HCC in Elderly Patients. Curative Intraoperative Strategies and Management in Recurrences

Hepatocellular carcinoma (HCC) incidence is growing among general population and especially in elderly patients. Recent development in surgical technique, surgical equipment, interventional radiology, and radiotherapy (hadrontherapy) allows us to use different techniques and approaches in order to treat this cancer. Patients are conventionally considered disease-free after a 10-year recurrence-free period. Commonly, patients remain into a lifelong follow-up and recurrences are treated as they show. In this chapter, we will give description and indications of different curative techniques, especially hepatic resections and Radio-frequency thermal ablation (RFTA). We will also describe and give indications to palliative care techniques such as transarterial chemoembolization (TACE), Selective Internal Radio-Therapy (SIRT), hadrontherapy, and supportive care. The aim of this chapter is to give information to clinicians and specialists dealing with the disease about the most effective approach to treat HCC, taking into account not only biological age, but also “physiological age,” performance status, comorbidities, and number of liver operative treatments. This chapter highlights that patients advanced in age are in particular need of a tailored medicine, where benefits are well weighted against invasivity of treatment and its side effects, in spite of assuring the best QoL and survival

HCC in Cirrhotic and Non-cirrhotic Liver: Timing to Surgery and Outcome - State of the Art

In this chapter we aim at presenting the state of the art in liver surgery. After a brief introduction about natural evolution of hepatocellular carcinoma (HCC) either in cirrhotic or non-cirrhotic patients, this manuscript will focus on planning and timing surgery: CT evaluation of the remnant liver; biopsy and ultrasonography (US) evaluation of liver disease; intraoperative US; surgical techniques, such as major and limited hepatectomies and two-stage hepatectomies, each of them in open or mini-invasive approach; and their possible complications. Follow-up and further interventions during expected recurrences will be highlighted. Our chapter will also treat topics such as patient’s quality of life, importance of multidisciplinary evaluation and the role of surgeon in it

Hydrogen sulfide modulates the release of nitric oxide and VEGF in human keratinocytes.

none5Hydrogen sulphide (H2S) is a novel signaling molecule with both pro- or anti-inflammatory effect. The present study aimed to: i- characterize the in vitro effects of H2S on human keratinocyte’s proliferation and death; ii- investigate the ability of H2S to modulate VEGF and NO production; iii- examine the intracellular signaling pathways involved in VEGF and NO modulatory effect. We found that exogenous application of H2S (NaHS and GYY4137 as H2S donors) significantly enhances NO through increase of iNOS, in a manner Akt-dependent. The increment in NO down-regulates ERK1/2 activation thereby resulting in the decrease of VEGF release. We suggest that H2S-releasing agents may be promising therapeutics for chronic inflammatory disorders of the skin, i.e. psoriasis, in which NO increases as well as anti-VEGF treatments have been suggested to be novel effective approaches.noneMerighi S; Gessi S; Varani K; Fazzi D; Borea PA.Merighi, Stefania; Gessi, Stefania; Varani, Katia; Fazzi, Debora; Borea, Pier Andre

Case-report. Metastases in a low-stage middle-graded HCC in cleared HCV infection, non-cirrhotic liver. Surgical therapy

Introduction Hepatocellular carcinoma (HCC) is rare in non-cirrhotic liver. Achievement of sustained virological response (SVR) reduces even more the risk. Presentation of case Liver resection for small HCC was performed in cleared HCV infection non-cirrhotic 62-year-old man. Methacronous oligometastatic recurrences in intolerant to Nexavar® side-effects patient, were treated by multiple innovative microinvasive approaches: bilateral laparoscopic adrenalectomy, thoracic wall resection, laparoscopic sacrum cryoablation combined with hadron-therapy. Discussion Therapies allowed the patient to lead 6 years satisfying QoL with only a small residual presacral disease stable at 8 months. Conclusion Microinvasive surgery may be a valid resource of therapy in indolent HCC limited distant recurrences

Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue

Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bethighIFN-γ- "T-helper (Th)1-suppressing" phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-γ T-bet+IFN-γ+), thus becoming "Th1-like" cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40+ Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-γ, ultimately leading to complete,full Th1-like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ

Genetically-driven CD39 expression shapes human tumor-infiltrating CD8+ T cell functions

In this study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T cell exhaustion, we demonstrated a divergent functional activity in CD39+CD8+ TILs. On the one hand, CD39+CD8+ TILs (as compared with their CD39– counterparts) produced significantly lower IFN- and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A > G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+CD8+ T cell effector function ex vivo, and that CD39+CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+CD8+ T cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs