Innovations in Liver Preservation Techniques for Transplants from Donors after Circulatory Death: A Special Focus on Transplant Oncology.

Liver transplantation is the preferred treatment for end-stage liver disease. Emerging evidence suggests a potential role for liver transplantation in treating liver tumors such as colorectal liver metastases and cholangiocarcinoma. However, due to a limited donor pool, the use of marginal grafts from donation after circulatory death (DCD) donors is increasing to meet demand. Machine perfusion is crucial in this context for improving graft acceptance rates and reducing ischemia-reperfusion injury. Few studies have evaluated the role of machine perfusion in the context of transplant oncology. Perfusion machines can be utilized in situ (normothermic regional perfusion-NRP) or ex situ (hypothermic and normothermic machine perfusion), either in combination or as a complement to conventional in situ cold flush and static cold storage. The objective of this analysis is to provide an up-to-date overview of perfusion machines and their function in donation after circulatory death with particular attention to their current and likely potential effects on transplant oncology. A literature review comparing standard cold storage to machine perfusion methods showed that, so far, there is no evidence that these devices can reduce the tumor recurrence rate. However, some evidence suggests that these innovative perfusion techniques can improve graft function, reduce ischemia-reperfusion injury, and, based on this mechanism, may lead to future improvements in cancer recurrence.

Single large hepatocellular carcinoma > 5 cm with surgical indication: is it mandatory a major hepatectomy? a propensity-score weighted analysis.

PURPOSE: Single large hepatocellular carcinoma >5cm (SLHCC) traditionally requires a major liver resection. Minor resections are often performed with the goal to reduce morbidity and mortality. Aim of the study was to establish if a major resection should be considered the best treatment for SLHCC or a more limited resection should be preferred. METHODS: A multicenter retrospective analysis of the HE.RC.O.LE.S. Group register was performed. All collected patients with surgically treated SLHCC were divided in 5 groups of treatment (major hepatectomy, sectorectomy, left lateral sectionectomy, segmentectomy, non-anatomical resection) and compared for baseline characteristics, short and long-term results. A propensity-score weighted analysis was performed. RESULTS: 535 patients were enrolled in the study. Major resection was associated with significantly increased major complications compared to left lateral sectionanectomy, segmentectomy and non-anatomical resection (all p<0.05) and borderline significant increased major complications compared to sectorectomy (p=0.08). Left lateral sectionectomy showed better overall survival compared to major resection (p=0.02), while other groups of treatment resulted similar to major hepatectomy group for the same item. Absence of oncological benefit after major resection and similar outcomes among the 5 groups of treatment was confirmed even in the sub-population excluding patients with macrovascular invasion. CONCLUSION: Major resection was associated to increased major post-operative morbidity without long-term survival benefit; when technically feasible and oncologically adequate, minor resections should be preferred for the surgical treatment of SLHCC.

Cornerstones and divergencies in the implementation and use of liver hypertrophy techniques: results from a nationwide survey for the set-up of the prospective registry.

BACKGROUND: The aim of this national survey on liver hypertrophy techniques was to track the trends of their use and implementation in Italy and to detect analogies and heterogeneities among centers. METHODS: In December 2022, Italian centers with liver resection activity were specifically contacted and asked to fill an online questionnaire composed of 6 sections including a total of 51 questions. RESULTS: 46 Italian centers filled the questionnaire. The proportion of major/total number of liver resections was 27% and the use of hypertrophy techniques was required in 6,2% of cases. The most frequent reason of drop out was disease progression in 58.5% of cases. Most frequently used techniques were PVE and ALPPS with an increasing use of hepatic venous deprivation (HVD). Heterogeneous answers were provided regarding the cutoff values to indicate the need for hypertrophy techniques. Criteria to allocate a patient to different hypertrophy techniques are not standardized. CONCLUSIONS: The use of hypertrophy techniques is deep-rooted in Italy, documenting the established value of their role in improving resectability rate. While an evolution of techniques is detectable, still significant heterogeneity is perceived in terms of cutoff values, indications and managing protocols.

