Immunohistochemical expression of ephrin receptors in neuroendocrine neoplasms: a case-series of gastroenteropancreatic neuroendocrine neoplasms and a systematic review of the literature.

PURPOSE: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of tyrosine kinases receptors (TKR) in humans, implicated in cell proliferation, adhesion, migration, tumor angiogenesis, invasion and metastasis. The aim of the present study is to assess the expression of EPHs in neuroendocrine neoplasms (NENs). METHODS: Immunohistochemical staining of specimens of 30 patients with gastroenteropancreatic and lung NENs was performed for EPH-A1, EPH-A2, EPH-A4, EPH-A5 protein expression, in addition to ki-67 multiplication index and programmed death-ligand 1. Additionally, we performed a systematic review of the available literature in three different databases reporting on the expression of EPH in all neuroendocrine neoplasms. RESULTS: Positive expression was seen in 16/19 (84%) specimens for EPH-A1, 15/23 (65%) for EPH-A2, 21/24 (88%) for EPH-A4, 24/26 (92%) for EPH-A5. EPH-A1 was expressed in 9/9 pancreatic, 3/4 small intestine, but not in one lung NEN, EPH-A2 in 5/10 pancreatic, 3/4 small intestine and lung, and in one of each of gastric, appendix, colorectal, and cervical NENs, respectively. EPH-A4 showed positive expression in 9/11 pancreatic, 4/4 small intestine, 3/3 lung specimens and EPH-A5 in 10/11, 4/4 and 4/4, respectively. Data retrieved from the systematic review of the literature in combination with the data from the present study are suggestive of a frequent EPH expression in pituitary, thyroid, lung and gastroenteropancreatic NENs, yet, with varying expressions of the single receptor subtypes. CONCLUSION: EPHs may have a role in NEN tumorigenesis, prognosis as well as a role in the evolving molecular-targeted therapies.

Decoding the Prognostic Significance and Therapeutic Implications of Inflammation-Based Scores in Hepatocellular Carcinoma: A Comprehensive Review.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer, posing a significant global health challenge with an increasing incidence. In recent years, multiple staging systems and scores have been proposed, emphasising the necessity for the development of precise prognostic tools. The well-documented etiological relationship between chronic inflammation and carcinogenesis has prompted researchers to explore novel prognostic markers associated with the inflammatory status of HCC patients. This review summarises the current data about inflammation-based scores in the context of HCC. We discuss established scores like the Glasgow Prognostic Score (GPS), modified GPS (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) and others not as extensively studied, examining their utility in predicting survival outcomes and treatment response in HCC patients. Furthermore, we explore emerging scores, including the prognostic nutritional index (PNI) and other lymphocyte-based scores, assessing their potential in refining risk stratification and guiding therapeutic decisions in the era of precision medicine. As research progresses and these scores undergo further refinement and integration into the evolving landscape of HCC management, they carry significant potential for improving patient outcomes.

Liver transplantation for iatrogenic bile duct injury: a systematic review.

BACKGROUND: Bile duct injury (BDI) is an infrequent but serious complication of cholecystectomy, often with life-changing consequences. Liver transplantation (LT) may be required following severe BDI, however given the rarity, few large studies exist to guide management for complex BDI. METHODS: A systematic review was performed to assess post-operative complications, 30-day mortality, retransplant rate and 1-year and 5-year survival following LT for BDI in Medline, EMBASE, Web of Science or Cochrane Clinical Trials Database. RESULTS: Seven articles met inclusion criteria, describing 179 patients that underwent LT for BDI. Secondary biliary cirrhosis (SBC) was the main indication for LT (82.2% of patients). Median model for end-stage liver disease (MELD) scores at time of LT ranged from 16 to 20.5. Median 30-day mortality was 20.0%. The 1-year and 5-year survival ranges were 55.0-84.3% and 30.0-83.3% respectively, and the overall retransplant rate was 11.5%. CONCLUSION: BDI is rarely indicated for LT, predominantly for SBC following multiple prior interventions. MELD scores poorly reflect underlying morbidity, and exception criteria for waitlisting may avoid prolonged LT waiting times. 30-day mortality was higher than for non-BDI indications, with comparable long term survival, suggesting that LT remains a viable but high risk salvage option for severe BDI.

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.

Safety and Efficacy of Laparoscopic Caudate Lobectomy: A Systematic Review.

