC providing data on HBV reactivation. Forty-one studies with 10,223 patients, all from Asia, were included. The pooled HBV reactivation rate was 5% in patients receiving no specific HCC therapy and was higher in patients undergoing surgical resection (16%), transarterial chemoembolization (19%), or radiotherapy (14%) and intermediate in patients treated with local ablation therapy (7%) or systemic agents (7%). HBV reactivation rates were higher in those without compared to those with HBV prophylaxis (ablation, 9% versus 0%; resection, 20% versus 3%; chemoembolization, 23% versus 1%; external radiotherapy alone, 18% versus 0%; systemic therapy, 9% versus 3%). HBV-related biochemical reactivation rates varied between 6%-11% and 2% in patients receiving HCC therapies with high and intermediate HBV reactivation risk, respectively. Liver decompensation and death were rarely reported (0%-3%) and only in patients receiving HCC treatment with high HBV reactivation risk. CONCLUSIONS: HBsAg-positive patients with HCC are at high or intermediate risk of HBV reactivation depending on the type of HCC therapy. Nucleos(t)ide analogue prophylaxis reduces the risk of HBV reactivation, practically eliminates the risk of hepatitis flare, and should be administered regardless of HCC treatment.

Inappropriate prescribing in geriatric rural primary care: impact on adverse outcomes and relevant risk factors in a prospective observational cohort study.

BACKGROUND: Several tools have revealed an association between potentially inappropriate medications (PIM) and adverse outcomes, but the one most fitted for the rural population has not been determined. AIMS: We investigated the performance of the Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert doctors to the Right Treatment (START) in identifying inappropriate prescribing and its association with adverse outcomes among older rural primary health care users. METHODS: A cohort of consenting outpatients aged ≥ 65 years in a rural Greek primary care center was assessed for PIM and potential prescribing omissions (PPO) using the START/STOPP version 2 criteria. Medications, comorbidities, functional status, and laboratory data were recorded along with 6-month incidence of emergency department visits, hospitalization, and death prospectively. RESULTS: Among 104 participants (median age 78 years, 49.1% women, receiving a median of 6 drugs), PPO was found in 78% and PIMs in 61%. PIM was multivariately correlated with multimorbidity (p = 0.029) and polypharmacy (p < 0,001), while drug-PPO was only associated with multimorbidity (p = 0.039). The number of PIM predicted emergency department visits and hospitalizations at 6-month follow-up (p value 0.011), independent of age, sex, frailty, comorbidities, and total medication number. DISCUSSION: The START/STOPP tool is useful in identifying inappropriate prescribing patterns leading to increased utilization of acute care services in older adults followed at a rural primary care setting. CONCLUSION: Inappropriate prescribing as identified by the START/STOPP criteria is prevalent among older adults with multimorbidity in rural primary care, and independently associated with future acute care visits.

Cellular, Molecular and Proteomic Characteristics of Early Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early detection/diagnosis is vital for the prognosis of HCC, whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on 6-month surveillance of the patient and the use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulating tumor cells (CTCs) in the blood of patients with cirrhosis or early or advanced HCC. We studied 89 patients with HCC, of whom 33 had early HCC and 28 were cirrhotic. CTCs were detected by real-time quantitative reverse transcription PCR and immunofluorescence using the markers epithelial cell adhesion molecule (EPCAM), vimentin, alpha fetoprotein (aFP) and surface major vault protein (sMVP). Expression of the five most common HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in serum using quantitative real time PCR (qRT-PCR). Finally, patient serum was analyzed via whole proteome analysis (LC/MS). Of 53 patients with advanced HCC, 27 (51%) had detectable CTCs. Among these, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 2/28 (7%) cirrhotic patients had detectable CTCs. Patients with early or advanced HCC exhibited a significant increase in miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cirrhotic patients. When taken in combination, this covers the 100% of the patients with early HCC. miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be potentially useful in combination for the early diagnosis of HCC.

Treatment of chronic hepatitis C with direct-acting antivirals in patients with ß-thalassaemia major and advanced liver disease.

