Complex cystic liver lesions: classification, diagnosis, and management.

Cystic liver disease has been increasingly reported in the literature, with a prevalence as high as 15-18%. Hepatic cysts are usually discovered incidentally, while their characterization and classification rely on improved imaging modalities. Complex cystic liver lesions comprise a wide variety of novel, re-introduced, and re-classified clinical entities. This spectrum of disorders ranges from non-neoplastic conditions to benign and malignant tumors. Their clinicopathological features, prognostic factors, and oncogenic pathways are incompletely understood. Despite representing a heterogeneous group of disorders, they can have similar clinical and imaging characteristics. As a result, the diagnosis and management of complex liver cysts can become quite challenging. Furthermore, inappropriate diagnosis and management can lead to high morbidity and mortality. In this review, we aim to offer up-to-date insight into the diagnosis, classification, and management of the most common complex cystic liver lesions.

Development and internal validation of a clinical prediction model for serious complications after emergency laparotomy.

PURPOSE: Emergency laparotomy (EL) is a common operation with high risk for postoperative complications, thereby requiring accurate risk stratification to manage vulnerable patients optimally. We developed and internally validated a predictive model of serious complications after EL. METHODS: Data for eleven carefully selected candidate predictors of 30-day postoperative complications (Clavien-Dindo grade > = 3) were extracted from the HELAS cohort of EL patients in 11 centres in Greece and Cyprus. Logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) was applied for model development. Discrimination and calibration measures were estimated and clinical utility was explored with decision curve analysis (DCA). Reproducibility and heterogeneity were examined with Bootstrap-based internal validation and Internal-External Cross-Validation. The American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) model was applied to the same cohort to establish a benchmark for the new model. RESULTS: From data on 633 eligible patients (175 complication events), the SErious complications After Laparotomy (SEAL) model was developed with 6 predictors (preoperative albumin, blood urea nitrogen, American Society of Anaesthesiology score, sepsis or septic shock, dependent functional status, and ascites). SEAL had good discriminative ability (optimism-corrected c-statistic: 0.80, 95% confidence interval [CI] 0.79-0.81), calibration (optimism-corrected calibration slope: 1.01, 95% CI 0.99-1.03) and overall fit (scaled Brier score: 25.1%, 95% CI 24.1-26.1%). SEAL compared favourably with ACS-NSQIP in all metrics, including DCA across multiple risk thresholds. CONCLUSION: SEAL is a simple and promising model for individualized risk predictions of serious complications after EL. Future external validations should appraise SEAL's transportability across diverse settings.

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.

Long-term outcomes of thoracic endovascular aortic repair for the treatment of descending thoracic aortic aneurysms: a systematic review and meta-analysis.

INTRODUCTION: We undertook a systematic review of the currently published literature on TEVAR for DTAAs and we combined the eligible studies into a meta-analysis with the intention of evaluating the efficacy and the long-term durability of this treatment option. EVIDENCE ACQUISITION: A systematic search of the literature from January 2015 up to December 2022 was performed according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. For events during follow up we calculated the incidence rates (IRs) with 95% confidence intervals (95% CIs) per 100 patient-years (p-ys) as the number of patients with outcome events occurring during the specific time period divided by the total number of p-ys. EVIDENCE SYNTHESIS: A total of 4127 study titles were identified by the initial search strategy, of which 12 were considered eligible for inclusion in the meta-analysis. A Total of 1976 patients (62% male) were identified among the eligible studies. One-year survival was 90.1% (95% CI 86.3% to 93.0%), 3-year survival was estimated at 80.5% (95% CI 69.2% to 88.4%) and the 5-year survival was estimated at 73.2% (95%CI 64.3% to 80.5%) with significant heterogeneity among studies regarding these outcomes. Regarding freedom from reintervention analysis for 1 year and 5 years was 96.5% (95% CI 94.5% to 97.8%) and 85.4% (95% CI 56.7% to 96.3%) respectively. The pooled late complications IR per 100 p-ys was 55.0 (95% CI 39.1 to 70.9), whereas the pooled IR for late reinterventions per 100 p-ys was 21.2 (95% CI 26.0 to 87.5). Late type I endoleak was reported with a pooled IR of 26.7 per 100 p-ys (95% CI 19.8 to 33.6) and late type III endoleak with a pooled IR of 7.6 per 100 p-ys (95% CI 5.5 to 9.7). CONCLUSIONS: TEVAR presents a safe and feasible solution for the treatment of DTAA with sustained long-term effectivity. Current evidence supports a satisfactory 5-year survival with low rates of reinterventions.

