The Role of Oxidative Stress and Cellular Senescence in the Pathogenesis of Metabolic Associated Fatty Liver Disease and Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) represents a worryingly increasing cause of malignancy-related mortality, while Metabolic Associated Fatty Liver Disease (MAFLD) is going to become its most common cause in the next decade. Understanding the complex underlying pathophysiology of MAFLD-related HCC can provide opportunities for successful targeted therapies. Of particular interest in this sequela of hepatopathology is cellular senescence, a complex process characterised by cellular cycle arrest initiated by a variety of endogenous and exogenous cell stressors. A key biological process in establishing and maintaining senescence is oxidative stress, which is present in multiple cellular compartments of steatotic hepatocytes. Oxidative stress-induced cellular senescence can change hepatocyte function and metabolism, and alter, in a paracrine manner, the hepatic microenvironment, enabling disease progression from simple steatosis to inflammation and fibrosis, as well as HCC. The duration of senescence and the cell types it affects can tilt the scale from a tumour-protective self-restricting phenotype to the creator of an oncogenic hepatic milieu. A deeper understanding of the mechanism of the disease can guide the selection of the most appropriate senotherapeutic agent, as well as the optimal timing and cell type targeting for effectively combating HCC.

Individualized Approach in the Surgical Management of Hepatocellular Carcinoma: Results from a Greek Multicentre Study.

Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of death worldwide. The management of HCC is complex, with surgical treatment providing long-term survival in eligible patients. This study aims to present the experience of aggressive surgical management of HCC in Greece. Methods: This is a retrospective multicentre clinical study with 242 patients. Results: Most patients were male (79%) and had a median age of 71 yrs. According to the most recent BCLC criteria, 172 patients (71.1%) were classified as BCLC 0-A stage, 33 patients (13.6%) were classified as BCLC B, and 37 (15.3%) were classified as BCLC C. A total of 54% of the patients underwent major hepatectomy. Major postoperative morbidity was 15.6%, and the 90-day postoperative mortality rate was 4.5%. The median follow-up was 33.5 months. Three- and five-year overall survival was 65% and 48%, respectively. The median overall survival was 55 months. Significantly, five-year survival was 55% for BCLC A, and 34% and 21% for BCLC B and C, respectively. In univariate analysis, cirrhosis, type of resection (R status), and BCLC stage were associated with overall survival. Multivariate analysis indicated that R1 and R2 resections compared to R0, and BCLC C compared to BCLC 0-A, were independently associated with increased mortality. Conclusions: Aggressive surgical treatment of HCC offers satisfactory long-term survival prospects. A significant percentage (29%) of HCCs that underwent liver resection were of the intermediate and advanced BCLC stage. The management of patients with HCC should be discussed in multidisciplinary tumour board meetings on a case-by-case basis to be more effective.

Jejunal intussusception due to an atypical lipomatous tumor: a rare case report.

Intussusception in adults is rare, and the clinical symptoms of intussusception are subtle, making the diagnosis quite challenging. Gastrointestinal lipomas are rare benign tumors and are essentially adipose growths, most frequently found within the small intestine wall or mesentery. Limited up-to-date evidence exists regarding such lipomas. Intussusception due to a gastrointestinal lipoma constitutes an infrequent clinical entity, and the diagnosis of duodenal lipoma mainly depends on endoscopy examination, supplemented by computed tomography and magnetic resonance imaging. The present report describes a case of jejunal intussusception in an adult with a history of intermittent colicky abdominal pain located in the left upper quadrant over the last month. Contrast-enhanced computed tomography of the abdomen showed the typical target sign of a small intestinal intussusception along the left upper quadrant and a well-defined, low-density tumor in the intussusception. Exploratory laparotomy revealed jejuno-jejunal intussusception secondary to a lipoma, which was successfully treated with segmental intestinal resection.

The Role of Macroautophagy and Chaperone-Mediated Autophagy in the Pathogenesis and Management of Hepatocellular Carcinoma.

