Reply to: "Sorafenib efficacy for treatment of HCC recurrence after liver transplantation is an open issue"

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Reply to: "Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma".

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Repeated transarterial chemoembolization: An overfitting effort?

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Liver cancer: Approaching a personalized care

The knowledge and understanding of all aspects of liver cancer [this including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA)] have experienced a major improvement in the last decades. New laboratory technologies have identified several molecular abnormalities that, at the very end, should provide an accurate stratification and optimal treatment of patients diagnosed with liver cancer. The seminal discovery of the TP53 hotspot mutation [1,2] was an initial landmark step for the future classification and treatment decision using conventional clinical criteria blended with molecular data. At the same time, the development of ultrasound, computed tomography (CT) and magnetic resonance (MR) has been instrumental for earlier diagnosis, accurate staging and treatment advances. Several treatment options with proven survival benefit if properly applied are now available. Major highlights include: i) acceptance of liver transplantation for HCC if within the Milan criteria [3], ii) recognition of ablation as a potentially curative option [4,5], iii) proof of benefit of chemoembolization (TACE), [6] and iv) incorporation of sorafenib as an effective systemic therapy [7]. These options are part of the widely endorsed BCLC staging and treatment model (Fig. 1) [8,9]. This is clinically useful and it will certainly keep evolving to accommodate new scientific evidence. This review summarises the data which are the basis for the current recommendations for clinical practice, while simultaneously exposes the areas where more research is needed to fulfil the still unmet needs (Table 1)

Transplantation for metastatic liver disease

The liver is a common site of metastases from many cancers, particularly those originating in the gastrointestinal tract. Liver transplantation is an uncommonly used but promising and at times controversial treatment option for neuroendocrine and colorectal liver metastases. Transplantation with meticulous patient selection has been associated with excellent long-term outcomes in individuals with neuroendocrine liver metastases, but questions remain regarding the role of transplantation in those who could also be eligible for hepatectomy, the role of neoadjuvant/adjuvant treatments in minimising recurrence, and the optimal timing of the procedure. A prospective pilot study of liver transplantation for unresectable colorectal liver metastases that reported a 5-year overall survival rate of 60% reinvigorated interest in this area following initially dismal outcomes. This has been followed by larger studies, and prospective trials are ongoing to quantify the potential benefits of liver transplantation over palliative chemotherapy. This review provides a critical summary of currently available knowledge on liver transplantation for neuroendocrine and colorectal liver metastases, and highlights avenues for further study to address gaps in the evidence base

Exploiting liver immunity for the prevention of hepatic metastases

Over the last decade immunotherapy has progressively gained a significant clinical interest for cancer treatment. The actual benefit of active immunotherapy, namely cancer vaccines, has been repeatedly claimed as effective in several settings and prompted prospective investigations (phase III clinical trials) currently ongoing in patients with prostate carcinoma, melanoma, and lung cancer, while the first vaccine for the treatment of metastatic prostate carcinoma has been recently approved by the FDA [1,2]. Adoptive immunotherapy, based on the administration of antibodies (Ab) targeting tumor receptors or molecules expressed in the microenvironment, has also entered clinical practice in several cancers such as breast carcinoma, colorectal cancer, and haematological tumors [3], whereas adoptive transfer of ex vivo activated tumor-specific T cells has shown dramatic efficacy in metastatic melanoma [4], a known benchmark-tumor for immune manipulations both in animal and human models. Ab-therapy of cancer was initially conceived to directly eliminate tumor cells by interfering with the activity of either receptors involved in cancer cell proliferation (e.g. members of the HER family) or molecules regulating tumor blood supply (such in the case of anti-VEGF Ab) [5]. However, the clinical efficacy of broadly used Ab was subsequently found to rely, at least in part, on the contribution of the immune system through the activation of antibody-dependent cell cytotoxicity (ADCC) mediated by cellular components of innate immunity [5,6]. NK cells, monocytes, macrophages, and granulocytes can indeed bind to Ab thanks to the expression of specific receptors for the invariant portion of this molecule (the so called Fc portion) and be recruited to attack target cells, hence contributing to the therapeutic potential of Abbased therapies. Evidence proving such mechanism has been collected in preclinical studies, showing that anti-tumor antibodies, like trastuzumab, have reduced activity when administered in FcR knock-out mice or used in a FcR-binding defective form. Similarly in clinical setting, breast cancer trials have reported immune infiltrate in cancer lesions of Ab-treated patients, and better efficacy in subjects expressing defined FcR genotypes [6]. More recently, the anti-tumor activity of such strategy has been also potentiated through bi-specific engineered single-chain Ab designed to tether cytotoxic T lymphocytes to cancer cells, a

Heterologous and cross-species tropism of cancer-derived extracellular vesicles

Extracellular vesicles (EVs) are naturally occurring cargo delivery vesicles that have recently received considerable attention for their roles in intercellular communication in many physiological and pathological processes, including tumourigenesis. EVs generated by different tissues demonstrated specific homing: in particular, cancer-derived EVs showed a selective tropism for the tumor tissue from which the vesicles originated. For this property, EVs have been proposed as drug delivery tools for anti-cancer therapies, although the limited knowledge about their in vivo tropism hinders their therapeutic applications. The current study aimed to characterize the targeting properties of cancer- derived EVs in vitro and their biodistribution in vivo, by using an imaging approach. Methods. EVs were generated from: i) murine lung (LL/2) and colon (MC-38) cancer lines, ii) human lung cancer cell line (A549) and iii) human liver biopsy samples from healthy individuals. EVs were loaded with fluorescent dyes alone or in combination with a biopharmaceutical agent, the oncolytic adenovirus (OV), characterized for charge and size and tested for their activity in cancer cell lines. Finally, optical imaging was extensively applied to study in vivo and ex vivo the biodistribution of EVs originated from different sources in different mouse models of cancer, including xenograft, syngeneic graft and the MMTV-NeuT genetically modified animal. Results. We initially demonstrated that even loading EVs even with a large biopharmaceutical oncolytic viruses (OVs) did not significantly change their charge and dimension properties, while increasing their anti-neoplastic activity compared to the virus or EVs alone. Interestingly, this activity was observed even if the EVs derived from lung cancer were applied to colon carcinoma cell lines and vice versa, suggesting that the EV uptake occurred in vitro without any specificity for the cancer cells from which the vesicles originated. When administered i.v (intravenously) to the mouse models of cancer, the tumour-derived EVs, but not the EVs derived from a healthy tissue, demonstrated a selective accumulation of the fluorescence at the tumour site 24 h after injection; adding OVs to the formulation also did not change the tumour-specific tropism of the EVs also in vivo. Most interestingly, the in vivo experiments confirmed the in vitro observation of the generalized tropism of tumour-derived EVs for any neoplastic tissue, independent of the tumour type or even the species originating the vesicles. Conclusions. Taken together, our in vitro and in vivo data demonstrate for the first time a heterologous, cross-species tumour-tropism for cancer-derived EVs. This finding challenges our current view on the homing properties of EVs and opens new avenues for the selective delivery of diagnostic/therapeutic agents to solid tumours

Amino Acid Kinetics During the Anhepatic Phase of Liver Transplantation

Alanine and glutamine are interorgan nitrogen/carbon carriers for ureagenesis and gluconeogenesis, which are mainly but not necessarily only hepatic. The liver is central to alanine and glutamine metabolism, but most organs can produce and use them. We studied amino acid kinetics after liver removal to depict initial events of liver failure and to provide a model to study extrahepatic gluconeogenesis and nitrogen disposal in humans. We measured amino acid kinetics with [5,5,5-2H3]leucine and [3-13C]alanine or [1,2-13C2]glutamine tracers in 21 subjects during and after the anhepatic phase of liver transplantation: 12 were at 7 months posttransplantation, and 7 were healthy control subjects. Anhepatic leucine kinetics, including proteolysis, was unchanged. Alanine plasma and whole-body contents increased 3× and 2×, with a halved metabolic clearance and a doubled production, 2% greater than disposal. Free whole-body glutamine decreased 25% but increased 50% in plasma. Glutamine clearance was halved, and the production decreased by 25%, still 2% greater than disposal. Liver replacement decreased alanine and glutamine concentrations, leaving leucine unchanged. Liver removal caused doubled alanine fluxes, minor changes in glutamine, and no changes in leucine. The initial events after liver removal are an accumulation of three-carbon compounds, an acceleration of alanine turnover, and limited nitrogen storage in alanine and glutamine

Natural Killer and NK-Like T-Cell Activation in Colorectal Carcinoma Patients Treated with Autologous Tumor-Derived Heat Shock Protein 96

Heat shock proteins (HSPs) are involved in the activation of both adaptive and innate immune systems. Here, we report that vaccination with autologous tumor-derived HSP96 of colorectal cancer patients, radically resected for liver metastases, induced a significant boost of natural killer (NK) activity detected as cytokine secretion and cytotoxicity in the presence of NK-sensitive targets. Increased NK activity was associated with a raise in CD3−CD56+ NK and/or CD3+CD56+ NK-like T cells, displaying enhanced expression of NKG2D and/or NKp46 receptors. Up-regulated expression of CD83 and CD40 and increased interleukin-12 release on stimulation were observed in CD14+ cells from post-HSP96 peripheral blood mononuclear cells, suggesting an indirect pathway of NK stimulation by HSP96-activated monocytes. Additionally, CD3−CD56+ and CD3+CD56+ lymphocytes were found to undergo functional and phenotypic activation on in vitro exposure to HSP96 even in the absence of monocytes, supporting a potential direct activity of HSP96 on these cell subsets. This evidence was confirmed by the specific binding of FITC-conjugated HSP96 to a subset of both CD3−CD56+ and CD3+CD56+ cells in peripheral blood mononuclear cells from colorectal cancer patients. Altogether, these findings identify the activation of the NK compartment as an additional immunologic effect of autologous tumor-derived HSP96 administration in cancer patients