The Emerging Role of Metformin in the Treatment of Hepatocellular Carcinoma: Is There Any Value in Repurposing Metformin for HCC Immunotherapy?

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. There has been significant progress in understanding the risk factors and epidemiology of HCC during the last few decades, resulting in efficient preventative, diagnostic and treatment strategies. Type 2 diabetes mellitus (T2DM) has been demonstrated to be a major risk factor for developing HCC. Metformin is a widely used hypoglycemic agent for patients with T2DM and has been shown to play a potentially beneficial role in improving the survival of patients with HCC. Experimental and clinical studies evaluating the outcomes of metformin as an antineoplastic drug in the setting of HCC were reviewed. Pre-clinical evidence suggests that metformin may enhance the antitumor effects of immune checkpoint inhibitors (ICIs) and reverse the effector T cells' exhaustion. However, there is still limited clinical evidence regarding the efficacy of metformin in combination with ICIs for the treatment of HCC. We appraised and analyzed in vitro and animal studies that aimed to elucidate the mechanisms of action of metformin, as well as clinical studies that assessed its impact on the survival of HCC patients.

Incidence and risk factors for anastomotic bile leakage in hepatic resection with bilioenteric reconstruction - A international multicenter study.

BACKGROUND: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions. METHODS: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases. RESULTS: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001). CONCLUSION: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients' postoperative course negatively.

Bridging therapies for patients with hepatocellular carcinoma awaiting liver transplantation: A systematic review and meta-analysis on intention-to-treat outcomes.

INTRODUCTION: Locoregional therapies are commonly used as bridging strategies to decrease the drop-out of patients with hepatocellular carcinoma (HCC) awaiting liver transplantation (LT). The present paper aims to assess the outcomes of bridging therapies in patients with HCC considered for LT according to an intention-to-treat (ITT) survival analysis. MATERIAL AND METHODS: Medline and Web of Science databases were searched for reports published before May 2021. Papers assessing adult patients with HCC considered for LT and reporting ITT survival outcomes were included. Two reviewers independently identified, extracted the data, and evaluated the papers according to Newcastle-Ottawa criteria. Outcomes analyzed were: drop-out rate; time on the waiting list; 1-, 3-, and 5-year survival after LT and based on an ITT analysis. RESULTS: The search identified 3106 records; six papers (1043 patients) met the inclusion criteria. Patients with HCC, listed for LT and submitted to bridging therapies presented a longer waiting time before LT (MD 3.77, 95% CI 2.07-5.48) in comparison with the non-interventional group. However, they presented a raised post LT after 1-year (OR 2.00, 95% CI 1.18-3.41), 3-years (OR 1.47, 95% CI 1.01-2.15), and 5-years (OR 1.50, 95% CI 1.06-2.13) survival. CONCLUSION: Patients submitted to bridging procedures, despite having a longer interval on the waiting list, presented better post-LT survival outcomes. Bridging therapies for selected patients at low risk of post-procedural complications and long expected intervals on the waiting list should be encouraged. However, further clinical trials should confirm the survival benefit of bridging therapies in patients with HCC listed for LT.

Downstaging Therapies for Patients with Hepatocellular Carcinoma Awaiting Liver Transplantation: A Systematic Review and Meta-Analysis on Intention-to-Treat Outcomes.

Background: Locoregional therapies (LRTs) are commonly used to increase the number of potential candidates for liver transplantation (LT). The aim of this paper is to assess the outcomes of LRTs prior to LT in patients with hepatocellular carcinoma (HCC) beyond the listing criteria. Methods: In accordance with the PRISMA guidelines, we searched the Medline and Web of Science databases for reports published before May 2021. We included papers assessing adult patients with HCC considered for LT and reporting intention-to-treat (ITT) survival outcomes. Two reviewers independently identified and extracted the data and evaluated the papers. Outcomes analysed were drop-out rate; time on the waiting list; and 1, 3 and 5 year survival after LT and based on an ITT analysis. Results: The literature search yielded 3,106 records, of which 11 papers (1874 patients) met the inclusion criteria. Patients with HCC beyond the listing criteria and successfully downstaged presented a higher drop-out rate (OR 2.05, 95% CI 1.45−2.88, p < 0.001) and a longer time from the initial assessment to LT than those with HCC within the listing criteria (MD 1.93, 95% CI 0.91−2.94, p < 0.001). The 1, 3 and 5 year survival post-LT and based on an ITT analysis did not show significant differences between the two groups. Patients with HCC beyond the listing criteria, successfully downstaged and then transplanted, presented longer 3 year (OR 3.77, 95% CI 1.26−11.32, p = 0.02) and 5 year overall survival (OS) (OR 3.08, 95% CI 1.15−8.23, p = 0.02) in comparison with those that were not submitted to LT. Conclusions: Patients with HCC beyond the listing criteria undergoing downstaging presented a higher drop-out rate in comparison with those with HCC within the listing criteria. However, the two groups did not present significant differences in 1, 3 and 5 year survival rates based on an ITT analysis. Patients with HCC beyond the listing, when successfully downstaged and transplanted, presented longer 3 and 5-year OS in comparison with those who were not transplanted.

Ceramic-on-metal coupling in THA: long term clinical and radiographic outcomes using two different short stems.

BACKGROUND: Hip prosthetic replacement surgery is the gold standard for patients affected by symptomatic osteoarthritis. The ceramic-on-metal hybrid hard-on-hard bearing was initially launched on the market with the purpose of reducing adhesive and corrosion wear, loss of metal debris and ions and risk of fracture and squeaking. However, this bearing was withdrawn from the market, in the apprehension of local and systemic toxicity. The aim of this study is to evaluate the reliability and safety of ceramic-on-metal bearing at long term follow-up. METHODS: From 2 cohorts of patients suffering of hip osteoarthritis who underwent total hip arthroplasty using ceramic-on-metal bearing with two different short stems, 19 of the GROUP A and 25 of the GROUP B were suitable for this study. All patients were compared clinically using the Harris Hip Score (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), visual analogue scale (VAS), 12-item Short Form Health Survey (SF12P/M), and radiographically. Blood samples were collected in order to evaluate chromium and cobalt ions level. The two groups were compared in terms of metal ions blood levels, and finally all the implanted prostheses were compared with a healthy control group. RESULTS: All the implanted stems were well-positioned and osseointegrated at a mean follow-up of 114 months. Improvements were observed for all clinical scores comparing preoperative and postoperative values in both groups. Radiographic evaluation showed a good ability to restore proper articular geometry. Chromium and cobalt ion analysis revealed values below the safety threshold except for 1 case in GROUP A (cup malposition) and 2 cases in GROUP B (6.1%). No revision occurred. CONCLUSIONS: Ceramic-on-metal bearing is safe and reliable at long term follow-up in association to short stems arthroplasty, if the implant is correctly positioned. Chromium and cobalt metal ions blood levels evaluation should be performed annually.

Is postoperative hyponatremia a real threat for total hip and knee arthroplasty surgery?

Postoperative hyponatremia (POH) is thought to be a fearsome complication of orthopedic surgery. Primary aim of this cohort study was to evaluate the incidence of POH and its clinical relevance in elective surgery, outlining differences between total knee arthroplasty (TKA) and total hip arthroplasty, looking for the presence of any risk factor commonly related to POH.Four hundred two patients that underwent total hip arthroplasty and total knee arthroplasty performed between 2016 and 2017 were retrospectively examined. Serum electrolytes, hemoglobin, hematocrit, glucose, and creatinine were evaluated preoperatively and at day 0-I-II from surgery. Age, sex, body mass index, comorbidities, drugs, surgery data, transfusions, postoperative symptoms, and length of stay (LOS) were determined. All surgeries were performed by the same equipe. Patients had the same perioperative management, excluded those that took thiazides, already at risk of POH.Patients were divided in 2 groups: group A, patients with normal postoperative natremia (294 patients) and group B, patients who developed POH (108, 26.9%); 66.7% of these developed POH within 24 hours postoperatively. In group B mean postoperative natremia was 133.38 (127.78-134.85) mmol/L. Two patients (1.8%) developed moderate hyponatremia, no severe hyponatremia was documented. Type of surgery, operation time, LOS, and presence of postoperative symptoms did not show statistically significant differences within groups. At multivariate logistic analysis chronic use of thiazides was the only variable associated to a decreased risk of developing POH (OR = 0.39; P = .03). Hemoglobin postoperative values (OR = 1.22; P = .03), the need of postoperative transfusion (OR = 2.50; P = .02) and diabetes (OR = 2.70; P = .01) were associated to an increased risk of POH.Although 26.9% of our patients exhibited POH, the onset of this disorder had no implication on postoperative symptoms and on LOS. Diabetes and transfusion are factors most often associated to POH.