The Role of Preoperative Chemotherapy in the Management of Synchronous Resectable Colorectal Liver Metastases: A Meta-Analysis.

BACKGROUND: The indications of preoperative chemotherapy, for initially resectable synchronous colorectal liver metastases, remain controversial. This meta-analysis aimed to assess the efficacy and safety of preoperative chemotherapy in such patients. METHODS: Six retrospective studies were included in the meta-analysis with 1036 patients. Some 554 patients were allocated to the preoperative group, and 482 others were allocated to the surgery group. RESULTS: Major hepatectomy was more common in the preoperative group than in the surgery group (43.1% vs. 28.8%, p < 0.001). Furthermore, the percentage of patients with more than three liver metastases was higher in the preoperative group compared to the surgery group (12.6% vs. 5.4%, p < 0.002). Preoperative chemotherapy showed no statistically significant impact on overall survival. Combined disease free/relapse survival analysis of patients with high disease burden (liver metastases > 3, maximum diameter > 5 cm, clinical risk score ≥ 3) demonstrated that there is a 12% lower risk of recurrence in favor of preoperative chemotherapy. Combined analysis showed a statistically significant (77% higher probability) of postoperative morbidity in patients who received preoperative chemotherapy (p = 0.002). CONCLUSIONS: Preoperative chemotherapy should be suggested in patients with high disease burden. The number of cycles of preoperative chemotherapy should be low (3-4) to avoid increased postoperative morbidity. However more prospective studies are needed to clarify the exact role of preoperative chemotherapy in patients with synchronous resectable colorectal liver metastases.

Prospective multicenter external validation of postoperative mortality prediction tools in patients undergoing emergency laparotomy.

BACKGROUND: Accurate preoperative risk assessment in emergency laparotomy (EL) is valuable for informed decision making and rational use of resources. Available risk prediction tools have not been validated adequately across diverse health care settings. Herein, we report a comparative external validation of four widely cited prognostic models. METHODS: A multicenter cohort was prospectively composed of consecutive patients undergoing EL in 11 Greek hospitals from January 2020 to May 2021 using the National Emergency Laparotomy Audit (NELA) inclusion criteria. Thirty-day mortality risk predictions were calculated using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), NELA, Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (P-POSSUM), and Predictive Optimal Trees in Emergency Surgery Risk tools. Surgeons' assessment of postoperative mortality using predefined cutoffs was recorded, and a surgeon-adjusted ACS-NSQIP prediction was calculated when the original model's prediction was relatively low. Predictive performances were compared using scaled Brier scores, discrimination and calibration measures and plots, and decision curve analysis. Heterogeneity across hospitals was assessed by random-effects meta-analysis. RESULTS: A total of 631 patients were included, and 30-day mortality was 16.3%. The ACS-NSQIP and its surgeon-adjusted version had the highest scaled Brier scores. All models presented high discriminative ability, with concordance statistics ranging from 0.79 for P-POSSUM to 0.85 for NELA. However, except the surgeon-adjusted ACS-NSQIP (Hosmer-Lemeshow test, p = 0.742), all other models were poorly calibrated ( p < 0.001). Decision curve analysis revealed superior clinical utility of the ACS-NSQIP. Following recalibrations, predictive accuracy improved for all models, but ACS-NSQIP retained the lead. Between-hospital heterogeneity was minimum for the ACS-NSQIP model and maximum for P-POSSUM. CONCLUSION: The ACS-NSQIP tool was most accurate for mortality predictions after EL in a broad external validation cohort, demonstrating utility for facilitating preoperative risk management in the Greek health care system. Subjective surgeon assessments of patient prognosis may optimize ACS-NSQIP predictions. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level II.