Successful Recovery of Cardiac Function Following 20 min of a No-touch Period in a Donation After Circulatory Death: A Case Report.

BACKGROUND: Withdrawal of life-sustaining therapy (WLST) performed in the circulatory determination of death (DCD) donors leads to cardiac arrest, challenging the utilization of the myocardium for transplantation. The rapid initiation of normothermic regional perfusion or extracorporeal membrane oxygenation after death helps to optimize organs before implantation. However, additional strategies to mitigate the effects of stress response during WLST, hypoxic/ischemic injury, and reperfusion injury are required to allow myocardium recovery. METHODS: To this aim, our team routinely used a preconditioning protocol for each DCD donation before and during the WLST and after normothermic regional perfusion/extracorporeal membrane oxygenation. The protocol includes pharmacological treatments combined to reduce oxidative stress (melatonin, N -acetylcysteine, and ascorbic acid), improve microcirculation (statins), and mitigate organ's ischemic injury (steroids) and organ ischemia/reperfusion injury (remifentanil and sevoflurane when the heart is available for transplantation). RESULTS: This report presents the first case of recovery of cardiac function, with the only support of normothermic regional reperfusion, following 20 min of a no-touch period and 41 min of functional warm ischemic time in a DCD donor after the preconditioning protocol. CONCLUSIONS: Our protocol seems to be effective in abolishing the stress response during WLST and, on the other hand, particularly organ protective (and heart protective), giving a chance to donate organs less impaired from ischemia/reperfusion injury.

Bile Duct Lithiasis Mimicking a Perihilar Cholangiocarcinoma-An Endless Dilemma: A Case Report.

Hilar bile duct strictures are mostly caused by malignant lesions. The morphological appearance of perihilar cholangiocarcinomas in various imaging modalities have other malignant and even benign mimics, which pose challenges to an accurate diagnosis and treatment and drive to futile surgery. Herein, we present the case of a 50-year-old woman admitted with jaundice and abdominal pain, elevated bilirubin level, liver function tests and carbohydrate antigen 19-9 level. Magnetic resonance cholangio-pancreatography (MR-CP) and the computed tomography with contrast enhancement revealed a suspected extrahepatic cholangiocarcinoma of the common bile duct. Further spontaneous resolution of the scenario, confirmed by diagnostic assessment, changed the clinical hypothesis in favor of a non-oncological disease. Indeed, the multidisciplinary evaluation supported a diagnosis of transient cholangitis secondary to non-evident intrahepatic lithiasis rather than cholangiocarcinoma. After a 26-month follow-up, the patient was asymptomatic with normal tumor markers and laboratory data. Consecutive MR-CPs showed no suspicion of malignancy. This case report underlines the need for an accurate preoperative assessment in patients with suspected cholangiocarcinoma.

Prospective minimally invasive pancreatic resections from the IGOMIPS registry: a snapshot of daily practice in Italy on 1191 between 2019 and 2022.

