Impact of prolonged liver ischemia during intermittent Pringle maneuver on postoperative outcome following liver resection.

BACKGROUND: The aim of this study was to compare postoperative outcomes following liver resection between patients with prolonged cumulative ischemia time (CIT) which exceeded 60 min and patients with CIT less than 60 min. METHODS: Between March 2020 and October 2022, 164 consecutive patients underwent liver resection at the Unit for hepato-bilio-pancreatic surgery, University Clinic for Digestive Surgery in Belgrade, Serbia. Intermittent Pringle maneuver was routinely applied. Depending on CIT during transection, patients were divided into two groups: group 1 (CIT <60 min) included 101 patients, and group 2 (CIT ≥60 min) included 63 patients. RESULTS: Median operative time (210 vs. 400 min) and CIT (30 vs. 76 min) were longer in the Group 2 (p < 0.001). Intraoperative blood loss was higher in the Group 2 (150 vs 500 ml), p < 0.001. The perioperative transfusion rate was similar between the groups (p = 0.107). There was no difference in postoperative overall morbidity (50.5% vs. 58.7%, p = 0.337) and major morbidity (18.8 vs. 19%, p = 0.401). In-hospital mortality, 30-day mortality, and 90-day mortality were similar between the groups (p = 0.408; p = 0.408; p = 0.252, respectively). Non-anatomical liver resection was the only predictive factor of 90-day mortality identified by multivariate analysis (p = 0.047; Relative Risk = 0.179; 95% Confidence Interval 0.033-0.981). CONCLUSION: Intermittent Pringle maneuver with CIT exceeding 60 min is a safe method for bleeding control during liver resection with no impact on postoperative morbidity and mortality.

Liver resection versus transarterial chemoembolisation for the treatment of intermediate hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Transarterial chemoembolisation (TACE) is the primary treatment for intermediate-stage hepatocellular carcinoma (HCC), according to the updated Barcelona Clinic Liver Cancer (BCLC) staging system. Although growing evidence favours liver resection (LR) over TACE for intermediate-stage HCC, the best treatment option remains controversial. This meta-analysis aimed to compare the overall survival (OS) after LR versus TACE for intermediate-stage HCC. METHODS: A comprehensive literature review of PubMed, Embase, Cochrane Library, and Web of Science was performed. Studies that compared the efficacy of LR and TACE in patients with intermediate (BCLC stage B) HCC were selected. According to the recent updated BCLC classification, intermediate stage of HCC was defined as follows: (a) four or more HCC nodules of any size, or (b) two or three nodules, but if at least one tumour is larger than 3 cm. The main outcome was OS, expressed as the hazard ratio. RESULTS: Nine eligible studies of 3355 patients were included in the review. The OS of patients who underwent LR was significantly longer than that of patients who underwent TACE (hazard ratio=0.52; 95% CI: 0.39-0.69; I2=79%). Prolonged survival following LR was confirmed after sensitivity analysis of five studies using propensity score matching (HR=0.45; 95% CI: 0.34-0.59; I2=55%). CONCLUSION: Patients with intermediate-stage HCC who underwent LR had a longer OS that those who underwent TACE. The role of LR in patients with BCLC stage B should be clarified in future randomised controlled trials.

The Role of MRI in the Diagnosis of Solid Pseudopapillary Neoplasm of the Pancreas and Its Mimickers: A Case-Based Review with Emphasis on Differential Diagnosis.

Solid pseudopapillary neoplasm (SPN) is rare pancreatic tumor occurring most commonly in young females. The typical imaging appearance of SPN is of well-defined, encapsulated, and large heterogeneous tumors, consisting of solid and cystic components due to various degrees of intralesional hemorrhage and necrosis. However, atypical imaging presentation in the form of small solid tumors or uniformly cystic lesions might also be seen, which can be explained by specific pathological characteristics. Other imaging features such as a round shape, the absence of main pancreatic duct dilatation, and slow growth, in combination with vague symptoms, favor the diagnosis of SPNs. Nevertheless, the radiological findings of SPN might overlap with other solid and cystic pancreatic neoplasms, such as neuroendocrine tumors, serous and mucinous neoplasms, and even small pancreatic adenocarcinomas. In addition, a few benign non-tumorous conditions including walled-of-necrosis, and intrapancreatic accessory spleen may also pose diagnostic dilemmas simulating SPNs on imaging studies. The aim of this manuscript is to provide a comprehensive overview of the typical and atypical imaging features of SPNs and to describe useful tips for differential diagnosis with its potential mimickers.

