Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) represents one of the most common neoplasms worldwide. Surgical resection and local ablative therapies represent the most frequent first lines therapies adopted when liver transplantation can not be offered or is not immediately accessible. Hepatic resection (HR) is currently considered the most curative strategy, but in the last decade local ablative therapies have started to obtain satisfactory results in term of efficacy and, of them, radiofrequency ablation (RFA) is considered the reference standard. An extensive literature review, from the year 2000, was performed, focusing on results coming from studies that directly compared HR and RFA. Qualities of the studies, characteristics of patients included, and patient survival and recurrence rates were analyzed. Except for three randomized controlled trials (RCT), most studies are affected by uncertain methodological approaches since surgical and ablated patients represent different populations as regards clinical and tumor features that are known to affect prognosis. Unfortunately, even the available RCTs report conflicting results. Until further evidences become available, it seems reasonable to offer RFA to very small HCC (< 2 cm) with no technical contraindications, since in this instance complete necrosis is most likely to be achieved. In larger nodules, namely > 2 cm and especially if > 3 cm, and/or in tumor locations in which ablation is not expected to be effective or safe, surgical removal is to be preferred.

Ten years of sorafenib in hepatocellular carcinoma: Are there any predictive and/or prognostic markers?

Sorafenib has been considered the standard of care for patients with advanced unresectable hepatocellular carcinoma(HCC) since 2007 and numerous studieshave investigated the role of markers involved in the angiogenesis process at both the expression and genetic level and clinical aspect. What results have ten years of research produced? Several clinical and biological markers are associated with prognosis. The most interesting clinical parameters are adverse events, Barcelona Clinic Liver Cancer stage, and macroscopic vascular invasion, while several single nucleotide polymorphisms and plasma angiopoietin-2 levels represent the most promising biological biomarkers. A recent pooled analysis of two phase III randomized trials showed that the neutrophil-to-lymphocyte ratio, etiology and extra-hepatic spread are predictive factors of response to sorafenib, but did not identify any predictive biological markers. After 10 years of research into sorafenib there are still no validated prognostic or predictive factors of response to the drug in HCC. The aim of the present review was to summarize 10 years of research into sorafenib, looking in particular at the potential of associated clinical and biological markers to predict its efficacy in patients with advanced HCC.

Post reperfusion syndrome during liver transplantation:From pathophysiology to therapy and preventive strategies

This review aims at evaluating the existing evidence regarding post reperfusion syndrome, providing a description of the pathophysiologic mechanisms involved and possible management and preventive strategies. A Pub Med search was conducted using the Me SH database, "Reperfusion" AND "liver transplantation" were the combined Me SH headings; EMBASE and the Cochrane library were also searched using the same terms. 52 relevant studies and one ongoing trial were found. The concept of post reperfusion syndrome has evolved through years to a multisystemic disorder. The implications of the main organ, recipient and procedure related factors in the genesis of this complex syndrome are discussed in the text as the novel pharmacologic and technical approaches to reduce its incidence. However the available evidence about risk factors, physiopathology and preventive measures is still confusing, the presence of two main definitions and the numerosity of possible confounding factors greatly complicates the interpretation of the studies.

Liver transplantation for hepatocellular carcinoma:Role of inflammatory and immunological state on recurrence and prognosis

Criteria for liver transplantation(LT)for hepatocellular carcinoma(HCC)and post-LT indicators of prognosis are historically based on the measurement of the tumor mass.Recently,high throughput technologies have increased the prediction of recurrence,but these tools are not yet routinely available.The interaction between HCC and the immune system has revealed an imbalance of lymphocyte phenotypes in the peritumoral tissue,and the increase of regulatory T cells with respect to cytotoxic lymphocytes has been linked to a higher rate of post-LT HCC recurrence.Moreover,some inflammatory markers have shown good reliability in predicting cancer reappearance after surgery,as a result of either a systemic inflammatory response or a decreased capacity of the organism to control the tumor growth.Among these markers,the neutrophil-tolymphocyte ratio appears to be the most promising and easily available serum parameter able to predict HCC recurrence after LT and following other types of treatment,although the exact mechanisms determining its elevation have not been clarified.Post-LT immunosuppression may impact on cancer control,and the exposure to high levels of calcineurin inhibitors or other immunusuppressants has recently emerged as a negative prognostic factor for HCC recurrence and patient survival.Despite the absence of prospective randomized trials,inhibitors of the mammalian target of rapamycin have been shown to be associated with lower rates of tumor recurrence compared to other immunosuppressors,suggesting their use especially in patients with HCC exceeding the conventional indication criteria for LT.