Interferon-based regimens for chronic hepatitis C (CHC) were often deferred in patients with ß-thalasaemia major (ß-TM) due to poor efficacy and tolerance. Current guidelines recommend direct-acting antivirals (DAAs) for these patients. The aim of this study was to assess the safety and efficacy of DAAs in patients with ß-TM and advanced liver disease due to CHC. Patients were recruited from eight liver units in Greece. The stage of liver disease was assessed using transient elastography and/or liver histology. Five regimens were used: sofosbuvir (SOF) + ribavirin (RBV); SOF + simeprevir ± RBV; SOF + daclatasvir ± RBV; ledipasvir/SOF ± RBV and ombitasvir/paritaprevir-ritonavir + dasabuvir ± RBV. Sixty-one patients (median age 43 years) were included. The majority of patients was previously treated for hepatitis C (75%) and had cirrhosis (79%). Viral genotype distribution was: G1a: n = 10 (16%); G1b: n = 22 (36%); G2: n = 2 (3%); G3: n = 14 (23%); G4: n = 13 (22%). The predominant chelation therapy was a combination of deferoxamine and deferiprone (35%). Overall sustained virological response rates were 90%. All treatment regimens were well tolerated and no major adverse events or drug-drug interactions were observed. Approximately half of the patients who received RBV (7/16, 44%) had increased needs for blood transfusion. Treatment of CHC with DAAs in patients with ß-TM and advanced liver disease was highly effective and safe.

Isolated nonspecific terminal ileitis: prevalence, clinical evolution and correlation with metachronous diagnosis of Crohn's disease: a retrospective study and review of the literature.

Background: The existing literature does not provide adequate guidance on the diagnosis and management of patients with nonspecific terminal ileitis, while data regarding the percentage of patients who ultimately develop Crohn's disease (CD) are scarce. We evaluated the prevalence and natural course of nonspecific terminal ileitis in patients who underwent colonoscopy during a 11-year period. Methods: All patients with endoscopic findings of terminal ileitis and nonspecific histological findings were included. Exclusion criteria were a clinical history of CD or any other disease that can cause terminal ileitis, or a recent history of using drugs implicated in lesions of the terminal ileum. Results: From 5353 colonoscopies, 92 patients with nonspecific terminal ileitis were identified (prevalence: 1.7%). Among these patients, 56 (61%) had available follow up for ≥6 months after the initial endoscopy. Main indications for endoscopy were chronic diarrhea (37.5%), screening endoscopy (23%), and abdominal pain (20%). Sixteen (29%) patients received medical treatment, while recession of symptoms was recorded in 19 of 43 symptomatic patients (44.1%). Twenty-three (41%) of the 56 patients underwent a second endoscopy and 15 (65.2%) cases had persistent endoscopic findings. Eleven (19.6%) of the 56 patients were eventually diagnosed with CD. The probability of CD diagnosis was significantly higher in patients with persistent symptoms (P=0.002) and endoscopic findings at follow up (P=0.038). Conclusions: Nonspecific terminal ileitis generally has a benign clinical course. However, patients with persistent symptoms and endoscopic lesions are at increased risk for subsequent development of CD.

Management of Hepatocellular Carcinoma in Decompensated Cirrhotic Patients: A Comprehensive Overview.

Primary liver cancer is the sixth most common cancer and the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) accounts for 75% of primary liver cancer cases, mostly on the basis of cirrhosis. However, the data and therapeutic options for the treatment of HCC in patients with decompensated cirrhosis are rather limited. This patient category is often considered to be in a terminal stage without the possibility of a specific treatment except liver transplantation, which is restricted by several criteria and liver donor shortages. Systemic treatments may provide a solution for patients with Child Pugh class B or C since they are less invasive. Although most of the existing trials have excluded patients with decompensated cirrhosis, there are increasing data from real-life settings that show acceptable tolerability and satisfying efficacy in terms of response. The data on the administration of locoregional treatments in such patients are also limited, but the overall survival seems to be potentially prolonged when patients are carefully selected, and close adverse event monitoring is applied. The aim of this review is to analyze the existing data regarding the administration of treatments in decompensated patients with HCC, evaluate the effect of therapy on overall survival and highlight the potential risks in terms of tolerability.

The changing epidemiology of hepatocellular carcinoma in Greece.

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer globally, and is attributable mainly to viral hepatitis, alcohol and nonalcoholic fatty liver disease. METHODS: Three hundred Greek patients diagnosed with HCC between 2000 and 2019 were retrospectively evaluated for patient and HCC characteristics. Patients were classified as before 2011 (A) or after 2011 (B) and HCC risk factors were compared with historic Greek cohorts. RESULTS: The median age was 64 years and 86% were male; 45% had chronic hepatitis B virus (HBV) infection, 26% chronic hepatitis C virus (HCV) infection, and 30% non-viral liver diseases (nvLD). No change was observed among liver diseases between periods A and B. However, there was a trend towards a decrease in virally and an increase in non-virally induced HCC (P=0.075). Patients in period B (vs. A) were more likely to be diagnosed with fewer (<3, P=0.006) and smaller (<3 cm, P=0.005) nodules. Compared with 1558 Greek HCC patients from 1974-2000, there was a decrease in HBV and an increase in HCV and nvLD-related HCCs (P<0.001). CONCLUSIONS: In Greece, after 2000, there was a decrease in the proportion of HBV and an increase in the proportion of HCV and nvLD-related HCC, while over the last 2 decades there has been a trend towards a decrease in virally and an increase in non-virally induced HCC. Since 2011, HCC is being diagnosed at an earlier stage, possibly reflecting improved surveillance strategies.

