EASL-EORTC clinical practice guidelines : management of hepatocellular carcinoma

There is great geographical variation in the distribution of hepatocellular carcinoma (HCC), with the majority of all cases worldwide found in the Asia–Pacific region, where HCC is one of the leading public health problems. Since the “Toward Revision of the Asian Pacific Association for the Study of the Liver (APASL) HCC Guidelines” meeting held at the 25th annual conference of the APASL in Tokyo, the newest guidelines for the treatment of HCC published by the APASL has been discussed. This latest guidelines recommend evidence-based management of HCC and are considered suitable for universal use in the Asia–Pacific region, which has a diversity of medical environments.

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Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update

Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfill two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature.

The Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma proposed by the Japan Society of Hepatology was updated in June 2014 at a consensus meeting of the Liver Cancer Study Group of Japan. Three important items have been updated: the surveillance and diagnostic algorithm, the treatment algorithm, and the definition of transarterial chemoembolization (TACE) failure/refractoriness. The most important update to the diagnostic algorithm is the inclusion of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging as a first line surveillance/diagnostic tool. Another significant update concerns removal of the term "lipiodol" from the definition of TACE failure/refractoriness.

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JSH Consensus-Based Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma: 2014 Update by the Liver Cancer Study Group of Japan

Selected patients with hepatocellular carcinoma are candidates to receive potentially curative treatments, such as hepatic resection or liver transplantation, but nevertheless there is a high risk of tumor recurrence. Microvascular invasion is a histological feature of hepatocellular carcinoma related to aggressive biological behavior. We systematically reviewed 20 observational studies that addressed the prognostic impact of microvascular invasion, either after liver transplantation or resection. Outcomes were disease-free survival and overall survival. In liver transplantation, the presence of microvascular invasion shortened disease-free survival at 3 years (relative risk (RR) = 3.41 [2.05–5.7]; five studies, n = 651) and overall survival both at 3 years (RR = 2.41 [1.72–3.37]; five studies, n = 1,938) and 5 years (RR = 2.29 [1.85–2.83]; six studies, n = 2,003). After liver resection, microvascular invasion impacted disease-free survival at 3 and 5 years (RR = 1.82 [1.61–2.07] and RR = 1.51 [1.29–1.77]; four studies, n = 1,501 for both comparisons). However inter/intraobserver variability in reporting and the lack of definition and grading of microvascular invasion has led to great heterogeneity in evaluating this histological feature in hepatocellular carcinoma. Thus, there is an urgent need to clarify this issue, because determining prognosis and response to therapy have become important in the current management of hepatocellular carcinoma. In this systematic review, we summarize the diagnostic and prognostic data concerning microvascular invasion in hepatocellular carcinoma and present a basis for consensus on its definition.

A Systematic Review of Microvascular Invasion in Hepatocellular Carcinoma: Diagnostic and Prognostic Variability

Lymphangiogenesis and lymphatic vessel remodeling are complex biological processes frequently observed during inflammation. Accumulating evidence indicates that inflammation-associated lymphangiogenesis (IAL) is not merely an endpoint event, but actually a phenomenon actively involved in the pathophysiology of various inflammatory disorders. The VEGF-C/VEGFR-3 and VEGF-A/VEGF-R2 signaling pathways are two of the best-studied pathways in IAL. Methods targeting these molecules, such as prolymphangiogenic or antilymphatic treatments, were found to be beneficial in various preclinical and/or clinical studies. This Review focuses on the most recent achievements in the fields of lymphatic biology relevant to inflammatory conditions. Additionally, preclinical and clinical therapies that modulate IAL are summarized.

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Inflammation-associated lymphangiogenesis: a double-edged sword?

Microvessel invasion is a major prognostic factor in hepatocellular carcinoma (HCC) that influences the suitability of surgery, but rarely can be evaluated preoperatively. This study was performed to identify preoperative MRI findings that reflect histopathological microvessel invasion in hepatocellular carcinoma. Gadobenate dimeglumine-enhanced four-arterial phase dynamic study and hepatobiliary phase images of preoperative MRI of 70 HCC lesions were retrospectively reviewed. Tumor size (cm), peritumoral enhancement, tumor margins, and radiological capsule were analyzed as radiological parameters reflecting microvessel invasion and were compared with histopathological references. The chi-square test and the independent t-test were used for univariate analysis, and a logistic regression analysis was performed for multivariate analysis. In univariate analysis, tumor size (p = 0.030), peritumoral enhancement (p < 0.001), and tumor margins (p = 0.007) were associated with microvessel tumor invasion. However, in multivariate analysis irregular circumferential peritumoral enhancement only showed statistical significance (odds ratio 13.0), suggesting a high probability of microvessel invasion of HCC. Irregular circumferential peritumoral enhancement on contrast-enhanced multi-arterial phase dynamic MRI could be a preoperative surrogate marker for microvessel tumor invasion.