Successful Orthotopic Liver Transplant for Diffuse Biliary Papillomatosis With Malignant Transformation: A Case Report With Long-Term Follow-Up.

In patients with biliary papillomatosis, complete resection of the biliary tree (that is, liver transplant along with duodenocephalo-pancreatectomy) is considered the only potential curative treatment, given its diffuse pattern and likelihood of malignant transformation. Nevertheless, such a combined surgical approach can increase patient morbidity and mortality and should be considered only when the distal part of the common bile duct is involved. Here, we avoided duodenocephalo-pancreatectomy in a patient with distal common bile duct free from disease; this approach did not negatively influence survival and appeared to be safer during liver transplant.

The ALPPS procedure: hepatocellular carcinoma as a main indication. An Italian single-center experience.

The ALPPS is a technique that allows achieving hepatic resection by a rapid future liver remnant hypertrophy. The aim of this study was to report the experience of an Italian center with ALPPS in patients with liver tumors. A retrospective analysis of patients undergoing ALPPS between 2012 and 2017 was performed. Patients' characteristics and disease presentation, increase in future liver remnant (FLR) as well as intraoperative and postoperative short- and long-term outcomes were evaluated. A total of 24 patients underwent the ALPPS procedure: 17 procedures for hepatocarcinoma (HCC), 5 for colorectal liver metastases (CRLM), 1 for cholangiocarcinoma (CC) and 1 for Merkel Cell Carcinoma liver metastasis (MCCLM). Macrovascular invasion (MVI) was recorded in 10 (41.6%) patients: 8 (33.3%) patients with HCC had invasion of portal vein (5), middle hepatic vein (2) and inferior vena cava (1). One patient with CRLM had involvement of middle hepatic vein and one patient with CC had involvement of right portal vein and middle hepatic vein. A p-ALPPS in 14 cases (58.3%), 10 t-ALPPS (41.6%) and hanging maneuver in 19 patients (80%) were performed. Median postoperative stay was 26 days (range 16-68 days). 90-day mortality was 8.3% (two patients, one with CC and one with HCC), 90-day mortality for HCC was 5.8%. After stage 1, we counted 15 complications all of grade I; after stage 2 the number of complications was increased to 37:33 were of grade I and 4 were of grade IV. R0 resection was achieved in all patients with 100% oncology feasibility. After a median follow-up of 10 months (range 2-54), disease recurrence has been recorded in 6 patients with HCC and in 2 with CRLM. Eleven patients died, nine affected by HCC, one by CRLM, and one by CC. 2-years OS and disease-free survival (DFS) for the entire group were 47.3% and 47.5%, respectively. Concerning patients operated on for HCC, the 2-years OS and DFS were 38.5% and 60%, respectively. The ALPPS procedure is an interesting approach for large primary or secondary liver tumor with small FLR above all for large HCC associated with MVI, with acceptable OS and DFS.

Effectiveness and versatility of biological prosthesis in transplanted patients.