Intrahepatic recurrence of hepatocellular carcinoma after resection: an update.

Hepatocellular carcinoma recurrence occurs in 40-70% of patients after hepatic resection. Despite the high frequency of hepatocellular cancer relapse, there is no established guidance for the management of such cases. The evaluation of prognostic factors that indicate a high risk of recurrence after surgery such as the tumor number and size and the presence of microvascular invasion may guide the therapeutic strategy and point out which patients should be strictly monitored. Additionally, the administration of adjuvant treatment or ab initio liver transplantation in selected patients with high-risk characteristics could have a significant impact on the prevention of relapse and overall survival. Once the recurrence has occurred in the liver remnant, the available therapeutic options include re-resection, salvage liver transplantation and locoregional treatments, although the therapeutic choice is often challenging and should be based on the characteristics of the recurrent tumor, the patient profile and most importantly the timing of relapse. Aggressive combination treatments are often required in challenging cases of early relapse. The results of the above treatment strategies are reviewed and compared to determine the optimal management of patients with recurrent hepatocellular cancer following liver resection.

Characteristics and Prognosis of Hepatocellular Carcinoma in Multi-Transfused Patients with ß-Thalassemia. Experience of a Single Tertiary Center.

BACKGROUND/AIM: The incidence of hepatocellular carcinoma (HCC) in patients with transfusion dependent thalassemia (TDT) has been increasing, where viral hepatitis and iron overload are the two established HCC risk factors. The aim of this study was to investigate the etiological factors of HCC development and to evaluate the possible factors associated with survival in our cohort of TDT patients with HCC. METHODS: Records of patients with TDT diagnosed with HCC from 2008 to 2018 were reviewed. Liver iron concentration (LIC) has been assessed by the signal-intensity-ratio MRI. The diagnosis of HCC was made by a 3-phase contrast magnetic resonance imaging (MRI) and patients were staged and treated for HCC according to Barcelona Clinic Liver Cancer (BCLC) grading system. RESULTS: Forty-two TDT patients with HCC have been included. Most of them (78.5%) were anti-HCV positive, 59.5% HCV-RNA positive, and 16.5% had serological markers of resolved HBV infection. Patients with HCV infection have been treated successfully with either Peg-IFNa±Ribavirin or with the new direct antivirals (DAAs). At the time of HCC diagnosis, all patients with chronic HCV infection were HCV-RNA negative, 78.5% had underlying cirrhosis, and the vast majority (98%) had average or mild elevated LIC values. According to the BCLC system, patients were classified as 0-A: 28.5%, B: 57% and C-D: 14.5%. HCC has been treated with loco-regional treatment in 78.5% of our patients, while the rest have received sorafenib. Twenty-eight patients (66.5%) died due to HCC with a median survival time of 6 months (range: 2-60). Using the Cox proportional hazard model, the only factors associated with poor survival were BCLC stages C and D. CONCLUSIONS: In conclusion, BCLC staging is the main prognostic factor of survival in patients with TDT who develop HCC.

Association of TIM-3 with BCLC Stage, Serum PD-L1 Detection, and Response to Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

Considering the increasing importance of immune checkpoints in tumor immunity we investigated the clinical relevance of serum T-cell immunoglobulin and mucin domain-3 (TIM-3) in patients with hepatocellular carcinoma (HCC). Serum TIM-3 levels were measured and their association with HCC stage and the detection of serum programmed death ligand-1 (PD-L1) were assessed. In patients submitted to transarterial chemoembolization (TACE), pre- and 1-week post-treatment TIM-3 levels were also evaluated. We studied 53 HCC patients with BCLC stages: 0 (5.7%), A (34%), B (32.1%), C (22.6%), and D (5.7%). The patients with advanced HCC (BCLC C) had significantly higher TIM-3 levels than patients with BCLC A (p = 0.009) and BCLC B (p = 0.019). TIM-3 levels were not associated with HCC etiology (p = 0.183). PD-L1 detection (9/53 patients) correlated with TIM-3 levels (univariate analysis, p = 0.047). In 33 patients who underwent TACE, post-treatment TIM-3 levels (231 pg/mL, 132-452) were significantly higher than pre-TACE levels (176 pg/mL, 110-379), (p = 0.036). Complete responders had higher post-TACE TIM-3 levels (534 pg/mL, 370-677) than partial responders (222 pg/mL, 131-368), (p = 0.028). Collectively, TIM-3 may have a role in anti-tumor immunity following TACE, setting a basis for combining immunotherapy and chemoembolization.

