Treatment allocation is extremely complex in patients with hepatocellular carcinoma (HCC) because this neoplasm arises, in most cases, in patients with cirrhosis and additional comorbidities. The ...“stage hierarchy” approach, which involves linking each stage (or substage) of the disease to a specific treatment, has become the main proposed treatment strategy for the clinical management of HCC, particularly in the West. The Barcelona Clinic Liver Cancer (BCLC) scheme serves as the main example of the application of this strategy. In an attempt to increase the plasticity of the “stage hierarchy” approach as well as its adaptability to the requirements of real‐world clinical practice, the latest versions of European and American guidelines have introduced certain relevant elements of flexibility, which were not intrinsic to the original BCLC scheme. These elements are as follows: the “treatment stage migration” strategy, which allows moving to another treatment (generally the one that is associated with the subsequent stage) if the approach linked with the current stage proves to be unfeasible, and the “treatment stage alternative” approach, which proposes further therapeutic options for each BCLC‐defined stage. In regard to most of the solid cancers, another potential strategy is to consider the treatment decision to be hierarchically dictated by the efficacy of each therapy with complete or partial independence from the tumor stage. This concept of “therapeutic hierarchy” has been historically endorsed by the Asia‐Pacific treatment algorithm as well as by the recent Italian multisociety guidelines. The present review provides a critical analysis of the different conceptual approaches to HCC management, highlighting their advantages and disadvantages and focusing on the remarkable differences between the stage‐guided and the hierarchical strategies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Gastritis OLGA-staging ranks the risk for gastric cancer (GC) in progressive stages (0-IV). This long-term follow-up study quantifies the GC risk associated with each OLGA stage.
Consecutive patients ...(7436) underwent esophagogastroscopy (T-0), with mapped gastric biopsies, OLGA staging, and H. pylori status assessment. Patients with neoplastic lesion (invasive or non-invasive) at the index endoscopy (and/or within 12 months) were excluded. All patients were followed-up (T-1) by combining different sources of clinical/pathological information (Regional Registries of: (i) esophagogastroduodenoscopies; (ii) pathology reports; (iii) cancer, (iv) mortality). The endpoint was histologically documented development of gastric epithelial neoplasia.
At T-0, the patients' distribution by OLGA stage was: Stage 0 = 80.8%; Stage I = 12.6%; Stage II = 4.3%; Stage III = 2.0%; Stage IV = 0.3%; H. pylori infection was detected in 25.9% of patients. At the end of the follow-up (mean/median = 6.3/6.6 years), 28 incident neoplasia were documented (overall prevalence = 0.60 per 10
/person-years; low-grade intraepithelial neoplasia = 17/28; high-grade intraepithelial neoplasia = 4/28; GC = 7/28). By OLGA stage at the enrollment, the rate of incident neoplasia was: Stage 0 = 1 case; rate/10
person-years = 0.03; 95%CI: 0.004-0.19; Stage I = 2 cases; rate/10
person-years = 0.34; 95%CI: 0.09-1.36; Stage II = 3 cases; rate/10
person-years = 1.48; 95%CI: 0.48-4.58; Stage III = 17 cases; rate/10
person-years = 19.1; 95%CI: 11.9-30.7; Stage IV = 5 cases; rate/10
person-years = 41.2; 95%CI: 17.2-99.3. Multivariate analysis including gender, age, H. pylori status, and OLGA stage at enrollment only disclosed OLGA stage as predictor of neoplastic progression (OLGA stage III: HR = 712.4, 95%CI = 92.543-5484.5; OLGA stage IV: HR = 1450.7, 95%CI = 166.7-12626.0).
Among 7436 patients, OLGA stages at the enrollment correlated significantly with different risk for gastric neoplasia. Based on the obtained results, gastritis staging is a critical adjunct in endoscopy follow-up protocols aimed at GC secondary prevention.