AIM: To emphasize the effectiveness and versatility of prosthesis, and good tolerance by patients with incisional hernia (IH). METHODS: From December 2001 to February 2016, 270 liver transplantations were performed at San Camillo Hospital. IH occurred in 78 patients (28.8%). IH usually appeared early within the first year post-orthotopic liver transplantation. In the first era, fascial defect was repaired by primary closure for defects smaller than 2.5 cm or with synthetic mesh for greater defects. Recently, we started using biological mesh (Permacol™, Covidien). We present a series of five transplanted patients submitted to surgery for abdominal wall defect correction repaired with biological mesh (Permacol™, Covidien). RESULTS: In our cases, the use of biological prosthesis (Permacol™, Covidien) have proven to be effective and versatile in repairing hernia defects of different kinds; patients did not suffer infections of the prosthesis and no recurrence was observed. Furthermore, the prosthesis remains intact even in the years after surgery. CONCLUSION: The cases that we presented show that the use of biological mesh (Permacol™, Covidien) in transplanted patients may be safe and effective, being careful in the management of perioperative immunosuppression and renal and graft function, although the cost of the product itself has been the main limiting factor and there is need for prospective studies for further evaluations.

Hepatocellular carcinoma with macrovascular invasion treated with yttrium-90 radioembolization prior to transplantation.

BACKGROUND: Yttrium-90 microspheres radioembolization (Y90-RE) has shown to be an effective and safe treatment of primary liver tumors. According to the staging system of the Barcelona Clinic Liver Cancer (BCLC), patients with macrovascular invasion are staged as BCLC-C. This paper comprises a presentation of the results following application of the procedure. METHODS: From January 2002 to December 2015, 367 patients were transplanted at the San Camillo Hospital Center. One hundred and forty-three patients were transplanted for hepatocellular carcinoma (HCC) and in 22 cases patients were treated with Y90-RE before liver transplantation (LT), of them 4 with macrovascular invasion were included in this study. RESULTS: The four patients had a complete response for the thrombosis, and were included in the waiting list within the Milan criteria. Means interval time between Y90-RE and LT was 15.86 months. No patient death was observed at Y90-RE procedure or at LT. We obtain a free-survival of 39.1 (range, 6-76) months. In all four cases the complete thrombosis regression was observed. CONCLUSIONS: We reported a short series of patients transplanted after Y90-RE in patients with BCLC stage C. In our experience we achieved acceptable overall and disease-free survival. Eventually, Y90-RE seems to have a place in the downstaging strategy for LT candidates.

Continuous monitoring of the liver graft temperature: relationship between bacterial contamination of the perfusion fluid and early outcome.

BACKGROUND: A potential mechanism of the infection would be an infected donor, contamination at the time of the infusion and/or packaging, back-table procedure, and finally during the transplantation, all are potential sources of infection. The aim of our study is to analyze the incidence and significance of infection in the preservation solution according with the graft temperature. The second aim was to analyze the impact graft temperature on the clinical infections and the ischemia reperfusion injury. METHODS: Sixteen donors were prospectively included in this study, including 9 males and 7 females. The liver graft temperature monitoring shows variation in four different phases: at the harvesting beginning, before the graft packaging, at the beginning of the backtable, at the end of the backtable. RESULTS: There was no correlation between the functionality of the graft and the temperature of the perfusion fluid. CONCLUSIONS: In conclusion, we did not found a correlation between graft temperature, culture of the preservation solution and early post-transplant follow up.

Review of a non-epithelial tumour of the small bowel after c-kit revolution.

UNLABELLED: In this article, we reviewed the case of a patient who was object, in 1999, of a published case report of schwannoma of the jejunal wall. Recently, the patient has been referred to our institution for a mass of the stomach identified by upper gastrointestinal endoscopy. The patient underwent a wedge resection of the stomach and a histopathological diagnosis of GIST of the stomach, based on a positive immunohistochemical staining of c-kit and CD34, was made. In consideration of these findings, we performed immunohistochemistry for c-kit and for CD34 on the previous lesion of the jejunal wall, which resulted strongly positive for CD117 and negative for CD34. A new diagnosis of gastrointestinal stromal tumour (GIST) of jejunal wall with moderate risk of progression was made. The lesion was also classified, according to the AJCC Seventh Edition, as a pT3, pN0, Stage II, GIST. This case shows the importance of a reassessment of the diagnosis of mesenchymal neoplasm of the small intestine made before the development of anti-CD117 antibody for a correct prognostic stratification, a better therapeutic management and a close follow-up, if necessary. KEY WORDS: Adjuvant therapy, c-kit, GIST Imatinib.