Low-Profile Altura Endograft System for Endovascular Abdominal Aorta Aneurysm Repair. Preliminary Results in Elective and Emergent Situations.

BACKGROUND: The objective of this study was to assess the Altura endoprosthesis outcomes up to 12 months for patients affected by infrarenal abdominal aortic aneurysms (AAA) either in elective or emergent situations. METHODS: This was a single-center retrospective study identifying all patients undergoing endovascular aneurysm repair (EVAR) with the Altura endoprosthesis from January 2021 to August 2022. Outcomes evaluated included mortality, technical and clinical success (freedom from procedure-related death, endoleak, migration, thrombosis, and reintervention), and the freedom from reintervention rate. RESULTS: A total of 34 (25 elective and 8 emergent) patients who underwent AAA with Altura endoprosthesis were retrospectively reviewed. The technical success of the Altura endograft either in elective or emergent situations was 100%. There was no inhospital mortality, but 1 (3%) patient who underwent AAA repair emergently, died unexpectedly 7 days after the discharge due to massive pulmonary embolism. The clinical success and the freedom from reintervention during the median follow-up of 12 months (interquartile range [IQR] 12-18), were 97%. One patient presented with disabling intermittent claudication at third month postoperatively, and the computed tomographic angiography (CTA) revealed thrombosis of one of the iliac endografts (3%). The patient underwent femorofemoral bypass with an uneventful postoperative course and immediate relief of the symptoms. One type II endoleak was spontaneously resolved on the sixth month. Sac shrinkage (>3 mm) was registered in 12 patients (35%), but the sac size was stable in the remaining 22 (65%) patients. CONCLUSIONS: The preliminary outcomes of the Altura endograft seem to be promising, suggesting that the endograft could be safely used either in elective or emergent situations. Further studies with a major number of participants are needed to document its technical and clinical performance, especially in emergency situations that could be amenable to improvement.

The Hellenic Emergency Laparotomy Study (HELAS): A Prospective Multicentre Study on the Outcomes of Emergency Laparotomy in Greece.

BACKGROUND: Emergency laparotomy (EL) is accompanied by high post-operative morbidity and mortality which varies significantly between countries and populations. The aim of this study is to report outcomes of emergency laparotomy in Greece and to compare them with the results of the National Emergency Laparotomy Audit (NELA). METHODS: This is a multicentre prospective cohort study undertaken between 01.2019 and 05.2020 including consecutive patients subjected to EL in 11 Greek hospitals. EL was defined according to NELA criteria. Demographics, clinical variables, and post-operative outcomes were prospectively registered in an online database. Multivariable logistic regression analysis was used to identify independent predictors of post-operative mortality. RESULTS: There were 633 patients, 53.9% males, ASA class III/IV 43.6%, older than 65 years 58.6%. The most common operations were small bowel resection (20.5%), peptic ulcer repair (12.0%), adhesiolysis (11.8%) and Hartmann's procedure (11.5%). 30-day post-operative mortality reached 16.3% and serious complications occurred in 10.9%. Factors associated with post-operative mortality were increasing age and ASA class, dependent functional status, ascites, severe sepsis, septic shock, and diabetes. HELAS cohort showed similarities with NELA patients in terms of demographics and preoperative risk. Post-operative utilisation of ICU was significantly lower in the Greek cohort (25.8% vs 56.8%) whereas 30-day post-operative mortality was significantly higher (16.3% vs 8.7%). CONCLUSION: In this study, Greek patients experienced markedly worse mortality after emergency laparotomy compared with their British counterparts. This can be at least partly explained by underutilisation of critical care by surgical patients who are at high risk for death.