Liver transplantation for hepatic tumors:a systematic review

Improvements in the medical and pharmacological management of liver transplantation(LT)recipients have led to a better long-term outcome and extension of the indications for this procedure.Liver tumors are relevant to LT;however,the use of LT to treat malignancies remains a debated issue because the high risk of recurrence.In this review we considered LT for hepatocellular carcinoma(HCC),cholangiocarcinoma(CCA),liver metastases(LM)and other rare tumors.We reviewed the literature,focusing on the past 10 years.The highly selected Milan criteria of LT for HCC(single nodule<5 cm or up to 3 nodules<3cm)have been recently extended by a group from the University of S.Francisco(1 lesion<6.5 cm or up to3 lesions<4.5 cm)with satisfying results in terms of recurrence-free survival and the"up-to-seven criteria".Moreover,using these criteria,other transplant groups have recently developed downstaging protocols,including surgical or loco-regional treatments of HCC,which have increased the post-operative survival of recipients.CCA may be treated by LT in patients who cannot undergo liver resection because of underlying liver disease or for anatomical technical challenges.A well-defined protocol of chemoirradiation and staging laparotomy before LT has been developed by the Mayo Clinic,which has resulted in long term diseasefree survival comparable to other indications.LT for LM has also been investigated by multicenter studies.It offers a real benefit for metastases from neuroendocrine tumors that are well differentiated and when a major extrahepatic resection is not required.If LT is an option in these selected cases,liver metastases from colorectal cancer is still a borderline indication because data concerning the disease-free survival are still lacking.Hepatoblastoma and hemangioendothelioma represent rare primary tumors for which LT is often the only possible and effective cure because of the frequent multifocal,intrahepatic nature of the disease.LT is a very promising procedure for both primary and secondary liver malignancies;however,it needs an accurate evaluation of the costs and benefits for each indication to balance the chances of cure with actual organ availability.

Liver grafts from hepatitis B surface antigen-positive donors: A review of the literature

The scarcity of available organs and the gap between supply and demand continue to be the main limitations of liver transplantation. To relieve the organ shortage, current transplant strategies have implemented extended criteria, which include the use of liver from patients with signs of past or present hepatitis B virus(HBV) infection. While the use of liver grafts from donors with evidence of past HBV infection is quite limited, some data have been collected regarding the feasibility of transplanting a liver graft from a hepatitis B surface antigen(HBs Ag) positive donor. The aim of the present work was to review the literature regarding liver transplants from HBs Ag-positive donors. A total of 17 studies were identified by a search in Medline. To date, HBs Ag positive grafts have preferentially been allocated to HBs Ag positive recipients. The large majority of these patients continue to be HBs Ag positive despite the use of immunoglobulin, and infection prevention can only be guaranteed by using antiviral prophylaxis. Although serological persistence is evident, no significant HBV-related disease has been observed, except in patients coinfected with delta virus. Consistently less data are available for HBs Ag negative recipients, although they are mostly promising. HBs Agpositive grafts could be an additional organ source for liver transplantation, provided that the risk of reinfection/reactivation is properly prevented.

