Combined treatments in hepatocellular carcinoma: Time to put them in the guidelines?

The time for battling cancer has never been more suitable than nowadays and fortunately against hepatocellular carcinoma (HCC) we do have a far-reaching arsenal. Moreover, because liver cancer comprises a plethora of stages-from very early to advanced disease and with many treatment options–from surgery to immunotherapy trials–it leaves the clinician a wide range of options. The scope of our review is to throw light on combination treatments that seem to be beyond guidelines and to highlight these using evidence-based analysis of the most frequently used combination therapies, discussing their advantages and flaws in comparison to the current standard of care. One particular combination therapy seems to be in the forefront: Transarterial chemoembolization plus ablation for medium-size non-resectable HCC (3-5 cm), which is currently at the frontier between Barcelona Clinic Liver Cancer classification A and B. Not only does it improve the outcome in contrast to each individual therapy, but it also seems to have similar results to surgery. Also, the abundance of immune checkpoint inhibitors that have appeared lately in clinical trials are bringing promising results against HCC. Although the path of combination therapies in HCC is still filled with uncertainty and caveats, in the following years the hepatology and oncology fields could witness an HCC guideline revolution

Ultrasound or Sectional Imaging Techniques as Screening Tools for Hepatocellular Carcinoma: Fall Forward or Move Forward?

Hepatocellular carcinoma (HCC) is probably the epitome of a screening target, with a well-defined high-risk population, accessible screening methods, and multiple curative-intent treatments available for early disease. Per major societies guideline consensus, biannual ultrasound (US) surveillance of the at-risk patients is the current standard of care worldwide. Yet, despite its documented success in the past decades, this standard is far from perfect. While the whole community is working to further tighten the knots, a worrying number of cases still slip through this safety net. Consequently, these patients lose their chance to a curative solution which leads to a high disease burden with disproportionate mortality. While US will probably remain the fundamental staple in the screening strategy, key questions are seeking better answers. How can its caveats be addressed, and the technique be improved? When are further steps needed? How to increase accuracy without giving up on accessibility? This narrative review discusses the place of US surveillance in the bigger HCC picture, trying to navigate through its strengths and limits based on the most recent available evidence

Combined regimen of photodynamic therapy mediated by Gallium phthalocyanine chloride and Metformin enhances anti-melanoma efficacy.

BACKGROUND:Melanoma therapy is challenging, especially in advanced cases, due to multiple developed tumor defense mechanisms. Photodynamic therapy (PDT) might represent an adjuvant treatment, because of its bimodal action: tumor destruction and immune system awakening. In this study, a combination of PDT mediated by a metal substituted phthalocyanine-Gallium phthalocyanine chloride (GaPc) and Metformin was used against melanoma. The study aimed to: (1) find the anti-melanoma efficacy of GaPc-PDT, (2) assess possible beneficial effects of Metformin addition to PDT, (3) uncover some of the mechanisms underlining cell killing and anti-angiogenic effects. METHODS:Two human lightly pigmented melanoma cell lines: WM35 and M1/15 subjected to previous Metformin exposure were treated by GaPc-PDT. Cell viability, death mechanism, cytoskeleton alterations, oxidative damage, were assessed by means of colorimetry, flowcytometry, confocal microscopy, spectrophotometry, ELISA, Western Blotting. RESULTS:GaPc proved an efficient photosensitizer. Metformin addition enhanced cell killing by mechanisms dependent on the cell line, namely apoptosis in the metastatic M1/15 and necrosis in the radial growth phase, WM35. Cell death mechanism relied on the inhibition of nuclear transcription factor (NF)-κB activation and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) sensitization, leading to TRAIL and TNF-α induced apoptosis. Metformin diminished the anti-angiogenic effect of PDT. CONCLUSIONS:Metformin addition to GaPc-PDT increased tumor cell killing through enhanced oxidative damage and induction of proapoptotic mechanisms, but altered PDT anti-angiogenic effects. GENERAL SIGNIFICANCE:Combination of Metformin and PDT might represent a solution to enhance the efficacy, leading to a potential adjuvant role of PDT in melanoma therapy

Microwave ablation in the treatment of liver tumors. A better tool or simply more power?