Good results of surgery for renal cell carcinoma depend on early diagnosis. The need for an extensive screening program.

AIM: The aim of our study was to assess the value of several prognostic factors for patients with clear cell renal carcinoma without distant metastases (M0) who underwent surgery in our Department from 1980 to 2010. MATERIAL OF STUDY: We analyzed131 consecutive patients with clear cell renal carcinoma who had nephrectomy and extended lymph node dissection from 1980 to 2010 were reviewed. Free from cancer survivals were correlated to several prognostic factors including preoperative blood cell count, tumour cellular differentiation and stage of the disease. RESULTS: In our study we confirmed the importance of the stage of the tumour, in particular of the T, as prognostic factor. Survival was strictly correlated to the stage of the disease: 10 year cancer free survival was 100% in patients with T1, 83% in patients with T2 N0 and 34% for patients with T3N0. No improvement of results was noted in the last years, due to unchanged proportion of early diagnosis. DISCUSSION: Long term survival after surgery for clear cell renal carcinoma depends mainly on the histology type of the tumour and on the stage of the disease. Renal carcinoma does not respond to radio and standard chemotherapy and surgery represents the only effective cure. CONCLUSION: Surgery at earlier stages is essential to improve results in patients with renal carcinoma. Earlier diagnosis at the present time is the best possibility to improve results, with the need for extensive use of screening ultrasound test. KEY WORDS: Lymph node dissection in renal carcinoma, Renal carcinoma, Results of surgery for renal carcinoma.

Phytobezoar-induced small bowel obstruction associated with a concomitant gastric phytobezoar and ulcer in an elderly woman.

Bezoars are aggregates of indigested foreign material that accumulate in the gastroenteric tract, expecially in the stomach and in the narrowest points of the small bowel. They often occur in subjects who follow a diet rich in fruit and vegetables and in those one who previously underwent gastric resective surgery for peptic ulcer. Bezoar formation has even been observed in case of reduced gastric motility and secretion due to diabetes, hypothyroidism, pernicious anemia, myotonic syndromes, and Guillain-Barré syndrome. As they are an uncommon cause of small bowel obstruction, phytobezoars are often not considered in the differential diagnosis of occlusive intestinal syndromes and so frequently come as an intraoperative finding. A consequence of this missed diagnosis in the preoperative period is an unnecessary diagnostic delay that can significantly increase morbidity and mortality. This case report illustrates the need to include phytobezoars in the preoperative diagnostic workout of intestinal obstruction in order to rule out the presence of multiple bezoars and prevent recurrent obstruction. Now that phytobezoars are becoming a less infrequent cause of small bowel obstruction than previously thought, such a diagnostic possibility should always be considered.

Bartholin's gland hyperplasia. Case report and a review of literature.

BACKGROUND: Tumors arising from glands of the female ano-genital area, such as minor and major vestibular glands, are very rare. Lesions affecting Bartholin's gland can be divided into two groups: benign and malignant lesions. In the first group we can include nodular hyperplasia, adenoma, adenomioma which can sometimes cause Bartholin's gland enlargement and difficult differential diagnosis. Surgery is considered the treatment of choice, frequently represented by marsupialization with rates of local recurrence. CASE REPORT: We describe a case of a 50-year-old woman with a several-years history of recurrent episodes of Bartholinitis, previously treated with marsupialization. Patient underwent complete excision of the left Bartholin's gland without operative complications. Pathological findings showed a Bartholin's gland hyperplasia. Post-operative course was regular, free from surgical complications. After one year, the patient is free from any local disease. RESULTS AND CONCLUSION: In women in postmenopausal age, in those cases in which marsupialization doesn't lead to an improvement in symptomatology and in those cases in which, at physical examination, Bartholin's gland enlargement appeared to be firm and irregular, because of the higher incidence of malignancy in these situations, total excision of the gland is recommended. Total excision of the Bartholin's Gland is a safe technique, given the low incidence of procedure- related morbilities. We do not consider biopsy of the gland a proper strategy for the high percentage of false negative results.