Wilson disease: 30-year data on epidemiology, clinical presentation, treatment modalities and disease outcomes from two tertiary Greek centers.

OBJECTIVE: Wilson disease is a rare genetic disorder of copper metabolism with a wide range of clinical presentations. The aim of this study is to describe the 30-year clinical experience in the management of Wilson disease patients followed at two Greek referral centers. METHODS: A retrospective chart review was performed to identify past and present Wilson disease patients diagnosed during the last 30 years. RESULTS: Sixty-three patients were included. The median age of diagnosis was 19 (3-59) years, while nine (14%) patients were older than 40 years old. Clinical presentation included asymptomatic liver disease (57.1%), neurological disease (20.6%), overt liver disease (12.7%), acute liver failure (6.3%) and other (3.2%). Kayser-Fleischer rings were detected in 27/62 with a higher frequency in neurologic patients (P < 0.001). Ceruloplasmin values were low in 55/63 with significantly lower values in patients with neurological disease (P = 0.048) and in cirrhotic patients (P = 0.017). Increased 24-hour urine copper was measured in 59/63 patients. D-penicillamine was administered in 56/63 patients (88.8%), followed by trientine (6/63, 9.5%), while one patient needed liver transplantation at baseline. At least one treatment switch was performed in 18 patients. By the end of follow-up, all non-cirrhotic patients (25/25) were stable, 3/23 (13%) cirrhotic developed decompensated liver disease, two developed HCC, three received a liver transplant and two died. Five out of 13 neurologic patients had persisting symptoms despite treatment. CONCLUSION: Wilson disease presents with a wide spectrum of clinical manifestations and should be investigated even in older patients, as early diagnosis, close follow-up and treatment monitoring usually provide favorable outcomes.

Impact of direct-acting antiviral agents on the development of hepatocellular carcinoma: evidence and pathophysiological issues.

Hepatitis C virus (HCV) infection is currently one of the main causes of cirrhosis and hepatocellular carcinoma (HCC) at a global level. Recently, a new generation of direct-acting antiviral agents (DAAs) has entered the HCV treatment landscape, providing impressively high rates of sustained virological response (SVR), and is expected to lead to an eventual decrease in HCV-related cirrhosis, liver transplantation and mortality. However, during the first years of their use, several studies reported a possible correlation between DAA treatment and an increased risk of HCC. Following the publication of larger prospective studies, the risk of de novo HCC occurrence has clearly been proven to be lower after the achievement of SVR, regardless of antiviral treatment. On the other hand, the risk of HCC recurrence following treatment with DAAs is debatable; existing data remain controversial, possibly because of the lack of large, well designed cohorts with more homogeneous patient populations. With regard to the pathophysiology behind the above observations, especially in patients with previous HCC history, HCC development could possibly be favored by the changes in the immunological milieu and the different cellular behavior after eradication of HCV infection with DAA treatment.

A multicenter, prospective, observational study of the long-term outcomes of Crohn's disease patients under routine care management in Greece.

BACKGROUND: Real-world data on management patterns and long-term outcomes of patients with inadequately controlled Crohn's disease (CD) in Greece are scarce. METHODS: This was a multicenter, prospective observational study of 18-65-year-old CD patients whose physicians judged that their current therapy was inadequate to control their condition and therefore decided to switch treatment. Data were collected at enrollment (time of switch), and 30, 54 and 104 weeks post-enrollment. RESULTS: Sixty-six eligible patients (median age: 35.8 years; 56.1% males; median CD diagnosis duration: 2.3 years) were enrolled by nine hospital sites. At the time of treatment switch, 66.7% had "mild" (CD activity index [CDAI] <220) and 30.3% "moderate-to-severe" (220≤CDAI≤450) disease activity. Ileocolonic involvement, extraintestinal manifestations, prior CD-related surgeries and prior corticosteroid use were reported in 65.2%, 51.5%, 24.2% and 78.8% of patients, respectively. Throughout the study, most patients were managed with anti-tumor necrosis factor (TNF) medications (74.2%/74.1% infliximab; 10.6%/13.8% adalimumab at enrollment/end of study, respectively). At 54 and 104 weeks post-enrollment, the baseline CDAI score (median 174.5) decreased to 145.5 and 146.0 points (P<0.001) and the baseline C-reactive protein level (median: 13.6 mg/L) decreased to 3.5 and 3.0 mg/L (P<0.001), respectively, not differing statistically between patients with "mild" and "moderate-to-severe" disease activity. In this patient population, 56.1% were corticosteroid-free throughout observation, while for the remaining 43.9%, the mean percentage corticosteroid-free period was 80.2%. CD-related surgeries and hospitalizations were reported in 8.1% and 19.4%, respectively. CONCLUSION: Under routine care in Greece, inadequately controlled CD patients were mainly switched to anti-TNFs, which lowered disease activity and reduced corticosteroid use.