Resection of the caudate lobe of the liver is considered a highly challenging type of liver resection due to the region's intimacy with critical vascular structures and deep anatomic location inside the abdominal cavity. Laparoscopic resection of the caudate lobe is considered one of the most challenging laparoscopic liver procedures. The objective of our systematic review was to evaluate the safety, technical feasibility and main outcomes of laparoscopic caudate lobectomy LCL. A systematic review of the literature was undertaken for studies published until September 2021. A total of 20 studies comprising 221 patients were included. Of these subjects, 36% were women, whereas the vast majority of resections (66%) were performed for malignant tumors. Tumor size varied significantly between 2 and 160 mm in the largest diameter. The mean operative time was 210 min (range 60-740 min), and estimated blood loss was 173.6 mL (range 50-3600 mL). The median hospital length of stay LOS was 6.5 days (range 2-15 days). Seven cases of conversion to open were reported. The vast majority of patients (93.7%) underwent complete resection (R0) of their tumors. Thirty-six out of 221 patients developed postoperative complications, with 5.8% of all patients developing a major complication (Clavien-Dindo classification ≥ III).No perioperative deaths were reported by the included studies. LCL seems to be a safe and feasible alternative to open caudate lobectomy OCL in selected patients when undertaken in high-volume centers by experienced surgeons.

Management of portal vein thrombosis in cirrhotic patients enlisted for liver transplantation: From diagnosis to treatment (Review).

Portal vein thrombosis (PVT) commonly occurs in patients with cirrhosis. Several classification systems of PVT have been proposed over the years reflecting the challenge in establishing a widely accepted system. To date, PVT has been considered an absolute contraindication for orthotopic liver transplantation (OLT) since it is associated with decreased graft survival and increased patient mortality. Nevertheless, the development of modern surgical techniques has enabled the inclusion of these candidates in OLT waiting lists, since their postoperative results are shown to be comparable to those of patients without PVT. The aim of the present review was to critically appraise the available treatment options for cirrhotic patients enlisted for liver transplantation in the setting of PVT.

Portal Vein Stent Placement in Anastomotic Stenosis After Deceased Donor Liver Transplantation: A Case Report.

Vascular complications (VCs) after liver transplantation (LT) frequently result in graft and patient loss. The smaller vessels and the insufficient length for reconstruction in living donor LT and pediatric transplantation predispose patients to a higher incidence of VCs. Herein we present a case of portal vein stenosis (PVS) in an adult deceased donor LT recipient with portal vein thrombosis requiring extended thrombectomy at the time of LT. He presented with ascites 4 months after LT, was diagnosed with PVS, and was successfully treated with percutaneous transhepatic venoplasty and placement of a portal stent. This case highlights the importance of Doppler ultrasound as a screening modality for detection of VCs after LT and the pivotal role of endovascular repair as a first-line treatment for PVS.

Changing biological behaviour of NETs during the evolution of the disease: progress on progression.

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

Currently available treatment options for neuroendocrine liver metastases.

Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.

Inguinal Hernias in Cirrhotic Patients: From Diagnosis to Treatment.

Cirrhosis has a strong association with abdominal wall hernias, especially in the presence of concomitant ascites. Major predisposing factors for hernia formation in this particular group of patients include increased intra-abdominal pressure and decreased muscle mass due to poor nutrition. Management of these patients is highly challenging and requires an experienced multidisciplinary surgical and medical approach. The aim of our review is to clarify crucial diagnostic and management approaches. Crucial medical and technical issues on this topic are widely discussed with special focus on indication, timing, and type of surgical repair, with an additional reference to the actual role of laparoscopy.

Liver transplantation as last-resort treatment for patients with bile duct injuries following cholecystectomy: a multicenter analysis.

BACKGROUND: Liver transplantation (LT) has been used as a last resort in patients with end-stage liver disease due to bile duct injuries (BDI) following cholecystectomy. Our study aimed to identify and evaluate factors that cause or contribute to an extended liver disease that requires LT as ultimate solution, after BDI during cholecystectomy. METHODS: Data from 8 high-volume LT centers relating to patients who underwent LT after suffering BDI during cholecystectomy were prospectively collected and retrospectively analyzed. RESULTS: Thirty-four patients (16 men, 18 women) with a median age of 45 (range 22-69) years were included in this study. Thirty of them (88.2%) underwent LT because of liver failure, most commonly as a result of secondary biliary cirrhosis. The median time interval between BDI and LT was 63 (range 0-336) months. There were 23 cases (67.6%) of postoperative morbidity, 6 cases (17.6%) of post-transplant 30-day mortality, and 10 deaths (29.4%) in total after LT. There was a higher probability that patients with concomitant vascular injury (hazard ratio 10.69, P=0.039) would be referred sooner for LT. Overall survival following LT at 1, 3, 5 and 10 years was 82.4%, 76.5%, 73.5% and 70.6%, respectively. CONCLUSION: LT for selected patients with otherwise unmanageable BDI following cholecystectomy yields acceptable long-term outcomes.