The prognosis of untreated patients with hepatocellular carcinoma (HCC) is heterogeneous, and survival data were mainly obtained from control arms of randomized studies. Clinical practice data on ...this topic are urgently needed, so as to help plan studies and counsel patients. We assessed the prognosis of 600 untreated patients with HCC managed by the Italian Liver Cancer Group. Prognosis was evaluated by subdividing patients according to the Barcelona Clinic Liver Cancer (BCLC) classification. We also assessed the main demographic, clinical, and oncological determinants of survival in the subgroup of patients with advanced HCC (BCLC C). Advanced (BCLC C: n = 138; 23.0%) and end‐stage HCC (BCLC D; n = 210; 35.0%) represented the majority of patients. Overall median survival was 9 months, and the principal cause of death was tumor progression (n = 279; 46.5%). Patients' median survival progressively and significantly decreased as BCLC stage worsened (BCLC 0: 38 months; BCLC A: 25 months; BCLC B: 10 months; BCLC C: 7 months; BCLC D: 6 months; P < 0.0001). Female gender (hazard ratio HR = 0.55; 95% confidence interval CI = 0.33‐0.90; P = 0.018), ascites (HR = 1.81; 95% CI = 1.21‐2.71; P = 0.004), and multinodular (>3) HCC (HR = 1.79; 95% CI = 1.21‐2.63; P = 0.003) were independent predictors of survival in patients with advanced HCC (BCLC C). Conclusion: BCLC adequately predicts the prognosis of untreated HCC patients. In untreated patients with advanced HCC, female gender, clinical decompensation of cirrhosis, and multinodular tumor are independent prognostic predictors and should be taken into account for patient stratification in future therapeutic studies. (Hepatology 2015;61:184–190)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This ...latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic(and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and(intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integratingendoscopy, serology, histology and molecular profiling.
Summary Worldwide, colorectal cancer (CRC) screening programs have significantly increased the detection of sub-mucosal (pT1) adenocarcinoma. Completion surgery may be indicated after endoscopic ...excision of these potentially metastasizing early cancers. However, the post-surgical prevalence of nodal implants does not exceed 15%, leading to questions concerning the clinical appropriateness of any post-endoscopy surgery. Eastern scientific societies (Japanese Society for Cancer of the Colon-Rectum, in particular) include tumor budding (TB), defined as the presence of isolated single cancer cells or clusters of fewer than five cancer cells at the tumor invasive front, among the variables that must be included in histological reports. In Western countries, however, no authoritative endorsements recommend the inclusion of TB in the histology report due to the heterogeneity of definitions and measurement methods as well as its apparent poor reproducibility. To assess the prognostic value of TB in pT1-CRCs, this meta-analysis evaluated 41 studies involving a total of 10,137 patients. We observed a strong association between the presence of TB and risk of nodal metastasis in pT1-CRC. In comparing TB-positive (684/2,401; 28.5%) versus TB-negative (557/7,736; 7.2%) patients, the prevalence of nodal disease resulted in an OR value of 6.44 (95%CI: 5.26–7.87; p<0.0001; I2=30%). This increased risk of regional nodal metastasis was further confirmed after accounting for potential confounders. These results support the priority of histologically reporting TB in any endoscopically removed pT1-CRC to direct more appropriate patient management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death. Although the burden of alcohol- and NASH-related HCC is growing, chronic viral hepatitis (HBV and HCV) remains a ...major cause of HCC development worldwide. The pathophysiology of viral-related HCC includes liver inflammation, oxidative stress, and deregulation of cell signaling pathways. HBV is particularly oncogenic because, contrary to HCV, integrates in the cell DNA and persists despite virological suppression by nucleotide analogues. Surveillance by six-month ultrasound is recommended in patients with cirrhosis and in "high-risk" patients with chronic HBV infection. Antiviral therapy reduces the risks of development and recurrence of HCC; however, patients with advanced chronic liver disease remain at risk of HCC despite virological suppression/cure and should therefore continue surveillance. Multiple scores have been developed in patients with chronic hepatitis B to predict the risk of HCC development and may be used to stratify individual patient's risk. In patients with HCV-related liver disease who achieve sustained virological response by direct acting antivirals, there is a strong need for markers/scores to predict long-term risk of HCC. In this review, we discuss the most recent advances regarding viral-related HCC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Although transcatheter arterial chemoembolization (TACE) is effective in hepatocellular carcinoma (HCC), it is not considered a curative procedure. Among the factors potentially interfering with its ...effectiveness is a hypothetical neoangiogenic reaction due to ischemia. In our study, we evaluated the changes in the levels of two angiogenic factors (vascular endothelial growth factor VEGF and basic fibroblast growth factor b-FGF) and one parameter of invasiveness (urokinase-type plasminogen activator uPA) in patients treated with TACE.