Prognostic criteria for postoperative mortality in 170 patients undergoing major right hepatectomy

BACKGROUND: Postoperative hepatic failure is a dreadful complication after major hepatectomy and carries high morbidity and mortality rates. In this study, we assessed the accuracy of the 50/50 criteria (bilirubin >2.9 mg/dL and international normalized ratio >1.7 on postoperative day 5) and the Mullen criteria (bilirubin peak >7 mg/dL on postoperative days 1-7) in predicting death from hepatic failure in patients undergoing right hepatectomy only. In addition, we identified prognostic factors linked to intra-hospital morbidity and mortality in these patients. METHODS: One hundred seventy consecutive patients underwent major right hepatectomy at a tertiary medical center from 2000 to 2008. Nineteen (11.2%) patients suffered from liver cirrhosis. Univariate and multivariate analyses were performed to identify predictors of intra-hospital mortality, morbidity and death from hepatic failure. RESULTS: The intra-hospital mortality was 6.5% (11/170). Of the six patients who died from hepatic failure, one was positive for the 50/50 criteria, but all six patients were positive for the Mullen criteria. Multivariate analysis showed that male gender, hepatitis C (HCV), hepatocellular carcinoma, postoperative bilirubin >7 mg/dL and ALT<188 U/L on postoperative day 1 were predictive of death from hepatic failure in the postoperative period. Age >65 years, HCV, reoperation, andrenal failure were significant predictors of overall intra-hospital mortality on multivariate analysis. CONCLUSIONS: The Mullen criteria were more accurate than the 50/50 criteria in predicting death from hepatic failure in patients undergoing right hepatectomy. A bilirubin peak >7 mg/dL in the postoperative period, HCV positivity, hepatocellular carcinoma, and an ALT level <188 U/L on postoperative day 1 were associated with death from hepatic failure in our patient population.

The impact of extent of pancreatic and venous resection on survival for patients with pancreatic cancer

Background:Borderline resectable pancreatic cancer may require extended resections in order to achieve tumor-free margins,especially in the case of up-front resections,but it is important to know the limits of surgical therapy in this disease.This study aimed to investigate the impact of extent of pancreatic and venous resection on short-and long-term outcomes in patients with pancreatic adenocarcinoma(PDAC).Methods:This was a retrospective study from a prospectively maintained database of pancreatic resections for PDAC.Short-and long-term outcomes were analyzed in patients having borderline resectable PDAC submitted to up-front total pancreatectomy(TP)or pancreaticoduodenectomy(PD)with simultaneous portal vein(PV)and/or superior mesenteric vein(SMV)resection.Venous resections were carried out as tangential venous resection(TVR)or segmental venous resection(SVR).Patients were divided into 4 groups:(1)PD+TVR,(2)PD+SVR,(3)TP+TVR,(4)TP+SVR.Uni-and multivariate Cox regression analysis were performed to identify factors associated with survival.Results:Ninety-nine patients were submitted to simultaneous pancreatic and venous resection for PDAC.Among them,25 were submitted to PD+TVR(25.3%),12 to PD+SVR(12.1%),23 to TP+TVR(23.2%),and 39 to TP+SVR(39.4%).Overall,major morbidity(Clavien-Dindo grade≥IIIA)was 26.3%.Thirty-and 90-day mortality were 3%and 11.1%,respectively.There were no significant differences among groups in terms of short-term outcomes.Median overall survival of patients submitted to PD+TVR was significantly higher than those to TP+SVR(29.5 vs 7.9 months,P=0.001).Multivariate analysis identified TP(HR=2.11;95%CI:1.31–3.44;P=0.002)and SVR(HR=2.01;95%CI:1.27–3.15;P=0.003)as the only independent prognostic factors for overall survival.Conclusions:Up-front TP associated to SVR was predictive of worse survival in borderline resectable PDAC.Perioperative treatments in high-risk surgical groups may improve such poor outcomes.