Surgical oncology during the post-COVID-19 era: What is next?

During first outburst of COVID-19, several strategies had been applied for surgical oncology patients to minimize COVID-19 transmission. COVID-19 infection seemed to compromise survival and major complication rates of surgical oncology patients. However, survival, tumor progression and recurrence rates of surgical oncology patients were associated to the consequences of COVID-19 pandemic on their management. In addition, the severity of COVID-19 infections has been downgraded. Therefore, management of surgical oncology patients should be reconsidered.

Accurate Characterization of Bladder Cancer Cells with Intraoperative Flow Cytometry.

Bladder cancer represents a major health issue. Transurethral resection is the first line treatment and an accurate assessment of tumor margins might warrant complete tumor removal. Genomic instability and proliferative potential are common hallmarks of cancer cells. We have previously demonstrated the utility of intraoperative flow cytometry (iFC), a next-generation margin evaluation methodology for assessment of DNA content, in the detection of several types of malignancy. In the current study we investigated the possible value of iFC in the characterization of bladder cancer during surgery. Samples from a population of 52 people with urothelial cancer were included in the study. The total time for iFC evaluation is 3-5 min per sample and included a two-step analysis, including DNA-index and Tumor-index calculation. First, DNA-index calculation revealed 24 hyperploid and one hypoploid tumor. Second, cell cycle analysis and Tumor-index calculation revealed that tumor samples are distinguished from normal cells based on their significantly higher proliferative potential. The standard for iFC evaluation was pathology assessment and revealed that our protocol exhibits an accuracy of 98% in defining the presence of cancer cells in a given sample. Our results support the further assessment of iFC value towards its use as a novel malignancy evaluation tool in transurethral resections.

Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury.

BACKGROUND: The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.). METHODS: HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay. We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions. RESULTS: The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model. CONCLUSIONS: Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.

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.

Colour Duplex and/or Contrast-Enhanced Ultrasound Compared with Computed Tomography Angiography for Endoleak Detection after Endovascular Abdominal Aortic Aneurysm Repair: A Systematic Review and Meta-Analysis.

This study aims to assess the role of Color Duplex Ultrasound with or without contrast media for surveillance following endovascular aortic aneurysm repair (EVAR). A systematic search of the literature published until April 2022 was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The pooled rates of endoleak detection through Contrast-Enhanced or Color Duplex Ultrasound (CEUS or CDUS) and Computed Tomography Angiography (CTA) with 95% confidence intervals (CIs) were estimated using random-effect analysis. Thirty-eight studies were considered eligible for inclusion. The total number of patients in the included studies was 5214 between 1997 and 2021. The overall pooled rate of endoleak detection using CDUS and CTA was 82.59% and 97.22%, while the rates for CEUS and CTA were 96.67% and 92.82%, respectively. The findings of the present study support the use of the CEUS for endoleak detection. However, it should be integrated into institutional protocols for EVAR surveillance to further evaluate its clinical utility in the post-EVAR period before it can be recommended as the sole imaging modality after EVAR.

Plasma VEGF and Leptin Values in Patients With Gastric Intestinal Metaplasia and Metabolic Syndrome.