This retrospective analysis of the prospective IGOMIPS registry reports on 1191 minimally invasive pancreatic resections (MIPR) performed in Italy between 2019 and 2022, including 668 distal pancreatectomies (DP) (55.7%), 435 pancreatoduodenectomies (PD) (36.3%), 44 total pancreatectomies (3.7%), 36 tumor enucleations (3.0%), and 8 central pancreatectomies (0.7%). Spleen-preserving DP was performed in 109 patients (16.3%). Overall incidence of severe complications (Clavien-Dindo ≥ 3) was 17.6% with a 90-day mortality of 1.9%. This registry analysis provided some important information. First, robotic assistance was preferred for all MIPR but DP with splenectomy. Second, robotic assistance reduced conversion to open surgery and blood loss in comparison to laparoscopy. Robotic PD was also associated with lower incidence of severe postoperative complications and a trend toward lower mortality. Fourth, the annual cut-off of ≥ 20 MIPR and ≥ 20 MIPD improved selected outcome measures. Fifth, most MIPR were performed by a single surgeon. Sixth, only two-thirds of the centers performed spleen-preserving DP. Seventh, DP with splenectomy was associated with higher conversion rate when compared to spleen-preserving DP. Eighth, the use of pancreatojejunostomy was the prevalent reconstruction in PD. Ninth, final histology was similar for MIPR performed at high- and low-volume centers, but neoadjuvant chemotherapy was used more frequently at high-volume centers. Finally, this registry analysis raises important concerns about the reliability of R1 assessment underscoring the importance of standardized pathology of pancreatic specimens. In conclusion, MIPR can be safely implemented on a national scale. Further analyses are required to understand nuances of implementation of MIPR in Italy.

Survival benefit of second line therapies for recurrent hepatocellular carcinoma: repeated hepatectomy, thermoablation and second-line transplant referral in a real life national scenario.

BACKGROUND: Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group). METHODS: Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups. RESULTS: 743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011). CONCLUSION: It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed.

Intrahepatic Cholangiocarcinoma Developing in Patients with Metabolic Syndrome Is Characterized by Osteopontin Overexpression in the Tumor Stroma.

Metabolic syndrome (MetS) is a common condition closely associated with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Recent meta-analyses show that MetS can be prodromal to intrahepatic cholangiocarcinoma (iCCA) development, a liver tumor with features of biliary differentiation characterized by dense extracellular matrix (ECM) deposition. Since ECM remodeling is a key event in the vascular complications of MetS, we aimed at evaluating whether MetS patients with iCCA present qualitative and quantitative changes in the ECM able to incite biliary tumorigenesis. In 22 iCCAs with MetS undergoing surgical resection, we found a significantly increased deposition of osteopontin (OPN), tenascin C (TnC), and periostin (POSTN) compared to the matched peritumoral areas. Moreover, OPN deposition in MetS iCCAs was also significantly increased when compared to iCCA samples without MetS (non-MetS iCCAs, n = 44). OPN, TnC, and POSTN significantly stimulated cell motility and the cancer-stem-cell-like phenotype in HuCCT-1 (human iCCA cell line). In MetS iCCAs, fibrosis distribution and components differed quantitatively and qualitatively from non-MetS iCCAs. We therefore propose overexpression of OPN as a distinctive trait of MetS iCCA. Since OPN stimulates malignant properties of iCCA cells, it may provide an interesting predictive biomarker and a putative therapeutic target in MetS patients with iCCA.

Machine Learning Predictive Model to Guide Treatment Allocation for Recurrent Hepatocellular Carcinoma After Surgery.

Importance: Clear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking. Objective: To create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment. Design, Setting, and Participants: Real-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021. Exposures: Patients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib. Main Outcomes and Measures: Survival after recurrence was the end point. Results: A total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation. Conclusions and Relevance: The herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.

The Effect of a Liver Transplant Program on the Outcomes of Resectable Hepatocellular Carcinoma: A Nationwide Multicenter Analysis.

OBJECTIVE: To evaluate the effect of a liver transplantation (LT) program on the outcomes of resectable hepatocellular carcinoma (HCC). BACKGROUND: Surgical treatment of HCC includes both hepatic resection (HR) and LT. However, the presence of cirrhosis and the possibility of recurrence make the management of this disease complex and probably different according to the presence of a LT program. METHODS: Patients undergoing HR for HCC between January 2005 and December 2019 were identified from a national database of HCC. The main study outcomes were major surgical complications according to the Comprehensive Complication Index, posthepatectomy liver failure (PHLF), 90-day mortality, overall survival, and disease-free survival. Secondary outcomes were salvage liver transplantation (SLT) and postrecurrence survival. RESULTS: A total of 3202 patients were included from 25 hospitals over the study period. Three of 25 (12%) had an LT program. The presence of an LT program within a center was associated with a reduced probability of PHLF (odds ratio=0.38) but not with overall survival and disease-free survival. There was an increased probability of SLT when HR was performed in a transplant hospital (odds ratio=12.05). Among transplant-eligible patients, those who underwent LT had a significantly longer postrecurrence survival. CONCLUSIONS: This study showed that the presence of a LT program was associated with decreased PHLF rates and an increased probability to receive SLT in case of recurrence.

