Finding the seed of recurrence:Hepatocellular carcinoma circulating tumor cells and their potential to drive the surgical treatment

The treatment for hepatocellular carcinoma(HCC)relies on liver resection,which is,however,burdened by a high rate of recurrence after surgery,up to 60%at 5 years.No pre-operative tools are currently available to assess the recurrence risk tailored to every single patient.Recently liquid biopsy has shown interesting results in diagnosis,prognosis and treatment allocation strategies in other types of cancers,since its ability to identify circulating tumor cells(CTCs)derived from the primary tumor.Those cells were advocated to be responsible for the majority of cases of recurrence and cancer-related deaths for HCC.In fact,after being modified by the epithelial-mesenchymal transition,CTCs circulate as“seeds”in peripheral blood,then reach the target organ as dormant cells which could be subsequently“awakened”and activated,and then initiate metastasis.Their presence may justify the disagreement registered in terms of efficacy of anatomic vs non-anatomic resections,particularly in the case of microvascular invasion,which has been recently pointed as a histological sign of the spread of those cells.Thus,their presence,also in the early stages,may justify the recurrence event also in the contest of liver transplant.Understanding the mechanism behind the tumor progression may allow improving the treatment selection according to the biological patient-based characteristics.Moreover,it may drive the development of novel biological tailored tests which could address a specific patient to neoadjuvant or adjuvant strategies,and in perspective,it could also become a new method to allocate organs for transplantation,according to the risk of relapse after liver transplant.The present paper will describe the most recent evidence on the role of CTCs in determining the relapse of HCC,highlighting their potential clinical implication as novel tumor behavior biomarkers able to influence the surgical choice.

Tumor microenvironment in primary liver tumors: A challenging role of natural killer cells

In the last years,several studies have been focused on elucidate the role of tumor microenvironment(TME)in cancer development and progression.Within TME,cells from adaptive and innate immune system are one of the main abundant components.The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth.This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer,such as hepatocellular carcinoma(HCC)and intrahepatic cholangiocarcinoma(iCCA).Liver is well-known to be an important immunological organ with unique microenvironment.Here,in normal conditions,the rich immune-infiltrating cells cooperate with non-parenchymal cells,such as liver sinusoidal endothelial cells and Kupffer cells,favoring self-tolerance against gut antigens.The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells,in order to understand how this cross-talk promotes tumor growth.Deeper attention is,in fact,focused on immune-based therapy for these tumors,as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment.In this review,we will examine the key pathways underlying TME cell-cell communications,with deeper focus on the role of natural killer cells in primary liver tumors,such as HCC and iCCA,as new opportunities for immune-based therapeutic strategies.

Is precision medicine for colorectal liver metastases still a utopia?New perspectives by modern biomarkers,radiomics,and artificial intelligence

The management of patients with liver metastases from colorectal cancer is still debated.Several therapeutic options and treatment strategies are available for an extremely heterogeneous clinical scenario.Adequate prediction of patients’outcomes and of the effectiveness of chemotherapy and loco-regional treatments are crucial to reach a precision medicine approach.This has been an unmet need for a long time,but recent studies have opened new perspectives.New morphological biomarkers have been identified.The dynamic evaluation of the metastases across a time interval,with or without chemotherapy,provided a reliable assessment of the tumor biology.Genetics have been explored and,thanks to their strong association with prognosis,have the potential to drive treatment planning.The liver-tumor interface has been identified as one of the main determinants of tumor progression,and its components,in particular the immune infiltrate,are the focus of major research.Image mining and analyses provided new insights on tumor biology and are expected to have a relevant impact on clinical practice.Artificial intelligence is a further step forward.The present paper depicts the evolution of clinical decision-making for patients affected by colorectal liver metastases,facing modern biomarkers and innovative opportunities that will characterize the evolution of clinical research and practice in the next few years.

Post-hepatectomy biliary fistula: from risk factors to the role of drain placement and management—still a lot to be answered

Hepatic resection represents the gold-standard treatment for different liver diseases. Among postoperative complications, bile leak remains one of the most common sources of morbidity, which can lead to an increase of hospital stay, need of invasive procedure and potentially death (1). The definition and acknowledge of risk factors for the development of biliary fistula as well as its early detection and optimal management is, in this sense, of crucial importance.

lmmunotherapy in hepatobiliary tumors: search for the missing pieces of the puzzle

In the current era of immunotherapy, the treatment of hepatobiliary cancers is rapidly evolving. The use of immunotherapeutic approaches, which include peptide-based vaccines, checkpoint inhibitors and antibodies, particularly applies to advanced hepatobiliary cancers, for which the availability of limited therapeutic options encourages the adoption of alternative strategies. Thanks to the published/presented, although conflicting, results of some of the clinical trials on this topic together with the incoming results of some other trials, clinicians involved in the cure of hepatobiliary cancer patients need to understand the basic and advanced applications of immunotherapies (1-6).

Hepatobiliary surgeons meet immunologists: the case of colorectal liver metastases patients

The burgeoning field of cancer immunology demands a change in the paradigm of cancer patient management. The understanding of the course of a given malignant disease should also include the host immune system as one of the key factors in determining the patient's prognosis. Surgical and medical oncologists need to understand the basic and advanced applications of immunotherapies, which are rapidly evolving, and are nowadays an integral part of the armamentarium for the treatment of cancer patients. In the present work, we review the current knowledge concerning the immune landscape of colorectal cancer (CRC) patients with liver metastases, as recently discovered.

Unravel hepatic artery infusion chemotherapy in patients with resected colorectal liver metastases

Over the past years,important progresses have been made in the treatment of patients with colorectal liver metastases(CLM).Now,5-year overall survival rate may exceed 50%by using the combination of multimodality therapies among which modern systemic chemotherapy,with or without monoclonal antibodies,and hepatic resection are the cornerstones(1,2).In such multimodality,hepatic artery infusion(HAI)has been proposed since many years with the rationale of increasing the concentration of chemotherapy agents in the liver(3).However,HAI still remains infrequently used,in particular in the adjuvant setting mainly because of the requirement of a multidisciplinary team to manage therapy,and the more widespread use of systemic chemotherapy-in particular following the perioperative“sandwich”schema(4).