Meta-analysis of laparoscopic versus open liver resection for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive hepatic malignancy. An up-to-date systematic review and meta-analysis was conducted aiming to compare outcomes between laparoscopic (LLR) and open liver resection (OLR) for patients with iCCA. A systematic literature search of Medline, Scopus, Google Scholar, and Cochrane databases was performed. A total of 8 studies comprising 2872 patients, who underwent LLR or OLR for iCCA, were included in our meta-analysis. LLR patients had smaller tumors [mean difference (MD): - 1.17 cm, 95% confidence intervals (CI) - 1.77 to - 0.57, p = 0.0001], underwent major resections less frequently [risk ratio (RR): 0.75, 95% CI 0.67-0.83, p < 0.00001] and R0 resections more frequently (RR: 1.05, 95% CI 1.01-1.09, p = 0.01), while lymphadenectomy was less common in the laparoscopic group (RR: 0.73, 95% CI 0.58-0.92, p = 0.007). The LLR group presented reduced blood loss (MD: - 270.16 ml, 95% CI - 381.53 to - 32.79, p = 0.002), need for transfusion (RR: 0.39, 95% CI 0.21-0.73, p = 0.003), overall morbidity (RR: 0.58, 95% CI 0.4-0.83, p = 0.003) and hospital stay (MD: - 3.48 days, 95% CI: - 6.94 to - 0.02, p = 0.05) compared to the OLR group. No differences were shown in operative time (MD: 1.6 min, 95% CI - 34.17-37.37, p = 0.93), major morbidity (RR: 0.65, 95% CI 0.38-1.11, p = 0.12), mortality (RR: 1.42, 95% CI 0.13-15.07, p = 0.77), overall (HR: 0.9, 95% CI 0.59-1.38, p = 0.63) and relapse-free survival (HR: 0.77, 95% CI 0.5-1.16, p = 0.21) between the two groups. LLR seems to benefit patients with iCCA in terms of short-term outcomes, whilst long-term outcomes are comparable among the two approaches.

Intrahepatic cholangiocarcinoma: Limitations for resectability, current surgical concepts and future perspectives.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common hepatic malignancy and its incidence has been shown to increase significantly during the past decades. Complete surgical resection is currently acknowledged as the only curative treatment option able to provide adequate long-term outcomes. We herein review technical, functional and oncologic limitations for resectability, discuss current surgical aspects as well as highlight the fields in which future research and practice should focus on in order to ameliorate long-term outcomes in patients with iCCA.

Treatment of colon cancer with multiple liver metastases.

Treatment of patients with colorectal cancer and synchronous liver metastases is challenging. We present the case of a 34-year-old woman who had about 50 liver metastases from an adenocarcinoma of the sigmoid colon. Neoadjuvant chemotherapy led to a remarkable response of the hepatic metastases. The patient was subjected to sigmoidectomy with primary anastomosis and synchronous treatment of all liver metastases. The number of liver lesions should not in itself present a contraindication to resection. This is the first report of successful concomitant surgical treatment of sigmoid adenocarcinoma and multimetastatic liver disease.

Is Single-Incision Laparoscopic Liver Surgery Safe and Efficient for the Treatment of Malignant Hepatic Tumors? A Systematic Review.

PURPOSE: The objective of this review was to evaluate the safety and efficiency of single-incision laparoscopic liver surgery (SILLS) for malignant liver lesions. METHODS: A retrospective review of the Medline database was performed, including studies published up to February 2019. RESULTS: Overall, 69 patients (50 males) with a median age of 61 years (range, 31-90) from 16 studies underwent SILLS for malignant liver disease and were included in this review. The majority of patients underwent resection for hepatocellular carcinoma (n = 52, 75 %), followed by metastatic disease (n = 15, 22 %). The hepatic lesions were located in anterolateral liver segments in 62 patients (90 %) and in posterosuperior liver segments in 7 patients (10 %). Sixty-five patients (94 %) underwent minor liver resection. The median blood loss was 200 mL (range 0-2500), while 4 patients that underwent single-port resection were converted to either conventional laparoscopy or open resections. Two cases were reported to be associated with postoperative complications in the single-port group (1 [1.7 %] grade Dindo-Clavien I-II, 1 [1.7 %] grade Dindo-Clavien III-IV), while no complications were noted in the multiport group. All patients successfully underwent R0 resection. CONCLUSIONS: SILLS seems to be a safe and efficient treatment modality for malignant liver disease when performed by experienced surgeons in carefully selected patients. More studies are needed to better identify which patients may benefit from such an operative approach.