It has been a long time since tumor ablation was first tested in patients with liver cancer, especially hepatocellular carcinoma. Since than it has become a first line treatment modality for hepatocellular carcinoma. Over the years, the indications of thermal ablation have expanded to colorectal cancer liver metastases and intrahepatic cholangiocarcinoma as well. Together with the new indication for ablation, new ablation devices have been developed as well. Among them microwave ablation shows potential in replacing radiofrequency ablation as the preferred method of thermal ablation in liver cancer. The debate whether radiofrequency or microwave ablation should be the preferred method of treatment in patients with liver cancer remains open. The main purpose of this review is to offer some answers to the question: Microwave ablation in liver tumors: a better tool or simply more power? Various clinical scenarios will be analyzed including small, medium, and intermediate size hepatocellular carcinoma, colorectal cancer liver metastases and intrahepatic cholangiocarcinoma. Furthermore, the advantages, limitations, and technical considerations of MWA treatment will be provided also

Navigating through the Lipid Metabolism Maze: Diagnosis and Prognosis Metabolites of Hepatocellular Carcinoma versus Compensated Cirrhosis

(1) Background: The pursuit of finding biomarkers for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has never been so paramount in the days of personalized medicine. The main objective of our study is to identify new biomarkers for diagnosing HCC, and to identify which patients are at risk of developing tumor recurrence, decompensation, or even possesses the risk of cancer-related death. (2) Methods: We have conducted an untargeted metabolomics study from the serum of 69 European patients—32 compensated cirrhotic patients without HCC (controls), and 37 cirrhotic patients with HCC with compensated underlying liver disease (cases), that underwent curative treatment (surgery or ablation), performing ultra-high-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-QTOF- (ESI+)-MS) with an emphasis on lipid metabolites. (3) Results: 1,25-dihydroxy cholesterol (m/z = 419.281), myristyl palmitate (m/z = 453.165), 25-hydroxy vitamin D2 (m/z = 413.265), 12-ketodeoxycholic acid (m/z = 391.283), lysoPC (21:4) (m/z = 558.291), and lysoPE (22:2) (m/z = 534.286) represent notable biomarkers that differentiate compensated cirrhosis from early HCC, and ceramide species are depleted in the serum of HCC patients. Regarding prognosis, no metabolite identified in our study could determine tumor relapse. To distinguish between the HCC patients that survived curative treatment and those at risk that developed tumor burden, we have identified two notable phosphocholines (PC (30:2); PC (30:1)) with AUROCs of 0.820 and 0.807, respectively, that seem to increase when patients are at risk. In a univariate analysis, arachidonic acid was the only metabolite to predict decompensation (OR = 0.1, 95% CI: 0–0.16, p < 0.005), while in the multivariate analysis, dismally, no variable was associated with decompensation. Furthermore, in the multivariate analysis, we have found out for the first time that the increased expression of 1,25-dihydroxy cholesterol, myristyl palmitate, 12-keto deoxycholic acid, lysoPC (21:4), and lysoPE (22:2) are independent markers of survival. (4) Conclusions: Our study reveals that lipids play a crucial role in discriminating compensated cirrhosis and early hepatocellular carcinoma, and might represent markers of survival and prognosis in personalized and minimally invasive medicine

Melanogenesis.

<p>Total melanin content (μg/ml) and tyrosinase enzymatic activity (Units/mg protein) measurements in WM35 (upper panels) and M1-15 (lower panels) were done by spectrophotometry. Each bar represents mean ± standard deviation (n = 3). ir = irradiated cells; # = not significant, * = p<5.0E-02, ** = p<1.0E-02, *** = p<1.0E-03.</p

Protein expression measured by Western Blot.

<p>Protein expressions of NF-κB, pNF-kB, IκKα, IκKβ, pIκK α/β, HIF1α, tyrosinase and MITF in melanoma cells treated with GaPc-PDT + Metformin, left panel (WM35), right panel (M1-15) were measured by WB. Image analysis of WB bands was done by densitometry, results were normalised to GAPDH.—WB images (upper panels) 1 = control, 2 = irradiated control, 3 = Metformin, 4 = irradiated Metformin, 5 = GaPc, 6 = GaPc-PDT, 7 = GaPc and Metformin, 8 = GaPc-PDT and Metformin; graphical representation of quantitative WB results for WM35 and M1-15 (lower panels); ir = irradiated cells; # = not significant, * = p<5.0E-02, ** = p<1.0E-02, *** = p<1.0E-03. Each bar represents mean ± standard deviation (n = 3).</p

Chemical formula.

<p>Chloro-gallium (III) phthalocyanine (a) and Metformin (b).</p

Viability testing after GaPc-PDT and Metformin exposure.

<p>WM35 (a, b), M1-15 (c, d) melanoma cell cultures exposed to GaPc-PDT (a, c), respectively GaPc-PDT+ Metformin (b, d). OD 540 graphs were generated using GraphPad Software and show mean values ± standard deviation, n = 3 for each sample. Cell viability of both cell lines was decreased by GaPc-PDT depending on GaPc concentration and irradiation dose; Metformin increased the efficacy of GaPc-PDT especially in WM35 cells. e-images of WM35 (upper panels) and M1-15 (lower panels) cells subjected to GaPc-PDT and Metformin. Cells exposed to GaPc w/o Metformin, showed a normal morphology, compared to controls, while PDT irradiation of treated cells induced loss of cell adhesion, pleiomorphysm with spherical or bipolar shaped cells, signs of treatment induced photo-toxicity.</p