Intestinal metaplasia of the stomach (IM) is considered a pre-cancerous lesion and is a potential precursor to adenocarcinoma. Metabolic syndrome (MetS) has been associated with lesions to the gastrointestinal tract such as the risk of developing Barett esophagus. Vascular endothelial growth factor and leptin have been associated with either gastrointestinal tract carcinogenesis or MetS. In this context, this study was designed to analyze plasma levels of VEGF and leptin in patients with IM and MetS. Four groups of 137 participants (a control group and three patient groups, IM, MetS and IM- MetS) were created. Inclusion criteria for the presence of IM were endoscopic findings and histological confirmation, while for MetS the ATP III and IDF guidelines. Levels of plasma vascular endothelial growth factor (VEGF) and leptin (Leptin) were determined. VEGF levels were increased in IM (IM vs Control, p=0,011) and IM-MetS groups (IM-MetS vs Control, p <0.001 and IM-MetS vs MetS, p=0.001). Leptin levels were found to be increased in the MetS group (MetS vs. Control, p <0.001 and MetS vs IM, p <0.001) and in IM-MetS (IM-MetS vs Control, p = 0.002, IM-MetS vs IM, p=0.033). Patients with intestinal metaplasia and metabolic syndrome (I M - Me t S g r o u p) have elevated levels of VEGF, while leptin levels were associated predominantly with MetS and not with IM.

Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis.

Introduction: The mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood. Objective: We evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability. Methods: A total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed via targeted next-generation sequencing (NGS). Results: The proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored mutations targetable by molecularly targeted drugs, either approved or currently under evaluation. Conclusion: Our proof-of-concept prospective study provides initial evidence on potential clinical superiority of IPH and warrants the conduction of precision oncology trials to evaluate the clinical utility of I PH-driven matched therapy.

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.

Description of a Recovery Model in Rabbits for the Study of the Late Phase of Liver Ischemia-Reperfusion Injury.

AIM: Description of an anesthetic recovery model with endotracheal intubation in rabbits which provides metabolic stability for the study of the late phase of liver ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: Two groups of New Zealand rabbits, n=7 in each, were used: Ischemia/reperfusion (I/R) group (45 min of partial liver ischemia/reperfusion) and no intervention (sham) group. Blood alanine aminotransferase, lactate, pH values, mean arterial pressure and pCO2 were calculated at baseline, and at 2 and 24 h post reperfusion. Tissue samples from left (ischemic) and right (non-ischemic) liver lobes were examined at 2 and 24 h after reperfusion. RESULTS: The I/R group presented significantly higher levels of alanine aminotransferase (p=0.001) at 2 and 24 h, and of lactate (p=0.016) at 2 h post reperfusion. No differences were documented for pH, mean arterial pressure and pCO2 Histological exanimation revealed significant injury at 24 h post reperfusion for the I/R group. CONCLUSION: This anesthetic recovery model permitted avoidance of hypoxia and respiratory acidosis, allowing the study of the late phase of I/R injury.

Urine 8-Hydroxyguanine (8-OHG) in Patients Undergoing Surgery for Colorectal Cancer.

PURPOSE: Cellular RNA is less compact than DNA, more easily accessible to ROS and therefore could be more susceptible to oxidative damage. This study was conceived in order to analyze the RNA oxidative damage in the urine of patients undergoing operation for colorectal cancer (CRC), to compare with healthy controls, and correlate with the stage. MATERIALS AND METHODS: The study population was constituted by a group of 147 patients and a group of 128 healthy controls. Urine and blood samples were collected before the colonoscopy in all participants and 24 hours post-operatively for those who underwent surgery. Urine 8-hydroxyguanine (8-OHG) was determined as marker of RNA oxidation, and serum uric acid (UA) as antioxidant marker. RESULTS: Preoperatively, 8-OHG (ng/ml) values of CRC patients were found to be significantly higher than those of controls (p = 0.001). More specifically, stages II/III had significantly higher 8-OHG values (p < 0.001 and p = 0.007) than stages 0/I. Post-operatively, 8-OHG values were similar to controls (p = 0.053). Preoperatively, UA values (mg/dl) were significantly lower (p = 0.001), while postoperatively were similar to controls (p = 0.069). CONCLUSION: Oxidative RNA damage occurs in CRC patients. Stages II/III are associated with higher values of 8-OHG than stages 0/I. 8-OHG could act as a marker for the identification of patients with advanced disease.

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.