Hepatocarcinogenesis is a long process with a complex pathophysiology. The current therapeutic options for HCC management, during the advanced stage, provide short-term survival ranging from 10-14 months. Autophagy acts as a double-edged sword during this process. Recently, two main autophagic pathways have emerged to play critical roles during hepatic oncogenesis, macroautophagy and chaperone-mediated autophagy. Mounting evidence suggests that upregulation of macroautophagy plays a crucial role during the early stages of carcinogenesis as a tumor suppressor mechanism; however, it has been also implicated in later stages promoting survival of cancer cells. Nonetheless, chaperone-mediated autophagy has been elucidated as a tumor-promoting mechanism contributing to cancer cell survival. Moreover, the autophagy pathway seems to have a complex role during the metastatic stage, while induction of autophagy has been implicated as a potential mechanism of chemoresistance of HCC cells. The present review provides an update on the role of autophagy pathways in the development of HCC and data on how the modulation of the autophagic pathway could contribute to the most effective management of HCC.

Metronomic chemotherapy with cyclophosphamide for the treatment of advanced hepatocellular cancer: A case report.

INTRODUCTION AND IMPORTANCE: Metronomic chemotherapy entails chronic, equally spaced administration of low doses of various chemotherapeutic drugs without extended rest periods. Its use as a second-line treatment in advanced or metastatic hepatocellular cancer remains under investigation. CASE PRESENTATION: We report a case of a 49-year-old Caucasian female patient with an enlarged (∼14 cm) hepatocellular cancer. In July 2016, she underwent right hepatectomy (after preceding TACE). During the follow-up period, she presented early disease recurrence with lung and peritoneal metastasis. Initially, she received an inhibitor of protein kinase (sorafenib) for six months without response. Afterwards, cyclophosphamide administration at low doses as metronomic chemotherapy provided complete regression of the metastatic lesions. The patient remains in good performance status almost 4 years after initial treatment, without signs of recurrence in her recent follow-up. CLINICAL DISCUSSION: Using cyclophosphamide as metronomic chemotherapy in advanced hepatocellular cancer may have a promising antiangiogenic antitumor effect. Future clinical trials need to demonstrate this effect in terms of tumor suppression and increased disease-free survival. CONCLUSION: Large multi-centered clinical trials have to be planned to investigate the precise role of cyclophosphamide in the therapy of hepatocellular cancer while defining the patients' profile that will benefit most from cyclophosphamide.

Touch Imprint Intraoperative Flow Cytometry as a Complementary Tool for Detailed Assessment of Resection Margins and Tumor Biology in Liver Surgery for Primary and Metastatic Liver Neoplasms.

Liver resection is the main treatment for primary and metastatic liver tumors in order to achieve long-term survival with good quality of life. The ultimate goal of surgical oncology is to achieve complete tumor removal with adequate clear surgical margins. Flow cytometry is a powerful analytical technique with applications such as phenotypic analysis and quantification of DNA content. Intraoperative flow cytometry (iFC) is the application of flow cytometry for DNA content/ploidy and cell cycle distribution analysis during surgery for tumor cell analysis and margin evaluation. It has been used for cell analysis of intracranial tumors and recently of head and neck carcinomas and breast carcinomas, as well as for tumor margin evaluation. Herein, we present a novel touch imprint iFC protocol for the detailed assessment of tumor margins during excision of malignant hepatic lesions. The protocol aims to offer information on surgical margins after removal of malignant liver tumors based on DNA content of cancer cells and to corroborate the results of iFC with that of histopathological analysis. Based on the established role of iFC in other types of malignancies, our specialized protocol has the potential, through characterization of cells in liver transection surface post hepatectomy, to offer significant information on the type of resection and tumor biology. This information can be used to effectively guide intra- and postoperative patient management.