Urea cycle disorders:A case report of a successful treatment with liver transplant and a literature review

The urea cycle is the final pathway for nitrogen metabolism. Urea cycle disorders(UCDs) include a variety of genetic defects, which lead to inefficient urea synthesis. Elevated blood ammonium level is usually dominant in the clinical pattern and the primary manifestations affect the central nervous system. Herein, we report the case of a 17-year-old girl who was diagnosed with UCD at the age of 3. Despite a controlled diet, she was hospitalized several times for acute attacks with recurrent life risk. She came to our attention for a hyperammonemic episode. We proposed an orthotopic liver transplant(OLT) as a treatment; the patient and her family were in complete agreement. On February 28, 2007, she successfully received a transplant. Following the surgery, she has remained well, and she is currently leading a normal life. Usually for UCDs diet plays the primary therapeutic role, while OLT is often considered as a last resort. Our case report and the recent literature data on the quality of life and prognosis of traditionally treated patients vs OLT patients, support OLT as a primary intervention to prevent life-threatening acute episodes and chronic mental impairment.

Competing risk analysis on outcome after hepatic resection of hepatocellular carcinoma in cirrhotic patients

AIM To investigate death for liver failure and for tumor recurrence as competing events after hepatectomy of hepatocellular carcinoma.METHODS Data from 864 cirrhotic Child-Pugh class A consecutive patients, submitted to curative hepatectomy(1997-2013) at two tertiary referral hospitals, were used for competing-risk analysis through the Fine and Gray method, aimed at assessing in which circumstances the oncological benefit from tumour removal is greater than the risk of dying from hepatic decompensation. To accomplish this task, the average risk of these two competing events, over 5 years of follow-up, was calculated through the integral of each cumulative incidence function, and represented the main comparison parameter. RESULTS Within a median follow-up of 5.6 years, death was attributable to tumor recurrence in 63.5%, and to liver failure in 21.2% of cases. In the first 16 mo, the risk of dying due to liver failure exceeded that of dying due to tumor relapse. Tumor stage only affects death from recurrence; whereas hepatitis C infection, Model for End-stage Liver Disease score, extent of hepatectomy and portal hypertension influence death from liver failure(P < 0.05 in all cases). The combination of these clinical and tumoral features identifies those patients in whom the risk of dying from liver failure did not exceed the tumour-related mortality, representing optimal surgical candidates. It also identifies those clinical circumstances where the oncological benefit would be borderline or even where the surgery would be harmful. CONCLUSION Having knowledge of these competing events can be used to weigh the risks and benefits of hepatic resection in each clinical circumstance, separating optimal from non-optimal surgical candidates.

Revisiting the role of pathological analysis in transarterial chemoembolization-treated hepatocellular carcinoma after transplantation

AIM: To define the histopathological features predictive of post-transplant hepatocellular carcinoma(HCC) recurrence after transarterial chemoembolization, applicable for recipient risk stratification.METHODS: We retrospectively reviewed the specimens of all suspicious nodules(total 275) from 101 consecutive liver transplant recipients which came to our Pathology Unit over a 6-year period. All nodules were sampled and analyzed, and follow-up data were collected. We finally considered 11 histological variables for each patient: total number of nodules, number of viable nodules, size of the major nodule, size of the major viable nodule, occurrence of microscopic vascular invasion, maximum Edmondson's grade, clear cell/sarcomatous changes, and the residual neoplastic volume. Survival data were computed by means of the Kaplan-Meier procedure and analyzed by means of the Cox proportional hazards model. The multivariate linear regression and a k-means cluster analysis were also used in order to compute the standardized histological score.RESULTS: The total number of nodules, the residual neoplastic volume(the total volume of all evaluated nodules minus the necrotic portion) and the microvascular invasion entered the Cox multivariate hazard model with HCC recurrence as dependent variable. The histological score was therefore computed and a cluster analysis sorted recipients into 3 risk groups, with 3.3%, 18.5% and 53.8% respectively of tumor recurrence rates and 1.6%, 11.1% and 38.5% of tumor-related mortality respectively at the end of follow-up.CONCLUSION: The histological score allows a reliable stratification of HCC recurrence risk, especially in those recipients found out to be beyond the Milan criteria after orthotopic liver transplantation(OLT).