Circulating biomarkers of hepatocellular carcinoma response after locoregional treatments: New insights.

Hepatocellular cancer is the 5(th) most common cancer in the world and the third cause of death by malignant disease. Locoregional therapies are the most usual treatment of choice for patients with early or intermediate stage of disease. The main diagnostic tools for the detection of recurrence are the radiological techniques such as 4-phase computed tomography or dynamic contrast enhanced magnetic resonance imaging. However, in order to achieve best evaluation of treatment outcome and recurrence rates, there is a great need for the identification of specific and easily measured circulating biomarkers. The aim of this review is to analyze the existing data considering the prognostic significance of changes of serum diagnostic markers such as alpha-fetoprotein, des-gamma-carboxy prothrombin, alpha-fetoprotein-L3, angiogenetic factors (vascular endothelial growth factor, hypoxia inducible factor-1a) and immune parameters before and after radiofrequency ablation or transarterial chemoembolization.

Extrahepatic immune related manifestations in chronic hepatitis C virus infection.

The association of chronic hepatitis C with immune related syndromes has been frequently reported. There is a great range of clinical manifestations affecting various systems and organs such as the skin, the kidneys, the central and peripheral nervous system, the musculoskeletal system and the endocrine glands. Despite the high prevalence of immune related syndromes in patients with chronic hepatitis C, the exact pathogenesis is not always clear. They have been often associated with mixed cryoglobulinemia, a common finding in chronic hepatitis C, cross reaction with viral antigens, or the direct effect of virus on the affected tissues. The aim of this review is to analyze the reported hepatitis C virus immune mediated syndromes, their prevalence and clinical manifestations and to discuss the most supported theories regarding their pathogenesis.

Hepatitis C virus (HCV)-related cryoglobulinemia: cryoglobulin type and anti-HCV profile.

Cryoglobulin characteristics in chronic hepatitis C (CHC) might be of importance for knowing more about the pathogenesis and treatment of the disease. We aimed to investigate the relationship between cryoglobulin types and their specificity against hepatitis C virus (HCV) antigenic epitopes in CHC patients. We analyzed samples from 43 patients with HCV-associated cryoglobulinemia, of whom 4 had concomitant lymphoma. Cryoglobulins were measured, purified, typed by immunofixation electrophoresis, and tested for IgG and IgM anti-HCV antibodies by immunoblot analysis and an enzyme-linked immunosorbent assay (ELISA). Clinical and other laboratory data were recorded. The median cryocrit level of the tested samples was 6%. Type I cryoglobulins were detected in 9.3% (4/43) of the cryoprecipitates, and type II cryoglobulins were detected in 48.8% (21/43) of the cryoprecipitates. IgM monoclonal protein, mainly IgM(κ), was found in 92% (23/25) of type I and II cryoprecipitates. Type III cryoglobulins were identified in 41.9% (18/43) of the patients and were associated with high blood serum IgG levels. In 81.3% (13/16) of type II and 92.3% (12/13) of type III cryoglobulins, there was IgG reactivity against the viral core region. Ninety-two percent and 32% of IgG anti-HCV core-positive cryoprecipitates had additional specificities against the NS3 and NS4 regions, respectively. Also, IgM anti-HCV antibodies were detected in 31% of the cryoprecipitates. In conclusion, all types of cryoglobulins were found in patients with HCV-associated cryoglobulinemia, with type II being the most frequently identified. Type III cryoglobulins were common and were associated with high serum IgG levels. HCV-related cryoglobulins demonstrated IgM, and particularly IgG, anti-HCV specificities, mainly against the core and NS3 epitopes.