Recent advances in the surgical management of hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) is increasing, despite effective antiviral treatment for hepatitis B (HBV) and C virus infection and the application of preventive measures such as vaccination at birth against HBV infection. This is mainly due to the increase in metabolic syndrome and its hepatic components, nonalcoholic fatty liver disease and steatohepatitis. Liver resection and transplantation are the main treatment options, offering long-term survival and potential cure. In this review, the recent advances in the surgical management of HCC are presented. More specifically, the role of liver resection in the intermediate and advanced stages, according to the Barcelona Clinic Liver Cancer classification, is analyzed. In addition, the roles of minimally invasive surgery and of living-related liver transplantation in the management of patients with HCC are discussed. Finally, recent data on the role of molecular markers in the early diagnosis and recurrence of HCC are presented. The management of HCC is complex, as there are several options for each stage of the disease. In order for, each patient to get the maximum benefit, an individualized approach is suggested, in specialized liver units, where cases are discussed in multidisciplinary tumor boards.

Clinical heterogeneity in patients with non-alcoholic fatty liver disease-associated hepatocellular carcinoma.

INTRODUCTION: The indisputable increase in nonalcoholic Fatty Liver Disease (NAFLD) prevalence (25% of population) has consequently led to an increase in Hepatocellular Carcinoma (HCC) and liver-related mortality worldwide. The characteristics of patients with HCC, secondary to NAFLD, are older age, large tumors due to late diagnosis, often without cirrhosis and high prevalence of the metabolic syndrome components, leading to an increased mortality rate. Although the mechanisms of disease remain partially obscure, insulin resistance, oxidative stress, apoptosis, iron overload, and excessive local and systemic inflammation are identified as culprits for hepatocarcinogenesis in the presence of NAFLD. AREA COVERED: In this review, the authors report that there are no uniform guidelines for surveillance and early diagnosis in this patient group. Barcelona Clinic Liver Cancer staging is generally applicable to HCC due to NAFLD and management depends on liver function, tumor characteristics, and cardiovascular comorbidity. Evidence suggests that HCC due to NAFLD can be associated with worse survival due to late diagnosis. EXPERT OPINION: The need for effective early diagnosis and management of NAFLD is urgent, considering the galloping incidence of the obesity and the fact that liver cirrhosis and HCC due to NAFLD will become the first indication for liver transplantation in foreseeable future.

Acute Acalculous Cholecystitis with Empyema due to Salmonellosis.

Empyema of acalculous gallbladder in the setting of salmonellosis represents an extremely rare and life-threatening clinical condition in adults. In this unique case report, we deal with a previously healthy patient who developed acalculous cholecystitis and empyema due to infection by Salmonella. He underwent explorative laparotomy in emergency setting, and cholecystectomy was performed due to his toxic clinical condition. Empyema of gallbladder was revealed and cultures were collected. A combination of antibiotics (ciprofloxacin and metronidazole) was set, and the patient was discharged 8 days after the surgical operation in good condition. It has to be highlighted that acalculous cholecystitis is a rare entity, mostly at critically ill patients, and treatment options depend on clinical condition, risk factors, and etiology. To our knowledge, this is the first case report dealing with acalculous cholecystitis with empyema due to salmonellosis up to date. Although it is extremely rare, high index of suspicion is needed by the operating surgeon in order to avoid unfavorable outcomes.

Sentinel node navigation in gastric cancer: new horizons for personalized minimally invasive surgical oncology?

Complete (R0) resection and regional lymph nodes (LNs) dissection represent undoubtedly the basic surgical tools for patients with gastric cancer. It is reported that the LN metastasis rate in patients with early gastric cancer (EGC) is approximately 15-20%. Therefore, the innovative clinical application of sentinel node navigation surgery (SNNS) for EGC might be able to prevent unnecessary LN dissection as well as to reduce significantly the volume of gastric resection. Recent evidence suggests that double tracer methods appear superior compared to single tracer techniques. However, the researchers' interest is now focused on the identification of new LN detection methods utilizing sophisticated technology such as infrared ray endoscopy, fluorescence imaging and near-infrared technology. Despite its notable limitations, hematoxylin-eosin is still considered the mainstay staining for assessing the metastatic status of LNs. In this review, we summarize the current evidences and we provide the latest scientific information assessing safety, efficacy and potential limitations of the innovative sentinel node (SN) navigation technique for gastric cancer. We try also to provide a "view" towards a future potential application of personalized minimally invasive surgery in gastric cancer field.