Preoperative Chemotherapy and Resection Margin Status in Colorectal Liver Metastasis Patients: A Propensity Score-Matched Analysis

In this article, we compared the early and long-term outcomes of patients with metastatic colorectal cancer treated with chemotherapy followed by resection with those of patients undergoing surgery first, focusing our analysis on resection margin status. Patients who underwent liver resection with curative intent for colorectal liver metastases from July 2001 to January 2018 were included in the analysis. Propensity score matching was used to reduce treatment allocation bias. The cohort comprised 164 patients; 117 (71.3%) underwent liver resection first, whereas the remaining 47 (28.7%) had preoperative chemotherapy. After a 1:1 ratio of propensity score matching, 47 patients per group were evaluated. A positive resection margin was found in 13 patients in the surgery-first group (25.5%) versus 4 (8.5%) in the preoperative chemotherapy group (P = 0.029). Postmatched logistic regression analysis showed that only preoperative chemotherapy was significantly associated with the rate of positive resection margin (odds ratio 0.24, 95% confidence interval 0.07-0.81; P = 0.022). Median follow-up was 41 months (interquartile range 8-69). Cox proportional hazard regression analysis revealed that only positive resection margin was a significant negative prognostic factor (hazard ratio 2.2, 95% CI 1.18-4.11; P = 0.014). Within the preoperative chemotherapy group, median overall survival was 40 months in R0 patients and 10 months in R1 patients (P = 0.016). Although preoperative chemotherapy in colorectal liver metastasis patients may affect the rate of positive resection margin, its impact on survival seems to be limited. In the present study, the most important prognostic factor was the resection margin status

Role of SIRT-3, p-mTOR and HIF-1\u3b1 in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin

The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1\u3b1) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1\u3b1 expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1\u3b1 as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Historical assumptions of lymphadenectomy

Abstract: The role of lymphadenectomy for the treatment of gastric cancer is still very much open to debate. Consequently, Japanese, European and American surgeons perform different typologies of lymphadenectomy because of the absence of randomized clinical trials confirming the superiority of extended lymphadenectomy over less invasive surgery. In Japan, D2 lymphadenectomy has been considered as the gold standard for advanced gastric carcinoma for many years. Although numerous European studies have been conducted in an attempt to find differences between D1 and D2 lymphadenectomy, none has succeeded to date. The decision to wait for results attesting to the fact that D2 guarantees a better outcome than D1 resulted in a long delay in the implementation of D2 as the gold standard treatment in Europe. In the U.S., the study by Macdonald et al. established D1 lymphadenectomy followed by chemoradiotherapy as the treatment of choice for advanced cancer, whereas D2 is officially indicated as the gold standard in the most recent European guidelines [the Italian Research Group for Gastric Cancer (GIRGC), German, British, ESSO]. Interestingly, European guidelines for lymphadenectomy are not based on evidence-based medicine but rather on the experience of the most important centers involved in the treatment of gastric cance

INTRAHEPATIC BILIARY STRICTURES WITH UNDERLYING PRE-MALIGNANT BILIARY LESIONS: IS IT TIME TO BUILD GUIDELINES ON DIAGNOSIS AND MANAGEMENT?

Biliary intraepithelial neoplasia (BilIN) is defined as a precursor lesion of invasive adenocarcinoma and it can develop both in intrahepatic and extrahepatic bile ducts. BilIN grossly presents as flat lesions but is usually macroscopically and radiologically unidentifiable 10 , 21 . Interestingly, in the last decades due to the spread of imaging techniques, focal intrahepatic biliary strictures (FIHS) are more commonly incidentally founded in clinical practice. It is currently unknown which is their correct management and in what percentage they can harbor pre-neoplastic alterations (as BilIN) or malignancy 20 . Due to the concomitant increase in western countries of intrahepatic cholangiocarcinoma, it would be useful to understand the natural history of FIHS, as they can represent a radiological manifestation of underlying pre-malignant disease: in that perspective, the ideal treatment could be an early surgery to prevent cholangiocarcino

First 100 minimally invasive liver resections in a new tertiary referral centre for liver surgery

none8noBackground: In the last decades, there has been an exponential diffusion of minimally invasive liver surgery (MILS) worldwide. The aim of this study was to evaluate our initial experience of 100 patients undergoing MILS resection comparing their outcomes with the standard open procedures. Materials and methods: One hundred consecutive MILS from 2016 to 2019 were included. Clinicopathological data were reviewed to evaluate outcomes. Standard open resections were used as the control group and compared exploiting propensity score matching. Results: In total, 290 patients were included. The rate of MILS has been constantly increasing throughout years, representing the 48% in 2019. Of 100 (34.5%) MILS patients, 85 could be matched. After matching, the MILS conversion rate was 5.8% (n = 5). The post-operative complication rates were higher in the open group (45.9% vs. 31.8%, P = 0.004). Post-operative blood transfusions were less common in the MILS group (4.7% vs. 16.5%, P = 0.021). Biliary leak occurred in 2 (2.4) MILS versus 13 (15.3) open. The median comprehensive complication index was higher in the open group (8.7 [0-28.6] vs. 0 [0-10.4], P = 0.0009). The post-operative length of hospital stay was shorter after MILS (median 6 [5-8] vs 8 [7-13] days, P < 0.0001). Conclusions: The rate of MILS has been significantly increasing throughout the years. The benefits of MILS over the traditional open approach were confirmed. The main advantages include lower rates of post-operative complications, blood transfusions, bile leaks and a significantly decreased hospital stay.noneBarba, Giuliano La; Solaini, Leonardo; Radi, Giorgia; Mirarchi, Maria Teresa; D'Acapito, Fabrizio; Gardini, Andrea; Cucchetti, Alessandro; Ercolani, GiorgioBarba, Giuliano La; Solaini, Leonardo; Radi, Giorgia; Mirarchi, Maria Teresa; D'Acapito, Fabrizio; Gardini, Andrea; Cucchetti, Alessandro; Ercolani, Giorgi

Low recurrence rate of hepatocellular carcinoma after liver transplantation: better patient selection or lower immunosuppression?

Background. Liver transplantation is currently offered to a limited number of patients with hepatocellular carcinoma (HCC) because of strict criteria introduced in the past to avoid recurrence. Immunosuppression represents a risk factor for tumor growth; the schedules of the immunosuppressant drugs have been modified through the years, aiming to reduce their dosage to the effective minimum.Methods. A series of 106 consecutive patients with HCC who underwent transplantation over a 15-year period at a single institution was retrospectively reviewed to ascertain whether tumor recurrence was influenced by the Milano criteria presently adopted in patient selection and whether the dosage of immunosuppressant agents administered was associated with tumor recurrence. Fifteen patients who died postoperatively and 9 with a follow-up of less than 1 year were excluded; presence of the Milano criteria, tumor-node-metastasis staging, and the cumulative dosage of the single immunosuppressants given at different intervals in the first postoperative year were analyzed in the remaining 82 patients. The influence of these variables on overall and recurrence-free survival was assessed statistically.Results. The Milano criteria did not influence recurrence-free survival, which was instead associated with the cumulative dosage of cyclosporine administered in the first postoperative year (93% 5-year recurrence-free survival for patients given low dosage vs. 76% for those given high dosage; P=0.01); T3 and T4 tumors did worse than T1 and T2 tumors.Conclusions. Current limits to transplantation for HCC might be reassessed in view of modified patient management; immunosuppression should be minimized in these patients

Liver metastases from colorectal cancer: present surgical approach

New developments in surgical techniques and strategies are modifying the indications to resection of liver metastases

Laparoendoscopic rendezvous in the treatment of cholecysto-choledocholitiasis: a single series of 200 patients

Background and aim: Although the ideal management of cholecysto-choledocholitiasis is controversial, the two-stage approach, namely the common bile duct (CBD) clearance through endoscopic retrograde cholangiopancreatography (ERCP) followed by laparoscopic cholecystectomy, remains the standard way of management. However, whenever feasible, the one-stage approach, using the so-called \u201claparoendoscopic rendezvous\u201d (LERV) technique, offers some advantages, mainly reducing the hospital stay and the risk of post-ERCP pancreatitis. The aim of this study was to evaluate the safety and the efficacy of the one-stage approach, and to compare our results with data from available large studies. Materials and methods: We reviewed our series of consecutive patients with cholecysto-choledocholitiasis treated by LERV from January 2003, to October 2016. Both elective and emergency cases were included. The primary end-point was the efficacy to obtain the CBD stones clearance. Secondary end-points were morbidity and mortality, operative time, conversion rate, and in-hospital stay. Results: A total of 200 patients underwent a LERV procedure for the intra-operative diagnosis by intra-operative cholangiogram of cholecysto-choledocholitiasis. In 187 patients (93.5%), it was possible to cannulate the cystic duct with the jag-wire. Success rate was 95%. Conversion rate was 3%. The mean operative time was 135\ua0min and the mean in-hospital stay was 4 days. 29 (14.5%) were the early complications, six mild pancreatitis. Four patients required re-operation during the hospital stay. 11 patients (5.5%) developed late complications during a median follow-up of 57.7\ua0months. Conclusions: Our results confirm that LERV technique is a safe procedure with high success rates for the treatment of cholecysto-choledocholitiasis. The major advantages include the single-stage treatment, the shorter hospital stay, and the lower incidence of post-ERCP pancreatitis