Which octogenarian patients are at higher risk after cholecystectomy for symptomatic gallstone disease? A single center cohort study

BACKGROUND Incidence of gallstones in those aged≥80 years is as high as 38%-53%.The decision-making process to select those oldest old patients who could benefit from cholecystectomy is challenging.AIM To assess the risk of morbidity of the“oldest-old”patients treated with cholecystectomy in order to provide useful data that could help surgeons in the decision-making process leading to surgery in this population.METHODS A retrospective study was conducted between 2010 and 2019.Perioperative variables were collected and compared between patients who had postoperative complications.A model was created and tested to predict severe postoperative morbidity.RESULTS The 269 patients were included in the study(193 complicated).The 9.7%of complications were grade 3 or 4 according to the Clavien-Dindo classification.Bilirubin levels were lower in patients who did not have any postoperative complications.American Society of Anesthesiologists scale 4 patients,performing a choledocholithotomy and bilirubin levels were associated with Clavien-Dindo>2 complications(P<0.001).The decision curve analysis showed that the proposed model had a higher net benefit than the treating all/none options between threshold probabilities of 11%and 32%of developing a severe complication.CONCLUSION Patients with American Society of Anesthesiologists scale 4,higher level of bilirubin and need of choledocholithotomy are at the highest risk of a severely complicated postoperative course.Alternative endoscopic or percutaneous treatments should be considered in this subgroup of octogenarians.

Gastric splenosis mimicking a gastrointestinal stromal tumor:A case report

BACKGROUND Mass lesions located in the wall of the stomach(and also of the bowel)are referred to as“intramural.”The differential diagnosis of such lesions can be challenging in some cases.As such,it may occur that an inconclusive fine needle aspiration(FNA)result give way to an unexpected diagnosis upon final surgical pathology.Herein,we present a case of an intramural gastric nodule mimicking a gastric gastrointestinal stromal tumor(GIST).CASE SUMMARY A 47-year-old Caucasian woman,who had undergone splenectomy for trauma at the age of 16,underwent gastroscopy for long-lasting epigastric pain and dyspepsia.It revealed a 15 mm submucosal nodule bulging into the gastric lumen with smooth margins and normal overlying mucosa.A thoraco-abdominal computed tomography scan showed in the gastric fundus a rounded mass(30 mm in diameter)with an exophytic growth and intense enhancement after administration of intravenous contrast.Endoscopic ultrasound scan showed a hypoechoic nodule,and fine needle FNA was inconclusive.Gastric GIST was considered the most probable diagnosis,and surgical resection was proposed due to symptoms.A laparoscopic gastric wedge resection was performed.The postoperative course was uneventful,and the patient was discharged on the seventh postoperative day.The final pathology report described a rounded encapsulated accumulation of lymphoid tissue of about 4 cm in diameter consistent with spleen parenchyma implanted during the previous splenectomy.CONCLUSION Splenosis is a rare condition that should always be considered as a possible diagnosis in splenectomized patients who present with an intramural gastric nodule.

Solid serous cystadenoma of the pancreas:A rare tumor with challenging differential diagnosis

To the Editor:Cystic tumors of the pancreas are rare,accounting for 1%-5%of exocrine pancreatic tumors.Serous cystadenoma(SCA)was firstly described by Compagno and Oertel in 1978 as a benign glycogenrich neoplasm[1].In 1996 Perez-Ordonez et al.[2]reported the first case of a solid variant of SCA;since then,23 cases of this extremely uncommon tumor variant were reported.

西方单中心18年肝门胆管癌外科治疗变化

背景肝门胆管癌由于化疗敏感性低和术后放疗效果不佳,手术治疗仍然是其治疗的金标准。本文评估了死亡率,生存率,预后因子以及1997年以后外科治疗的变化。方法共有51患者进行了肝脏切除组成研究人群。分为姑息性治疗组与切除组。随访时间33.5±30.0（12.0~134.0）月。结果 Bismuth-Ⅳ型,伴门脉侵犯,肝蒂旁淋巴结转移的肝门胆管癌1998年前通常认为是手术禁忌症,

Cytoreductive surgery and HIPEC after neoadjuvant chemotherapy for advanced epithelial ovarian cancer