Three blood samples were provided from 71 HCC patients undergoing TACE: before TACE (t0), after 3 days (t1), and after 4 wk, when they had spiral computed tomography (sCT) scanning (t2). The referring radiologists blindly evaluated tumor burden and vascularization at t0 and residual activity at t2. The choice of TACE as treatment was based on the American Association for the Study of Liver Diseases (AASLD) guidelines.
Complete response at sCT was recorded in 27% of patients; mean survival was 35 months (confidence interval CI 31-40) and the 4-yr survival was 57%. VEGF levels were significantly correlated with the number of nodes and were higher in nonresponders at t2 (P = 0.01); below-median VEGF levels predicted a longer survival (P = 0.008). b-FGF correlated with VEGF, tumor size, vascularization, and residual activity, showing a borderline correlation with survival. uPA correlated with tumor size and VEGF. VEGF was singled out in the Cox multivariate analysis as an independent predictor of survival.
When TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF following treatment; this affects patient survival. VEGF emerges as the most reliable prognostic parameter, so it could be measured for judging TACE efficacy. Finally, antiangiogenic drugs may be indicated in TACE-treated HCC.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. The hypervascular nature of the majority of HCCs and the peculiar vascular derangement occurring during liver ...carcinogenesis underscore the importance of angiogenesis in the development and progression of these tumors. Indeed, several angiogenic molecular pathways have been identified as deregulated in HCC. The hypervascular nature and the peculiar vascularization of HCC, as well as deregulated angiogenic pathways, represent major therapeutic targets. To a large extent, intra-arterial locoregional treatments (transarterial-(chemo)embolization) rely on tumor ischemia caused by embolization of tumor feeding arteries, even though this may represent the "primum movens" of tumor recurrence through the activation of neoangiogenesis. Considering systemic therapies, the currently available tyrosine kinase inhibitors (sorafenib, regorafenib, cabozantinib and lenvatinib) and monoclonal antibodies (ramucirumab and bevacizumab, in combination with the anti-PD-L1, atezolizumab) primarily target, among others, angiogenic pathways. Considering the importance of angiogenesis in the pathogenesis and treatment of liver cancer, in this paper, we aim to review the role of angiogenesis in HCC, addressing the molecular mechanisms, available antiangiogenic therapies and prognostic biomarkers in patients receiving these treatments.
In recent years, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with hepatocellular carcinoma (HCC). Following the positive results of the IMbrave150 trial, the ...combination of atezolizumab (an anti-PD-L1 antibody) and bevacizumab (an anti-VEGF antibody) became the standard of care frontline treatment for patients with advanced stage HCC. Several other trials evaluated immunotherapy in HCC, demonstrating that ICIs-based regimens are currently the most effective treatment strategies and expanding the therapeutic possibilities. Despite the unprecedent rates of objective tumor response, not all patients benefit from treatment with ICIs. Therefore, in order to select the appropriate therapy as well as to correctly allocate medical resources and avoid unnecessary treatment-related toxicities, there is great interest in identifying the predictive biomarkers of response or resistance to immunotherapy-based regimens. Immune classes of HCC, genomic signatures, anti-drug antibodies, and patient-related factors (e.g., etiology of liver disease, gut microbiota diversity) have been associated to the response to ICIs, but none of the proposed biomarkers have been translated into clinical practice so far. Considering the crucial importance of this topic, in this review we aim to summarize the available data on tumor and clinical features associated with the response or resistance of HCC to immunotherapies.
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