Diagnosis, surgical treatment and postoperative outcomes of hepatic endometriosis: A systematic review.

Endometriosis is characterized by the presence of endometrial-like tissue and stroma in extra-uterine locations. Hepatic endometriosis (HE) is one of the rarest forms of extrapelvic endometriosis. We aimed to summarize the existing evidence on HE with special consideration to natural history, diagnosis and surgical treatment. Three electronic databases were systematically searched for articles published up to March 2019. All appropriate observational studies and case reports addressing cases of women with HE were considered eligible for inclusion. A total of 27 studies which comprised 32 patients with HE were included. Mean age of patients was 39.7 years. Ten (62.5%) were nulliparous and 24 (75%) were women of reproductive age. Eleven patients (36.7%) had a history of pelvic endometriosis of various sites. Abdominal pain was the primary symptom in 28 patients (87.5%). Preoperative diagnosis of endometriosis was available for 5 patients and 6 underwent a preoperative diagnostic procedure. Cyst resection, minor and major liver resections were performed in 14/31, 9/31 and 8/31 patients, respectively. Preoperative diagnosis of HE is challenging due to variable radiologic features and clinical symptomatology. Nonetheless, it should be considered in the differential diagnosis of a liver mass especially in premenopausal women with a history of endometriosis. The type of resection of the endometriotic lesion is based on the extent and the location of the disease and presented with favourable outcomes concerning morbidity, symptom relief and recurrence.

AGMA Score: A Novel Prognostic Score for Patients Undergoing Liver Transplant for Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) in cirrhosis represents one of the leading indications for liver transplant. In an effort to expand the listing criteria, a variety of scoring systems have been suggested, mainly based on the tumor number/size criterion. The objective of our study was to evaluate the feasibility of proposing a transplant score for HCC excluding the tumor number/size criterion. PATIENTS AND METHODS: Data corresponding to patients who received transplants because of HCC were reviewed for the purposes of this study. Deceased donor and living donor liver transplants were included. Demographic, clinical and tumor-related parameters were evaluated. Uni- and multivariate regression analyses and survival analysis were performed. RESULTS: One hundred patients were included in the study. Fifty-five patients underwent deceased donor liver transplant, and 45 patients received living donor liver transplants. Tumor differentiation (G1/2 vs G3), alpha-fetoprotein levels (AFP), recipient age, and recipient laboratory Model for End-Stage Liver Disease Score (MELD) showed statistical significance. A scoring system was developed, with prognostic points assigned as follows: age 60 years or younger:age older than 60 years = 1:0 points, tumor grading well or moderate:tumor grading poor = 1:0 points, MELD score ≤22:MELD score >22 = 1:0 points, and AFP level ≤400 ng/mL:AFP level >400 ng/mL = 1:0 points. This stratification delineated 3 separate population samples corresponding to patients with scores of 4, 3, and 1 to 2, respectively. The calculated 5-year survival for scores 4, 3, and 1 to 2 was 76%, 47%, and 20%, respectively (P < .001). CONCLUSION: The AGMA score (age, grading, MELD, AFP) showed prognostic value in this single-center analysis and may find clinical implication avoiding the tumor number/size criterion.

Harvesting the Liver From a Donor With a Biventricular Assist Device (BiVAD)-An Unexpectedly Challenging Procedure: A Case Report.

BACKGROUND: Organ procurement from deceased donors is usually a standard procedure. Nevertheless, the performing surgeon is often confronted with demanding situations, such as atherosclerotic or aneurysmatic aortic disease or even other pathologies, which may alter the surgical steps. We report on an interesting case of solid organ harvesting from a donor with a biventricular assist device (BiVAD) due to global heart failure. CASE REPORT: A 42-year-old male donor with a BiVAD, enlisted for heart transplantation, died of intracerebral hemorrhage. Dressing the surgical field was challenging because the extracorporal portions of all 4 tubes and the pump device rested on the donor's body, covering his whole abdomen. To ensure enough space, the pump and tubes had been covered with sterile swabs and drapes. The second surgical assistant was tasked with holding the device slightly deviated to the left and the ankle elevated at 45°, to avoid any tube kinking. The dissection of the main vessels distally was performed using the standard technique. No encirclement of the proximal aorta beneath the diaphragm was necessary, as the cardiac output could be arrested by clamping the left ventricle's outflow tube. Once the perfusion was completed, the procedure continued in the standard fashion. CONCLUSION: So far, the literature has no data on organ harvesting from deceased donors with BiVAD. Although such a retrieval is quite challenging and requires an experienced team, the transplantation of the corresponding organs can be performed without any further special technical problems.