Can microvessel invasion of hepatocellular carcinoma be predicted by pre-operative MRI?

To determine whether magnetic resonance imaging (MRI)-detected extramural vascular invasion (EMVI) could predict synchronous distant metastases in rectal cancer. Patients who underwent rectal MRI between July 2011 and December 2012 were screened. This study included 447 patients with pathologically confirmed rectal adenocarcinoma who had undergone MRI without previous treatment. Distant metastases were recorded at the initial work-up and over a 6-month follow-up. Univariate/multivariate logistic regression models were used to determine the risk of metastasis. The diagnostic performance was calculated using pathologic lymphovascular invasion (LVI) as a gold standard. Among 447 patients, 79 patients (17.7 %) were confirmed to have distant metastases. Three MRI features are significantly associated with a high risk of distant metastasis: positive EMVI (odds ratio 3.02), high T stage (odds ratio 2.10) and positive regional lymph node metastasis (odds ratio 6.01). EMVI in a large vessel (≥3 mm) had a higher risk for metastasis than EMVI in a small vessel (<3 mm). Sensitivity, specificity and accuracy of MRI-detected EMVI were 28.2 %, 94.0 % and 80.3 %, respectively. MRI-detected EMVI is an independent risk factor for synchronous metastasis in rectal cancer. EMVI in large vessels is a stronger risk factor for distant metastasis than EMVI in small vessels. • EMVI, LN metastasis and T staging on MRI are risk factors for metastasis.
 • EMVI in large vessels has greater risk for metastasis than in small vessels.
 • Regional LN metastasis on MRI has highest risk for predicting metastasis.
 • MR findings could be helpful for selecting patients at high risk for metastasis.

MRI-detected extramural vascular invasion is an independent prognostic factor for synchronous metastasis in patients with rectal cancer

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Essential Items for Structured Reporting of Rectal Cancer MRI: 2016 Consensus Recommendation from the Korean Society of Abdominal Radiology

Human pancreatic ductal adenocarcinoma (PDAC) is a cancer with a dismal prognosis. The efficacy of PDAC anticancer therapies is often short-lived; however, there is little information on how this disease entity so frequently gains resistance to treatment. We adopted the concept of cancer stem cells (CSCs) to explain the mechanism of resistance and evaluated the efficacy of a candidate anticancer drug to target these therapy-resistant CSCs. We identified a subpopulation of cells in PDAC with CSC features that were enriched for aldehyde dehydrogenase (ALDH), a marker expressed in certain stem/progenitor cells. These cells were also highly resistant to, and were further enriched by, treatment with gemcitabine. Similarly, surgical specimens from PDAC patients showed that those who had undergone preoperative chemo-radiation therapy more frequently displayed cancers with ALDH strongly positive subpopulations compared with untreated patients. Importantly, these ALDH-high cancer cells were sensitive to disulfiram, an ALDH inhibitor, when tested in vitro. Furthermore, in vivo xenograft studies showed that the effect of disulfiram was additive to that of low-dose gemcitabine when applied in combination. In conclusion, human PDAC-derived cells that express high levels of ALDH show CSC features and have a key role in the development of resistance to anticancer therapies. Disulfiram can be used to suppress this therapy-resistant subpopulation.

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Honsoul Kim

Papers

Inflammation-associated lymphangiogenesis: a double-edged sword?

Can microvessel invasion of hepatocellular carcinoma be predicted by pre-operative MRI?

MRI-detected extramural vascular invasion is an independent prognostic factor for synchronous metastasis in patients with rectal cancer

Essential Items for Structured Reporting of Rectal Cancer MRI: 2016 Consensus Recommendation from the Korean Society of Abdominal Radiology

Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells.