Prognostic role of metformin in diabetes mellitus type 2 patients with hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the commonest malignancies associated with significant cancer-related death. The identification of chemo-preventive agents following HCC treatments with the potential to lower the risk of HCC adverse course is intriguing. Metformin, a first-line agent used in the treatment of type 2 diabetes mellitus (T2DM), has been associated with inhibition of HCC growth. AIM: To determine whether metformin can prevent adverse events (i.e., death, tumor progression, and recurrence) after any HCC treatment in T2DM patients. METHODS: A systematic review of the published literature was undertaken focused on the role of metformin on outcomes in patients with T2DM and HCC receiving any tumor therapy. A search of the PubMed and Cochrane Central Register of Con-trolled Trials Databases was conducted. RESULTS: A total of 13 studies (n = 14886 patients) were included in this review. With regard to the risk of death, a decreased risk was reported in cases receiving metformin, although this decrease was not statistically significant [odds ratio (OR) = 0.89, P = 0.42]. When only patients treated with curative strategies were considered, a more marked correlation between metformin and favorable cases was reported (OR = 0.70, P = 0.068). When analyzing palliative treatment, there was no statistical significance in terms of the correlation between metformin and favorable cases (OR = 0.74, P = 0.66). As for the risks of progressive disease and recurrence, no obvious correlation between metformin use and reduced risk was reported. When sub-analyses were performed for patients from different regions, the results for patients from Eastern countries showed a tendency for decreased risk of death in T2DM cases receiving metformin (OR = 0.69, P = 0.17), but the same was not seen in patients from Western countries (OR = 1.19, P = 0.31). CONCLUSION: Metformin failed to show a marked impact in preventing adverse effects after HCC treatment. A trend was reported in T2DM cases receiving curative therapies in relation to the risk of death, especially in patients from Eastern regions. Great heterogeneity was reported among the different studies. Further large studies are required to definitively clarify the real impact of metformin as a chemopreventive agent for HCC.

New Insights in the Setting of Transplant Oncology.

Background and Objectives: Liver transplantation (LT) is the best strategy for curing several primary and secondary hepatic malignancies. In recent years, growing interest has been observed in the enlargement of the transplant oncology indications. This paper aims to review the most recent developments in the setting of LT oncology, with particular attention to LT for unresectable colorectal liver metastases (CRLM) and cholangiocellular carcinoma (CCA). Materials and Methods: A review of the recently published literature was conducted. Results: Growing evidence exists on the efficacy of LT in curing CRLM and peri-hilar and intrahepatic CCA in well-selected patients when integrating this strategy with (neo)-adjuvant chemotherapy, radiotherapy, or locoregional treatments. Conclusion: For unresectable CCA and CRLM management, several prospective protocols are forthcoming to elucidate LT's impact relative to alternative therapies. Advances in diagnosis, treatment protocols, and donor-to-recipient matching are needed to better define the oncological indications for transplantation. Prospective, multicenter trials studying these advances and their impact on outcomes are still required.

The challenging surgical management of hepatic epithelioid hemangioendothelioma: a narrative review.

BACKGROUND AND OBJECTIVE: Hepatic epithelioid hemangioendothelioma (HEHE) is an uncommon vascular endothelial cell cancer involving the hepatic tissue with full malignant potential. HEHE diagnosis is challenging because blood tests and radiological findings are often non-pathognomonic. Therapeutic possibilities are manifold, ranging from a simple "wait and see" to surgical approaches, up to systemic therapies with vascular endothelial growth factor (VEGF) and mechanistic target of rapamycin (mTOR) inhibitors. The standardized adoption of the surgical approaches, namely resection or transplantation, still remains unclear. Aim of this review is to clarify the role of the surgical strategies for the management of HEHE. METHODS: A review of the literature was done with the intent to focus on the relevant studies exploring the role of the different surgical therapies. A search of these studies was done using the electronic database MEDLINE-PubMed. KEY CONTENT AND FINDINGS: The surgical approaches, namely resection or transplantation, represent the best option in treating well-selected patients with HEHE. Resection is indicated in the case of single lesion or oligonodular monolobar disease. Liver transplantation is indicated in the case of multifocal bilobar disease, even in the presence of resectable extrahepatic disease. The potential role of a minimally invasive approach should represent a relevant field to explore. CONCLUSIONS: The impact of surgery for the treatment of HEHE requires further studies to further clarify its relevant role. Standardized approaches are required.

The role of hypothermic machine perfusion in selecting renal grafts with advanced histological score.

BACKGROUND: Few studies explored the role of hypothermic machine perfusion (HMP) in the sub-group of non-standard renal grafts with a biopsy-proven advanced histological impairment. This study aimed to investigate the role of HMP in grafts with a Karpinski Score >3 in terms of the need for dialysis, creatinine reduction ratio at day-7 (CRR7), and 3-year graft survival. METHODS: Twenty-three perfused grafts with Karpinski Score >3 evaluated between November 2017 and December 2018 were retrospectively analyzed and compared with a control group of 32 non-perfused grafts transplanted between January 2014 and October 2017. RESULTS: After transplantation, perfused grafts had fewer cases requiring dialysis (8.7% vs. 34.4%; p = 0.051), a better reduction in serum creatinine (median at 7 days: 2.2 vs. 4.3 mg/dl; p = 0.045), and shorter length of hospital stay (median 11 vs. 15 days; p = 0.01). Three-year death-censored graft survival was better in the perfused cases (91.3% vs. 77.0%; p = 0.16). In perfused grafts, initial renal resistance (RR) had the best predictive value for renal function recovery after the first week, as defined by CRR7 ≤ 70% (AUC = 0.83; p = 0.02). A cut-off value of 0.5 mm Hg/ml/min showed a sensitivity of 82.4%, a specificity of 83.3%, and diagnostic odds ratio = 23.4. After dividing the entire population into a Low-RR (n = 8) and a High-RR Group (n = 15), more cases with CRR7 ≤ 70% were reported in the latter group (86.7 vs. 13.3%; p = 0.03). CONCLUSION: HMP yielded promising results in kidneys with Karpinski Score >3. Initial RR should be of interest in selecting non-standard organs for single kidney transplantation even in impaired histology.

The prognostic role of diabetes mellitus type 2 in the setting of hepatocellular carcinoma: a systematic review and meta-analysis.

AIM: To evaluate the effect of diabetes mellitus type 2 (T2DM) on the outcomes after treatment of hepatocellular carcinoma (HCC). METHODS: PubMed and Cochrane Central Register of Controlled Trials Databases were systematically searched. Three HCC clinical outcomes were explored: death, progressive disease after locoregional therapies, and recurrence. Sub-analysis was performed according to the use of potentially curative (resection, transplantation, termo-ablation) or non-curative therapies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare the pooled data between T2DM and non-T2DM groups. RESULTS: A total of 27 studies were analyzed. Overall, 85.2% of articles were from Asia. T2MD was associated with an increased risk of death (OR 3.60; 95%CI 2.18-5.95; P<0.001), irrespective of the treatment approach: curative (OR 1.30 95%CI 1.09-1.54; P=0.003) or non-curative (OR 1.05; 95%CI 1.00-1.10; P=0.045), increased HCC recurrence (OR 1.30; 95%CI 1.03-1.63; P=0.03), and increased disease progressiveness (OR 1.24; 95%CI 1.09-1.41; P=0.001). CONCLUSIONS: Current data provide strong evidence that T2DM unfavorably affects HCC progression and recurrence, and patients' survival after treatment, irrespective of the approach used.

The impact of mini-invasive right hepatectomy in the setting of living donation: a meta-analysis.

Adult-to-adult living-donor liver transplantation (A2ALDLT) represents a challenging procedure, mainly when the right hepatic lobe is donated. Therefore, especially in Western countries, the medical community still considers it a "risky procedure". The present meta-analysis investigated the postoperative results reported in donors undergoing right hepatectomy for A2ALDLT through a minimally invasive liver resection (MILR) vs. open liver resection (OLR) approach, with the intent to clarify the hypothesis that the MILR approach should minimize the risks for the donor. A systematic literature search was performed using MEDLINE-PubMed, Cochrane Library, and EMBASE electronic databases. The primary outcome investigated was the complication rate after transplant. Fifteen studies were included (n = 2094; MILR = 553 vs. OLR = 1541). The MILR group only merged the statistical relevance in terms of advantage in terms of a lower number of complications (OR = 0.771, 95% CI 0.578-1.028; P value = 0.077). Investigating the complications ≥ IIIa according to the Dindo-Clavien classification, the estimated blood loss, and the length of hospital stay, no statistical difference was reported between the two groups. MILR represents a novel and promising approach for improving the results in A2ALDLT. However, no benefits have been reported regarding blood loss, length of stay, and postoperative complications. More extensive experiences are needed to re-evaluate the impact of MILR in right lobe live donation.

Immunoglobulin, nucleos(t)ide analogues and hepatitis B virus recurrence after liver transplant: A meta-analysis.

BACKGROUND: Prophylaxis with hepatitis B immunoglobulin (HBIG) represents an efficient strategy for reducing the risk of hepatitis B virus (HBV) recurrence after liver transplantation (LT). Unfortunately, the long-term use of HBIG presents high costs. Therefore, the use of prophylaxis based only on nucleos(t)ide analogues (NUC) has been recently postulated. The present meta-analysis aimed to evaluate the impact of HBIG ± NUC vs HBIG alone or NUC alone in post-LT HBV recurrence prophylaxis. MATERIALS AND METHODS: A systematic literature search was performed using PubMed and Cochrane databases. The primary outcome investigated was the HBV recurrence after LT. Three analyses were done comparing the effect of (a) HBIG + NUC vs HBIG alone; (b) HBIG+NUC vs NUC alone; and (c) HBIG alone vs NUC alone. Sub-analyses were also performed investigating the effect of low and high genetic barrierto-recurrence NUC. RESULTS: Fifty-one studies were included. The summary OR (95%CI) showed a decreased risk with the combination of HBIG + NUC vs HBIG alone for HBV recurrence, being 0.36 (95% CI = 0.22-0.61; P < .001). HBIG + NUC combined treatment reduced HBV reappearance respect to NUC alone (OR = 0.22; 95% CI = 0.16-0.30; P < .0001). Similarly, HBIG alone was significantly better than NUC alone in preventing HBV recurrence (OR = 0.20; 95% CI = 0.09-0.44; P < .0001). CONCLUSIONS: Prophylaxis with HBIG is relevant in preventing post-LT HBV recurrence. Its combination with NUC gives the best results in terms of protection. The present results should be considered in light of the fact that also old studies based on lamivudine use were included. Studies exploring in detail high genetic barrier-to-recurrence NUC and protocols with definite use of HBIG are needed.

Laparoscopic right posterior anatomic liver resections with Glissonean pedicle-first and venous craniocaudal approach.

BACKGROUND: Laparoscopic segment 7 segmentectomy and segment 6-7 bisegmentectomy are challenging resections because of the posterior position and the lack of landmarks. The anatomy of the right posterior Glissonean pedicle and the caudal view of laparoscopy make such resections suitable for the Glissonean pedicle-first approach. METHODS: The study population included all consecutive patients treated with laparoscopic liver resection from August 2019 to February 2020. The approach is based on the ultrasonographic identification of the right posterior or segmental pedicle from the dorsal side of the liver after complete mobilization. The pedicle of interest is isolated through mini-hepatotomy and clamped. The segment anatomy is defined by ischemia. The transection starts from the ventral side, close to the right hepatic vein that is exposed and followed craniocaudally. RESULTS: Ten patients underwent anatomical laparoscopic resection of right posterolateral segments. There were 7 colorectal liver metastases, 2 hepatocellular carcinoma, and 1 biliary cysto-adenoma. Five patients underwent Sg7 resection, one patient underwent a Sg7 subsegmentectomy, and 4 underwent Sg6-7 bisegmentectomy. The Glissonean pedicle-first approach was feasible in eight patients. The craniocaudal approach to the RHV was feasible in six patients, not indicated in three cases and was abandoned in one patient for technical difficulty. There was no operative morbidity or mortality. Median post-operative hospital stay was 5 days. CONCLUSIONS: The Glissonean pedicle-first approach is safe and effective for laparoscopic anatomic resections of the right posterior sector. The craniocaudal approach to right hepatic vein from the ventral side is a convenient procedure to follow the segmental anatomy deep in the parenchyma.

Minimally Invasive Approach in the Setting of ALPPS Procedure: a Systematic Review of the Literature.

BACKGROUND: Associating liver partition with portal vein ligation for staged hepatectomy (ALPPS) represents a new surgical technique for the resection of advanced hepatic malignancies with predicted insufficient future liver remnant. In some patients, ALPPS can be associated with an increased risk of poor outcomes. Minimally invasive surgery (MIS) has been proposed in combination with ALPPS with the intent to minimize this risk. We systematically evaluated the outcomes of MIS-ALPPS cases to compare the relative outcomes of open ALPPS versus MIS-ALPPS. METHODS: A systematic review was done in accordance with the PRISMA guidelines. Search terms utilized included the following: ("ALPPS"[Title/Abstract] OR "associating liver partition and portal vein ligation for staged hepatectomy"[Title/Abstract] OR "in situ split"[Title/Abstract]) AND ("minimally invasive"[Title/Abstract] OR "laparoscopic"[Title/Abstract] OR "robotic"[Title/Abstract]). RESULTS: Fifteen articles were identified, with a total of 27 patients reported. Colorectal metastatic disease was the most commonly observed indication for MIS-ALPPS (66.7%), followed by hepatocellular carcinoma (25.9%). Time passed from the first to the second stage ranged 7-30 days. MIS-ALPPS patients did not experience procedure failures between the first and second stages. Only four (15.4%) subjects had a grade IIIb complication. No perioperative mortality after the first or second stage was reported. Compared with open ALPPS, MIS-ALPPS demonstrated better results. Hospital stay duration ranged 8-33 days with a follow-up ranging 1-20 months. CONCLUSIONS: MIS-ALPPS appears to be safe, with potentially lower morbidities and mortalities relative to open patients. The present results should be considered with caution. A limited number of articles exist on this topic. Furthermore, selection biases exist when comparing open versus MIS-ALPPS data. Registry studies are needed to better define the outcomes of patients undergoing MIS-ALPPS.

Resection for hepatocellular cancer: overpassing old barriers.

Several recent studies have shown that the selection limits commonly used for patients with hepatocellular cancer (HCC) potentially requiring a liver resection (LR) are too restrictive. The present review aims at investigating the studies showing that LR is no longer a treatment suitable only for highly selected patients, but also for patients selectively presenting one-to-more negative factors. Several specific variables have been investigated, none of them showing to be an absolute contraindication for LR: age; single vs. multiple diseases; the dimension of the nodule; hyperbilirubinemia; clinically relevant portal hypertension; Child-Pugh status; macrovascular invasion. As a consequence, LR for the treatment of HCC-on-cirrhosis is a safe and effective procedure not only in "ideal cases", but also for selected patients presenting risk factors. The presence of only one of these factors does not represent an absolute contraindication for LR. On the opposite, the contemporaneous presence of risk factors should contraindicate the procedure. Further studies investigating the "borderline" cases are required, mainly looking at the possible decisive role of laparoscopy in this setting.

Donor-to-recipient gender match in liver transplantation: A systematic review and meta-analysis.

AIM: To perform a systematic review and meta-analysis on donor-to-recipient gender mismatch as a risk factor for post-transplant graft loss. METHODS: A systematic literature search was performed using PubMed, Cochrane Library database and EMBASE. The primary outcome was graft loss after liver transplantation. Odds ratios and 95% confidence intervals were calculated to compare the pooled data between groups with different donor-to-recipient gender matches. Three analyses were done considering (1) gender mismatches (F-M and M-F) vs matches (M-M and F-F); (2) Female-to-Male mismatch vs other matches; and (3) Male-to-Female mismatch vs other matches. RESULTS: A total of 7 articles were analysed. Gender mismatch (M-F and F-M) was associated with a significant increase of graft loss respect to match (M-M and F-F) (OR: 1.30; 95%CI: 1.13-1.50; P < 0.001). When F-M mismatch was specifically investigated, it confirmed its detrimental role in terms of graft survival (OR: 1.83; 95%CI: 1.20-2.80; P = 0.005). M-F mismatch failed to present a significant role (OR: 1.09; 95%CI: 0.73-1.62; P = 0.68). CONCLUSION: Gender mismatch is a risk factor for poor graft survival after liver transplantation. Female-to-male mismatch represents the worst combination. More studies are needed with the intent to better clarify the reasons for these results.

Collaterals management during pancreatoduodenectomy in patients with celiac axis stenosis: A systematic review of the literature.

BACKGROUND/OBJECTIVES: Celiac axis stenosis (CAS) represents an uncommon and typically innocuous condition. However, when a pancreatic resection is required, a high risk for upper abdominal organs ischemia is observed. In presence of collaterals, such a risk is minimized if their preservation is realized. The aim of the present study is to systematically review the literature with the intent to address the routine management of collateral arteries in the case of CAS patients requiring pancreatoduodenectomy. METHODS: A systematic search was done in accordance with the PRISMA guidelines, using "celiac axis stenosis" AND "pancreatoduodenectomy" as MeSH terms. Seventy-four articles were initially screened: eventually, 30 articles were identified (n = 87). RESULTS: The main cause of CAS was median arcuate ligament (MAL) (n = 31; 35.6%), followed by atherosclerosis (n = 20; 23.0%). CAS was occasionally discovered during the Whipple procedure in 15 (17.2%) cases. Typically, MAL was divided during surgery (n = 24/31; 77.4%). In the great majority of cases (n = 83; 95.4%), vascular abnormalities involved the pancreatoduodenal arteries (i.e., dilatation, arcade, channels, aneurysms). Collateral arteries were typically preserved, being divided or reconstructed in only 14 (16.1%) cases, respectively. Severe ischemic complications were reported in six (6.9%) patients, 20.0% of whom were reported in patients with preoperatively unknown CAS (p-value 0.06). CONCLUSIONS: A correct pre-operative evaluation of anatomical conditions as well as a correct surgical planning represent the paramount targets in CAS patients with arterial collaterals. Vascular flow must be always safeguarded preserving/reconstructing the collaterals or resolving the CAS, with the final intent to avoid dreadful intra- and post-operative complications.

Platelet-to-lymphocyte ratio in the setting of liver transplantation for hepatocellular cancer: A systematic review and meta-analysis.

AIM: To perform a systematic review and meta-analysis on platelet-to-lymphocyte ratio (PLR) as a risk factor for post-transplant hepatocellular cancer (HCC) recurrence. METHODS: A systematic literature search was performed using PubMed. Participants of any age and sex, who underwent liver transplantation for HCC were considered following these criteria: (1) studies comparing pre-transplant low vs high PLR values; (2) studies reporting post-transplant recurrence rates; and (3) if more than one study was reported by the same institute, only the most recent was included. The primary outcome measure was set for HCC recurrence after transplantation. RESULTS: A total of 5 articles, published between 2014 and 2017, fulfilled the selection criteria. As for the quality of the reported studies, all the investigated articles presented an overall high quality. A total of 899 cases were investigated: 718 cases (80.0%) were males. Three studies coming from European countries and one from Japan presented HCV as the main cause of cirrhosis. On the opposite, one Chinese study presented a greater incidence of HBV-related cirrhotic cases. In all the studies apart one, the PLR cut-off value of 150 was reported. At meta-analysis, high PLR value was associated with a significant increase in recurrence after transplantation (OR = 3.33; 95%CI: 1.78-6.25; P < 0.001). A moderate heterogeneity was observed among the identified studies according to the Higgins I2 statistic value. CONCLUSION: Pre-transplant high PLR values are connected with an increased risk of post-operative recurrence of hepatocellular cancer. More studies are needed for better clarify the biological mechanisms of this results.