Genetic analysis and allele-specific expression of SMAD7 3'UTR variants in human colorectal cancer reveal a novel somatic variant exhibiting allelic imbalance.

BACKGROUND: Considering the impact of SMAD7 deregulation in colorectal cancer (CRC) progression and the significance of single nucleotide variant (SNV)-mediated disruptions of microRNA (miRNA)-dependent regulation for cancer susceptibility, our study aimed to analyze genetic variation in the SMAD7 3' untranslated region ( 3'UTR) in CRC, measure differences in allelic mRNA expression, and evaluate its interference with miRNA-mediated post-transcriptional regulation. PATIENTS AND METHODS: This study included 80 patients with different CRC stages and six human colon cancer cell lines of various histological origins. SMAD7 3'UTR was analyzed by direct sequencing, followed by the relative quantification of differential allelic expression of detected variants by allele-specific qRT-PCR. In silico tools were employed for predictions of regulatory consequences of detected variants. RESULTS: A total of four different SNVs in one cell line and nine patients were found, among which were a novel somatic point variant and three already known germline variants (rs16950113, rs1050799536, and rs1043778717). All evaluated SNVs exhibited variable extents of allelic imbalance in expression. In silico analysis predicted significant effects of SNVs on miRNA binding efficiency, with each SNV disrupting existing and creating new target sites for one or more miRNAs. CONCLUSION: Imbalance observed in the expression of SNV alleles altering miRNA binding suggests that all investigated SNVs are potential contributing factors impacting SMAD7 expression regulation in CRC that further studies should investigate.

Hepatocellular Carcinoma Presenting Simultaneously with Echinococcal Cyst Mimicking a Single Liver Lesion in a Non-Cirrhotic Patient: A Case Report and Review of the Literature.

A coexistance of liver cystic echinococcosis (CE) and hepatocellular carcinoma (HCC) is very rare. HCC is the leading cause of cancer-related mortality worldwide, while CE is a globally endemic zoonosis caused by the cestode tapeworm Echinococcus granulosus. The association between these two diseases is still not well-defined. A preoperative diagnosis may be challenging, especially if HCC and CE present as a single lesion and if atypical imaging features are present. Herein, we present a case of the patient that was initially diagnosed as an extensive necrotic tumor in the left liver lobe and highly suspicious of being HCC associated with peritumoral hematoma. Left hemihepatectomy was performed, and the histopathological findings showed the collision of two lesions: a hydatid cyst and HCC.

Precision Medicine for Hepatocellular Carcinoma: Clinical Perspective.

Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by growing incidence and high mortality rates despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. Most HCCs occur in patients with liver cirrhosis, and the competing mortality risks from the tumor and the cirrhosis should be considered. Presently, previously identified risk factors, such as hepatitis virus infection, hepatic inflammation and fibrosis, and metabolic syndrome, may be used as chemoprevention targets. The application of precision medicine for HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology. Next-generation sequencing emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited. Moreover, genetic sequencing as part of a precision medicine concept may work as a promising tool for postoperative cancer monitoring. The use of genetic and epigenetic markers to identify therapeutic vulnerability could change the diagnosis and treatment of HCC, which so far was based on Barcelona clinic liver cancer (BCLC) staging. In daily clinical practice, the shift from a stage-oriented to a therapeutic-oriented approach is needed to direct the choice of HCC treatment toward the potentially most effective option on an individual basis. The important factor in precision medicine is the promotion of patient management based on the individual approach, knowing that the final decision must be approved by a multidisciplinary expert team.

Prognostic potential of circulating miR-93-5p in patients with colorectal cancer liver metastases.

This study aimed to examine the expression pattern of tumoral and circulating miR-93-5p in patients with colorectal cancer (CRC) liver metastasis (CRLM) and to explore its predictive and prognostic potential. CRLM tissue, surrounding non-tumor liver tissue, and serum were obtained from 35 patients with CRLM. The expression pattern of tissue and circulating miR-93-5p in patients with CRLM was determined using quantitative polymerase chain reaction, using miR-16-5p for normalization. Sample-based cut-off values for CRLM and serum miR-93-5p expression were calculated using Receiver Operating Characteristic curve analysis to stratify the patients into high and low miR-93-5p expression groups which were that compared with patients' clinicopathological data, therapy response, one-year disease-free survival, and disease recurrence. Relative miR-93-5p expression was higher in CRLM in comparison to the non-metastatic liver tissue (p<0.001). CRLM miR-93-5p expression showed moderate negative correlation with carcinoembryonic antigen levels (r=-0.406; p=0.016). There were no differences in high-/low-miR-93-5p expression and therapy responders vs. non-responders, which was confirmed in vitro using metastatic and normal colonic cells SW620 and HCEC-1CT, respectively. No difference was observed in one-year recurrence-free survival in patients with high vs. low miR-93-5p expression in CRLM or serum. However, high miR-93-5p serum levels were significantly associated with early disease recurrence (p=0.035). In conclusion, miR-93-5p serum levels could be potentially used as a prognostic factor for early disease recurrence in CRLM patients.

The Modified Sublay Technique for the Management of Major Subcostal Incisional Hernia: Long-Term Follow-up Results of 37 Consecutive Patients.

BACKGROUND: The aims of this study were to present the concept of original technique in the management of major incisional subcostal hernias and to evaluate short- and long-term outcome. METHOD: Between January 2010 and January 2020, 280 patients underwent hernia repair surgery for incisional lateral abdominal hernia at Clinic for Digestive Surgery, Clinical Center of Serbia. Among them, 37 patients underwent the modified sublay technique for major incisional subcostal hernia with minimal hernia defect surface of 100 cm2 or greater or minimal hernia defect width or height of 10 cm or greater. The operative techniques are as follows: retromuscular dissection of rectus muscle from posterior sheath on the both sides of hernia defect, external oblique muscle dissection from internal oblique muscle in a circle around hernia defect at the side of the hernia defect, complete reconstruction of the posterior myofascial layer, large heavyweight polypropylene mesh placement in a sublay position, and complete or partial reconstruction of anterior myofascial layer. RESULTS: A median (range) hernia defect surface was 150 (100-500) cm2. A median operative time was 130 (90-330) minutes. The morbidity rate was 18.9%. A median (range) postoperative hospital stay was 7 (2-24) days. After the median follow-up of 50 (1-108) months, 2 patients (5.4%) developed recurrent hernia. CONCLUSIONS: The modified sublay technique using large heavyweight polypropylene mesh provides good results in the management of major subcostal abdominal wall defects.

SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response.

Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-ß signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value.

Short- and Long-Term Outcomes After Hepatectomy in Elderly Patients with Hepatocellular Carcinoma: An Analysis of 229 Cases from a Developing Country.

BACKGROUND: The number of elderly patients with HCC who undergo liver resection is increasing. Because of the advanced age of the patients, increased postoperative morbidity and reduced overall survival are expected in this population. The study aim was to compare clinicopathologic and operative features, short- and long-term outcomes among hepatocellular carcinoma (HCC) patients from three age groups undergoing potentially curative liver resection in a developing country. METHODS: Prospectively collected data relating to 229 patients who underwent curative-intent liver resection from January 2009 until December 2018 were analyzed. The patients were divided into two age groups: G1 was below 70 years old (n=151) and G2 was 70 years old and older (n=78). Demographic, clinical, operative data, short- and long-term outcomes were compared between the two groups. Univariate and multivariate analyses of prognostic factors were performed. RESULTS: The mean overall morbidity rate of the patients was 31.1% (G1), and 46.2% (G2) by age group. Postoperative morbidity was significantly higher in the G2 group (p=0.03). There was no difference in major morbidity between the two groups (p=0.214). No significant difference in mortality rate and overall survival was found between the study groups (p=0.280, p=0.383). Both age ≥70 years (ie, G2 group) and liver cirrhosis were identified as prognostic factors for postoperative morbidity, and a Child-Pugh score B as a negative prognostic factor for overall survival. In subgroup analysis of patients with cirrhosis, age ≥70, diabetes mellitus and perioperative transfusion were identified as prognostic factors for postoperative morbidity. CONCLUSION: The study confirmed the safety and feasibility of liver resection in elderly patients with HCC. However, appropriate patient selection among the elderly is mandatory in order to improve short- and long-term outcomes.

Prognostic Significance of CDH1, FN1 and VIM for Early Recurrence in Patients with Colorectal Liver Metastasis After Liver Resection.

PURPOSE: There are limited data on expression of epithelial-mesenchymal transition (EMT) markers in patients with colorectal liver metastases (CRLM). The study aim was to evaluate the expression and prognostic significance of E-cadherin (CDH1), fibronectin (FN1) and vimentin (VIM) in patients with CRLM after curative-intent liver resection. PATIENTS AND METHODS: Thirty patients with CRLM managed by curative-intent liver resection were included in this prospective pilot study. Blood samples, colorectal liver metastases and surrounding non-tumor liver tissue were collected. Expression of CDH1, FN1 and VIM was analyzed by quantitative real-time polymerase chain reaction. Expression in CRLM and non-tumor liver tissue was compared, while expression in serum was correlated with CRLM expression. One-year recurrence-free survival was compared between patients with low and high CDH1, FN1 and VIM expression. RESULTS: The expression of CDH1 was similar in CRLM and non-tumor liver tissues, while FN1 and VIM expression was significantly lower in metastatic tissue (P=0.003 and pP<0.001, respectively). Serum expression of CDH1 and VIM was detected in 66.7% and 93.3% of patients, respectively, while FN1 was not detected in any of the patients. The correlation of CDH1 and VIM expression between CRLM and serum was not statistically significant. Decreased CDH1 expression in CRLM and decreased VIM expression in serum were associated with early recurrence after surgical treatment of CRLM. CONCLUSION: Lower expression of CDH1 in CRLM and lower serum expression of VIM were found to be associated with early recurrence after liver resection for CRLM.

Impact of diseased liver parenchyma on perioperative outcome among patients with hepatocellular carcinoma undergoing hepatectomy: Experience from a developing country.

INTRODUCTION: Limited data can be found about surgical outcome of patients with hepatocellular carcinoma (HCC) arising in non-diseased liver. The study aim was to compare short- and long-term outcomes among HCC patients with normal and diseased liver parenchyma, undergoing potentially curative liver resection in a developing country. MATERIALS AND METHODS: From November 2001 until January 2017, 228 patients with HCC underwent curative-intent hepatectomy at the University Clinic for Digestive Surgery. From that number, 190 patients were eligible for analysis. Diseased liver (DL) was present in 112 patients while 78 patients had HCC in non-diseased liver (NDL). RESULTS: Median age, sex, ASA score, the presence of extrahepatic disease and lobar distribution of tumors were similar in both groups. The number of tumors was higher in DL group, while tumor diameter was higher in NDL group. Anatomic liver resection and major liver resections were performed more commonly in NDL than in DL group (66.7 vs 47.4%, p = 0.008; 33.3 vs. 15.2%, p = 0.003). Postoperative morbidity was significantly higher in DL group (p = 0.004). Overall survival was statistically longer in NDL group (p = 0.024). By univariate analysis potential prognostic factors for long-term survival were identified: presence of chronic HCV infection, presence of cirrhosis, Child-Pugh score B and operative time longer than 240 min. The last two were confirmed by multivariate analysis as independent negative prognostic factors for overall survival. CONCLUSION: Liver resection in patients with HCC arising in non-diseased livers, despite of need for extended hepatectomies, provides favorable long-term prognosis.

Preoperative neutrophil-to-lymphocyte ratio as a prognostic predictor after curative-intent surgery for hepatocellular carcinoma: experience from a developing country.

PURPOSE: The aim of the study was to evaluate a prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) on long-term survival of cirrhotic and noncirrhotic hepatocellular cancer (HCC) patients managed by a curative-intent liver surgery in a developing country. PATIENTS AND METHODS: During the study period between November 1, 2001, and December 31, 2012, 109 patients underwent potentially curative hepatectomy for HCC. Data were retrospectively reviewed from the prospectively collected database. The median follow-up was 25 months. NLR was estimated by dividing an absolute neutrophil count by an absolute lymphocyte count from the differential blood count. Receiver operating characteristic curve was constructed to assess the ability of NLR to predict long-term outcomes and to determine an optimal cutoff value for all patients group, the subgroup with cirrhosis, and the subgroup without cirrhosis. The optimal cutoff values were 1.28, 1.28, and 2.09, respectively. RESULTS: The overall 3- and 5-year survival rates were 49% and 45%, respectively, for low NLR group and 38% and 26%, respectively, for high NLR group. The difference was statistically significant (p=0.015). Overall survival was similar between low and high NLR groups in patients with cirrhosis; no difference was found between the groups (p=0.124). In patients without cirrhosis, low NLR group had longer overall survival compared with high NLR group (p=0.015). Univariate analysis identified four factors as significant predictors of long-term survival: cirrhosis, Child-Pugh score, platelet count, and NLR. On multivariate analysis, only platelet count and NLR were independent prognostic factors of long-term survival. CONCLUSION: Prognostic value of NLR was confirmed in noncirrhotic HCC patients who underwent curative-intent liver surgery. In HCC patients with cirrhosis, the prognostic role of NLR was not confirmed.

Targeted therapy and personalized medicine in hepatocellular carcinoma: drug resistance, mechanisms, and treatment strategies.

Hepatocellular carcinoma (HCC) is characterized by a growing number of new cases diagnosed each year that is nearly equal to the number of deaths from this cancer. In a majority of the cases, HCC is associated with the underlying chronic liver disease, and it is diagnosed in advanced stage of disease when curative treatment options are not applicable. Sorafenib is a treatment of choice for patients with performance status 1 or 2 and/or macrovascular invasion or extrahepatic spread, and regorafenib is the only systemic treatment found to provide survival benefit in HCC patients progressing on sorafenib treatment. Other drugs tested in different trials failed to demonstrate any benefit. Disappointing results of numerous trials testing the efficacy of various drugs indicate that HCC has low sensitivity to chemotherapy that is in great part caused by multidrug resistance. Immunotherapy for HCC is a new challenging treatment option and involves immune checkpoint inhibitors/antibody-based therapy and peptide-based vaccines. Another challenging approach is microRNA-based therapy that involves two strategies. The first aims to inhibit oncogenic miRNAs by using miRNA antagonists and the second strategy is miRNA replacement, which involves the reintroduction of a tumor-suppressor miRNA mimetic to restore a loss of function.

Presentation of pericardial hydatid cyst as acute cardiac tamponade.

We report a case of a 47-year-old man with isolated pericardial hydatid cyst (without myocardial involvement) that presented as acute pericardial tamponade. After initial investigation and transthoracic echocardiography, emergent pericardial drainage was performed for downgrading the urgency of a definitive treatment for a hydatid cyst. A computed tomography examination after the pericardial drainage showed a pericardial cyst without heart muscle involvement, making the treatment possible through anterior thoracotomy and without performing cardiopulmonary bypass. Complete surgical removal of the cyst was performed. The postoperative course was uneventful. The patient received postoperative albendazole treatment. He remained asymptomatic and no recurrence was observed during a 1-year follow-up period.

Hepatocellular carcinoma: From clinical practice to evidence-based treatment protocols.

Hepatocellular carcinoma (HCC) is one of the major malignant diseases in many healthcare systems. The growing number of new cases diagnosed each year is nearly equal to the number of deaths from this cancer. Worldwide, HCC is a leading cause of cancer-related deaths, as it is the fifth most common cancer and the third most important cause of cancer related death in men. Among various risk factors the two are prevailing: viral hepatitis, namely chronic hepatitis C virus is a well-established risk factor contributing to the rising incidence of HCC. The epidemic of obesity and the metabolic syndrome, not only in the United States but also in Asia, tend to become the leading cause of the long-term rise in the HCC incidence. Today, the diagnosis of HCC is established within the national surveillance programs in developed countries while the diagnosis of symptomatic, advanced stage disease still remains the characteristic of underdeveloped countries. Although many different staging systems have been developed and evaluated the Barcelona-Clinic Liver Cancer staging system has emerged as the most useful to guide HCC treatment. Treatment allocation should be decided by a multidisciplinary board involving hepatologists, pathologists, radiologists, liver surgeons and oncologists guided by personalized -based medicine. This approach is important not only to balance between different oncologic treatments strategies but also due to the complexity of the disease (chronic liver disease and the cancer) and due to the large number of potentially efficient therapies. Careful patient selection and a tailored treatment modality for every patient, either potentially curative (surgical treatment and tumor ablation) or palliative (transarterial therapy, radioembolization and medical treatment, i.e., sorafenib) is mandatory to achieve the best treatment outcome.