Impact of Intensive Care Unit bed shortage on the short-term outcomes of major liver surgery during the pandemic: better safe than sorry?

BACKGROUND: Preoperative criteria to establish the need for intensive care unit (ICU) admission after major liver surgery have not been yet precisely defined and are often left to the anesthesiologist's judgment. The ICU bed shortage during the COVID-19 pandemic has challenged healthcare systems around the world. We sought to determine its impact on early outcomes of elective major liver surgery. METHODS: We performed a retrospective analysis of consecutive patients undergoing major oncological liver surgery from a single institution. Two time periods were compared considering a complete ban on ICU beds during the pandemic (index period, from November 2020 to May 2021), and the smoothly running ICU facility before the pandemic (control period, from November 2018 to October 2020). The main outcomes were 30-day morbidity and mortality, length-of-stay, and 30-day readmission rates. RESULTS: Overall, 57 consecutive patients were identified, of whom 18 (32%) in the index period, and 39 (68%) in the control period, with 24 (62%) patients in the latter group admitted to ICU. No significant differences were found in terms of ASA Score, P-POSSUM morbidity and mortality, operative times, and red blood cells transfusions between groups. The morbidity rate, as classified by the Clavien-Dindo system, was also similar. A slightly longer length-of-stay has been observed in the index period (mean difference of 1.12 [95% CI, -9.19;11.42] days; P=0.829) after controlling for age, gender, ASA Score, and P-POSSUM. The 30-day readmission rate was comparable between the index and control periods (5.0% vs. 4.8%, respectively). CONCLUSIONS: The ICU bed shortage in response to the COVID-19 emergency did not negatively impact on the early postoperative outcomes of major liver surgery.

Translational Value of Tumor-Associated Lymphangiogenesis in Cholangiocarcinoma.

The prognosis of cholangiocarcinoma remains poor in spite of the advances in immunotherapy and molecular profiling, which has led to the identification of several targetable genetic alterations. Surgical procedures, including both liver resection and liver transplantation, still represent the treatment with the best curative potential, though the outcomes are significantly compromised by the early development of lymph node metastases. Progression of lymphatic metastasis from the primary tumor to tumor-draining lymph nodes is mediated by tumor-associated lymphangiogenesis, a topic largely overlooked until recently. Recent findings highlight tumor-associated lymphangiogenesis as paradigmatic of the role played by the tumor microenvironment in sustaining cholangiocarcinoma invasiveness and progression. This study reviews the current knowledge about the intercellular signaling and molecular mechanism of tumor-associated lymphangiogenesis in cholangiocarcinoma in the hope of identifying novel therapeutic targets to halt a process that often limits the success of the few available treatments.

Ferroptosis in Intrahepatic Cholangiocarcinoma: IDH1105GGT Single Nucleotide Polymorphism Is Associated With Its Activation and Better Prognosis.