AIM: To reduce postoperative complications and to make possible an optimal cytoreduction, neoadjuvant chemotherapy(NACT) followed by interval debulking surgery has been applied with encouraging results. METHODS: Between December 2009 and February 2012, patients with stage ⅢC-Ⅳ epithelial ovarian cancer(EOC) underwent diagnostic laparoscopy, to assess the feasibility of optimal debulking surgery. The modifi ed Fagotti score was applied to assess the feasibility of resection with zero residual tumor. Patients who were not candidate for upfront debulking surgery were submitted to NACT, then reassessed according to the RECIST 1.1 criteria and submitted to cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) if they showed clinical response or stable disease. The remaining cycles of adjuvant systemic chemotherapy(ASCT) were administered postoperatively, to complete 6 cycles of systemic chemotherapy.RESULTS: Nine patients were included. Clinical response to NACT was complete in 3 patients and partial in 5 patients; one patient had stable disease. All patients underwent CRS resulting in CC0 disease prior to HIPEC. Average operative time was 510 min. Average intensive care unit stay was 2 d. Average postoperative hospital stay was 25 d. No postoperative mortality was observed. One patient experienced pelvic abscess. One patient refused ASCT. The remaining 8 patients started ASCT. Average time to chemotherapy was 36 d. All patients are alive, with an average follow up of 11 mo. Eight patients are disease-free at follow up.CONCLUSION: HIPEC after CRS for advanced EOC is feasible with acceptable morbidity and mortality. NACT may increase the chance for achieving complete cytoreduction. Phase 3 studies are needed to determine the effects of HIPEC on survival.

Local recurrence rate as quality indicator in surgery for pancreatic cancer?

To the Editor: As we all know, even with the current advancements regarding novel chemotherapy regimens, patients affected by pancreatic cancer(PC) have an extremely dismal prognosis(5-year survival rate 12% for all stages in the National Cancer Institute SEER database). Among the patients undergoing surgical treatment, the prognosis is mostly affected by recurrence. PC after surgery has mainly four patterns of recurrence, isolated or variously associated with each other: local, lymph nodal, peritoneal or distant(liver, lung, other sites).

Treatment options for recurrence of hepatocellular carcinoma after surgical resection: review of the literature and current recommendations for management

The recurrence rate after primary resection for hepatocellular carcinoma(HCC)has been reported to be up to 80%.There is no consensus or guideline about the best treatment option for such recurrent HCC(rHCC).It is therefore of paramount importance to select patients for suitable treatment due to the high risk of associated morbidity and mortality.In this paper,we review the literature on treatment for rHCC and propose a strategy based on the best evidence available.Even in rHCC,it is still possible to achieve cure and good survival rates through careful patient selection.Repeat hepatectomy is recognized as a feasible and safe procedure even in cirrhotic patients and should be considered as the best option with curative intent when the patient is fit enough.Greater adoption of minimally-invasive liver surgery could have the potential to increase the number of candidate patients with rHCC for repeat resection in the next few years.Liver transplantation offers longer disease-free survival compared to repeat resection,curing the underlying cirrhosis,but is not widely available due to organ shortage.When surgery is not feasible,locoregional treatments such as radiofrequency ablation and transarterial chemoembolization have an important role for patients who cannot tolerate repeat hepatectomy and are not suitable for transplantation.For advanced cases,systemic therapy could be considered.

Surgery for hepatocellular carcinoma can provide the same life-expectancy as transplant of that of general population

When deciding for the optimal treatment to adopt in patients suffering from hepatocellular carcinoma(HCC),the surgical approach is commonly considered as the most curative option(1,2).The scarcity of donors for liver transplantation(LT)led surgeons to bridge patients until an eventual future transplant(salvage LT),opting in first instance and when feasible for hepatic resection(HR)also for those patients otherwise transplantable(2).In the study published by Pinna and colleagues in Annals of Surgery 2018,it was verified in what measure LT and HR can provide for HCC the same mortality expected in the general population,defining the so called"statistical cure"(3).