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.

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.

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.

Surgical site infection in a Greek general surgery department: who is at most risk?

OBJECTIVE: Surgical site infections (SSIs) are associated with protracted hospitalisation, antibiotics administration, and increased morbidity and mortality. This work investigated the incidence rate of SSIs in the Department of General Surgery at the University Hospital of Ioannina, Greece, the associated risk factors and pathogens responsible. METHOD: In this prospective cohort study, patients who underwent elective procedures under general anaesthesia were enrolled. Risk factors monitored included age, sex, body mass index, smoking, alcohol consumption, preoperative length of stay, chemoprophylaxis, intensive care unit (ICU) stay, American Society of Anesthesiology (ASA) score, and the National Nosocomial Infections Surveillance System (NNIS) basic SSI risk index. RESULTS: Of the 1058 enrolled patients, 80 (7.6%) developed SSIs. Of the total cohort, 62.5% of patients received chemoprophylaxis for >24 hours. A total of 20 different pathogens, each with multiple strains (n=108 in total), were identified, 53 (49.5%) Gram-negative rods, 46 (42%) Gram-positive cocci, and nine (8.4%) fungi (Candida spp.). Escherichia coli was the prevalent microorganism (24.3%). SSI-related risk factors, as defined by univariate analysis, included: ICU stay, ASA score >2 (p<0.001), NNIS score >0, and wound classes II, III, and IV. Also, serum albumin levels <3.5g/dl were associated with increased rate of SSIs. The multivariate model identified an NNIS score of >0 and wound classes II, III, and IV as independent SSI-related risk factors. CONCLUSION: This study showed high SSI rates. Several factors were associated with increased SSI rates, as well as overuse of prophylactic antibiotics. The results of the present study could be a starting point for the introduction of a system for recording and actively monitoring SSIs in Greek hospitals, and implementation of specific guidelines according to risk factors.

Perioperative Use of Anti-TNFa Biological Agents in Open and Laparoscopic Surgery for Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) consists of two disorders: Crohn's disease (CD) and ulcerative colitis (UC). Over the past few decades, a great body of knowledge has accumulated regarding the pathogenesis of IBD, and effective pharmaceutical agents, such as inhibitors of tumor necrosis factor (anti-TNF), have been introduced. Although these agents have dramatically improved the outcome of IBD, up to 70% of patients with CD and 10-30% of those with UC still undergo surgery within 10 years from diagnosis. Because of their young age and high recurrence rates, these patients are appropriate candidates for laparoscopic surgery as an alternative to laparotomy. Recently, considerable attention has been focused on perioperative outcomes of patients who are receiving anti-TNF agents and require surgery. The aim of this narrative review is to discuss the current evidence regarding the impact of perioperative anti-TNF treatment on post-operative complication rates with a special focus on laparoscopic surgery.

Identification of novel genes by whole-exome sequencing can improve gastric cancer precision oncology.

AIM: By identifying cancer driver genes involved in tumorigenesis, whole-exome sequencing (WES) analyses enable the development of robust biomarkers and novel therapeutic targets to reach precision oncology. PATIENTS & METHODS: WES analyses were performed in matched gastric cancer-normal gastric tissues from two patients. We compared genes highlighted with those of a database and recent WES/whole-genome sequencing studies. RESULTS: We identified 32 highlighted gastric cancer genes, two of these (DEFB118 and RNF43) may provide future potential clinical implications. CONCLUSION: Definitive evidence on extensive genetic heterogeneity suggests the need for large-scale next-generation sequencing studies to validate gastric cancer driver genes catalog. This list represents the foundation for developing genome-based biomarkers to guide precision gastric cancer treatment.

From Clinical Standards to Translating Next-Generation Sequencing Research into Patient Care Improvement for Hepatobiliary and Pancreatic Cancers.

Hepatobiliary and pancreatic (HBP) cancers are associated with high cancer-related death rates. Surgery aiming for complete tumor resection (R0) remains the cornerstone of the treatment for HBP cancers. The current progress in the adjuvant treatment is quite slow, with gemcitabine chemotherapy available only for pancreatic ductal adenocarcinoma (PDA). In the advanced and metastatic setting, only two targeted drugs have been approved by the Food & Drug Administration (FDA), which are sorafenib for hepatocellular carcinoma and erlotinib for PDA. It is a pity that multiple Phase III randomized control trials testing the efficacy of targeted agents have negative results. Failure in the development of effective drugs probably reflects the poor understanding of genome-wide alterations and molecular mechanisms orchestrating therapeutic resistance and recurrence. In the post-ENCODE (Encyclopedia of DNA Elements) era, cancer is referred to as a highly heterogeneous and systemic disease of the genome. The unprecedented potential of next-generation sequencing (NGS) technologies to accurately identify genetic and genomic variations has attracted major research and clinical interest. The applications of NGS include targeted NGS with potential clinical implications, while whole-exome and whole-genome sequencing focus on the discovery of both novel cancer driver genes and therapeutic targets. These advances dictate new designs for clinical trials to validate biomarkers and drugs. This review discusses the findings of available NGS studies on HBP cancers and the limitations of genome sequencing analysis to translate genome-based biomarkers and drugs into patient care in the clinic.

BMI and lymph node ratio may predict clinical outcomes of gastric cancer.

AIM: BMI and the lymph node (LN) ratio can affect short- and long-term outcomes of patients with gastric cancer. PATIENTS & METHODS: This study includes 104 consecutive patients with gastric adenocarcinoma who underwent curative gastrectomy divided in two groups: overweight group (group A) and normal weight group (group B). RESULTS: We found that 53.4% of our patients were overweight (group A). The overall rate of postoperative complications was 16.3%, while mortality was 1%. Statistical analyses revealed that postoperative morbidity was significantly higher in group A (p < 0.05). Long-term survival was significantly higher in group B. Cox regression showed a statistically significant correlation between higher BMI and poor long-term survival after curative gastrectomy. Multivariate analysis has identified age and the LN ratios as independent prognostic factors of survival. CONCLUSION: In this retrospective analysis, BMI and LN ratio were independently associated with survival in patients with gastric cancer. Further studies are needed to confirm our findings.

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 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.

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.

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.

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.

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.

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.

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.