Objectives: Intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis and often demonstrates an anti-apoptotic landscape, which is a key step to chemotherapy resistance. Isocitrate dehydrogenase 1 or 2 (IDH1-2)-mutated ICCs have been described and associated with better prognosis. Ferroptosis is a regulated iron-mediated cell death induced by glutathione peroxidase 4 (GPX4) inhibition, and may be triggered pharmacologically. GPX4 is overexpressed in aggressive cancers, while its expression is inhibited by IDH1 R132C mutation in cell lines. We investigated tissue expression of ferroptosis activation markers in ICC and its correlation with clinical-pathological features and IDH1-2 status. Materials and Methods: We enrolled 112 patients who underwent hepatic resection or diagnostic liver biopsy for ICC. Immunostaining for transferrin-receptor 1 and GPX4, and Pearls' stain for iron deposits were performed to evaluate ferroptosis activation. Immunostaining for STAT3 was performed to study pro-inflammatory and anti-apoptotic landscape. Main IDH1-2 mutations were investigated in 90 cases by real-time polymerase chain reaction. Results: GPX4 overexpression was seen in 79.5% of cases and related to poor histological prognostic factors (grading and perineural and vascular invasion; p < 0.005 for all) and worse prognosis (OS p = 0.03; DFS p = 0.01). STAT3 was expressed in 95.5% of cases, confirming the inflammation-related anti-apoptotic milieu in ICC, and directly related to GPX4 expression (p < 0.0001). A high STAT3 expression correlated to a worse prognosis (OS p = 0.02; DFS p = 0.001). Nearly 12% of cases showed IDH1 105GGT single nucleotide polymorphism, which was never described in ICC up to now, and was related to lower tumor grade (p < 0.0001), longer overall survival (p = 0.04), and lower GPX4 levels (p = 0.001). Conclusion: Our study demonstrates for the first time that in most inflammatory ICCs ferroptosis is not active, and its triggering is related to IDH1-2 status. This supports the possible therapeutic role of ferroptosis-inducer drugs in ICC patients, especially in drug-resistant cases.

Anal Fistula Human Amniotic Membrane Endosealing (F-HAME): A Proof of Concept Study.

The treatment of cryptoglandular anal fistula (AF) is often a challenge for surgeons. Several sphincter-saving procedures have been described as an alternative to fistulotomy, with the common goal of promoting healing and preserve anal continence. The aim of this proof of concept study was to assess the outcomes of human amniotic membrane (HAM) implantation in cryptoglandular transphincteric AF. Two consecutive female were recruited. The primary outcome was clinical healing at 6 months. Secondary outcomes were ultrasonographic healing, complications and reinterventions, AF symptoms, fecal incontinence, psychological impact of treatment, recurrence, development of additional AF, patient satisfaction, and quality of life, as measured using validated questionnaires. Both patients (40 and 54-year-old) previously underwent incision and drainage of anal abscess with concomitant seton placement. HAM implantation was performed as a day case under local anesthesia. No intra- or post-procedural complications occurred. Clinical and radiological healing were not achieved at 6 months. However, the external outlet discharge diminished through time, with sustained improvements in quality of life. Clinical healing occurred at 7 months in both patients. Psychological impact of treatment and patient satisfaction were overall good, with improvements in the PHQ-9, GAD-7, and Short Assessment of Patients Satisfaction. HAM implantation is safe and improves patients' quality of life, progressively leading to clinical healing. Future studies are needed to assess its safety in other etiology of AF.

Benchmarking postoperative outcomes after open liver surgery for cirrhotic patients with hepatocellular carcinoma in a national cohort.

BACKGROUND: Benchmark analysis for open liver surgery for cirrhotic patients with hepatocellular carcinoma (HCC) is still undefined. METHODS: Patients were identified from the Italian national registry HE.RC.O.LE.S. The Achievable Benchmark of Care (ABC) method was employed to identify the benchmarks. The outcomes assessed were the rate of complications, major comorbidities, post-operative ascites (POA), post-hepatectomy liver failure (PHLF), 90-day mortality. Benchmarking was stratified for surgical complexity (CP1, CP2 and CP3). RESULTS: A total of 978 of 2698 patients fulfilled the inclusion criteria. 431 (44.1%) patients were treated with CP1 procedures, 239 (24.4%) with CP2 and 308 (31.5%) with CP3 procedures. Patients submitted to CP1 had a worse underlying liver function, while the tumor burden was more severe in CP3 cases. The ABC for complications (13.1%, 19.2% and 28.1% for CP1, CP2 and CP3 respectively), major complications (7.6%, 11.1%, 12.5%) and 90-day mortality (0%, 3.3%, 3.6%) increased with the surgical difficulty, but not POA (4.4%, 3.3% and 2.6% respectively) and PHLF (0% for all groups). CONCLUSION: We propose benchmarks for open liver resections in HCC cirrhotic patients, stratified for surgical complexity. The difference between the benchmark values and the results obtained during everyday practice reflects the room for potential growth, with the aim to encourage constant improvement among liver surgeons.

Necroptosis-driving genes RIPK1, RIPK3 and MLKL-p are associated with intratumoral CD3+ and CD8+ T cell density and predict prognosis in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8+ T cells seem to be related to a better prognosis, but the mechanisms affecting the immune landscape in HCC are still mostly unknown. Necroptosis is a programmed, caspase-independent cell death that, unlike apoptosis, evokes immune response by releasing damage-associated molecular factors. However, in HCC, the relationship between the necroptotic machinery and the tumor-infiltrating lymphocytes has not been fully investigated so far. METHODS: We investigated the association between the main necroptosis-related genes, that is, RIPK1, RIPK3, MLKL-p, and CD3+/CD8+ tumor-infiltrating T cell by RNA-seq data analysis in 371 patients with primary HCC from The Cancer Genome Atlas and then by immunohistochemistry in two independent cohorts of HCC patients from Italy (82) and Japan (86). RESULTS: Our findings highlighted the immunogenetic role of necroptosis and its potential prognostic role in HCC: RIPK1, RIPK3 and MLKL-p were found significantly associated with intratumoral CD3+ and CD8+ T cells. In addition, multivariate survival analysis showed that the expression of RIPK1, RIPK3 and MLKL-p was associated with better overall survival in the two independent cohorts. CONCLUSIONS: Our results confirmed the immunogenetic properties of necroptosis (NCP) in human HCC, showing that tumor-infiltrating lymphocytes (TILs) and, specifically, CD8+ T cells accumulate in tumors with higher expression of the necroptosis-related genes. These results suggest the importance of further studies to better assess the specific composition, as well as the functional features of the immune environment associated with a necroptotic signature in order to explore new possible diagnostic and immunotherapeutic scenarios.

Changes in hospital admissions and complications of acute appendicitis during the COVID-19 pandemic: A systematic review and meta-analysis.

Background: Acute appendicitis (AA) is one of the most common emergencies in general surgery worldwide. During the pandemic, a significant decrease in the number of accesses to the emergency department for AA has been recorded in different countries. A systematic review of the current literature sought to determine the impact of Coronavirus Disease 2019 (COVID-19) on hospital admissions and complications of AA. Method: A systematic search was undertaken to identify repeated cross-sectional studies reporting the management of AA during the COVID-19 pandemic (index period) as compared to the previous year, or at the turn of lockdown (reference period). Data were abstracted on article (country of origin) and patients characteristics (adults, children [i.e. non adults, <18-year-old]), or mixed population) within the two given timeframes, including demographics, number of admissions for AA, number of appendectomies, and complicated appendectomies. Results: Of 201 full-text articles assessed for eligibility, 54 studies from 22 world countries were included. In total, 27 (50%) were conducted on adults, 12 (22%) on children, and 15 (28%) on a mixed patients population. The overall rate ratio of admissions for AA between the two periods was 0.94 (95%CI, 0.75-1.17), with significant differences between studies on adults (0.90 [0.74-1.09]), mixed population (0.50 [0.27-0.90]), and children (1.50 [1.01-2.22]). The overall risk ratio of complicated AA was 1.65 (1.32-2.07), ranging from 1.32 in studies on children, to 2.45 in mixed population. Conclusion: The pandemic has altered the rate of admissions for AA and appendectomy, with parallel increased incidence of complicated cases in all age groups.