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Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Background: The objective of the current study was to summarize and evaluate all published evidence regarding viscoelastic testing in the field of liver surgery. Methods: A systematic search of the literature was performed using Medline/PubMed, Scopus, Cochrane Library Central, Google Scholar, and clinicaltrials.gov databases. The following keywords were used:“Thromboelastography”, “Thromboelastometry”, “Viscoelastic tests OR testing”, “Sonoclot Devices”, “Point-of-care tests OR testing”, “Coagulation OR Haemostasis OR Hemostasis”, “Liver OR Hepatic Surgery”, “Cirrhosis.” Results: A total of 12 studies analyzing 348 patients who underwent viscoelastic testing of coagulation during liver surgery for benign or malignant diseases were included; 7 (58.3%) studies reported on the use of thromboelastography (TEG), and 5 (41.7%) reported on rotational thromboelastometry (ROTEM). Viscoelastic testing (TEG and ROTEM) identified normo-, hyper- and hypo-coagulable status in 77% (n = 268/348), 18.4% (n = 64/348), and 4.6% (n = 16/348) of patients, respectively. In contrast, conventional coagulation tests indicated normo-coagulability in 111 patients (34.2% out of 325) and hypo-coagulability in 214 (65.8% out of 325) patients following liver resection. No patient (0% out of 291) experienced postoperative hemorrhage, whereas 5.8% (n = 17/291) experienced postoperative thromboembolic events. Conclusions: Global viscoelastic testing may be a reasonable adjunct to conventional coagulation testing to provide a more robust assessment of the coagulation status of patients undergoing liver surgery. © 2020 International Hepato-Pancreato-Biliary Association Inc.

Introduction: Cholangiocarcinoma is a malignant disease of the biliary tract and accounts for 3% of all gastrointestinal tumors. Surgical intervention is currently the only potentially curative strategy for cholangiocarcinoma. For patients with unresectable, advanced or metastatic disease, the combination of gemcitabine with cisplatin is considered the standard treatment. However, currently available therapeutic options have only a marginal benefit, especially among patients with relapsed/refractory tumors. Areas covered: We reviewed targeted agents under clinical evaluation for patients with cholangiocarcinoma. FGFR and IDH inhibitors are at the most advanced stage of clinical investigation. EGFR inhibitors have demonstrated contradictory results, whereas inhibition of other molecular pathways, including the RAS/RAF/MEK/ERK, the MET, the PI3K/AKT/mTOR and angiogenetic pathways, has shown minimal or null benefit. Expert opinion: Several targeted approaches are being investigated for advanced cholangiocarcinoma. However, randomized clinical trials are needed to define the optimal treatment regimen and address issues including the option of monotherapy or combination regimens, the optimal sequence of different treatments, ways to overcome resistance to targeted treatments, as well as determining the right time and tissue for assessing molecular signatures. Targeted therapies and immunotherapy hold promise for improving patient outcomes in the future. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) represents a novel surgical technique which provides rapid and effective liver regeneration allowing for the resection of lesions initially deemed unresectable. The objective of this systematic review is to summarize all technical modifications of the original ALPPS approach (mALPPS) for primary liver malignancies and evaluate short- and long-term outcomes. A systematic search of the literature was conducted using PubMed, Scopus, Cochrane Library Central, Google Scholar, and clinicaltrials.gov databases until July, 31 2019. The following keywords were utilized: “Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy”, “ALPPS”, “Portal Vein Embolization (PVE) And In Situ Split”, “Portal Vein Ligation (PVL) And In Situ Split”. A total of 24 studies were identified incorporating data on 83 patients who underwent a mALPPS for a primary liver malignancy. Median FLR hypertrophy after ALPPS-1 was 54% (range, 6.7–133%) and median EBL during the ALPPS 1 and ALPPS 2 stages was 200 mL (range 0–1000) and 700 ml (range 100–4000), respectively. R0 resections were achieved in all patients (100%). Most complications occurred post ALPPS- 2 (n = 33/72, 45.8%), while overall 30-day mortality was 13.3%. After a median follow up of 7 months (range 3–60), recurrence rate was 18.9%. Disease-free survival ranged from 3 to 60 months with a median of 10 months and overall survival ranged from 3 to 60 months with a median of 11 months. ALPPS with the various technical modifications offers a reasonable chance of complete tumor resection among patients with initially unresectable primary liver tumors. Further advances in patient selection, surgical techniques and perioperative management are required to minimize complications rates. Large scale prospective trials are needed to validate the role of the technical modifications of ALPPS in the treatment of patients with primary liver malignancies in an individualized setting. © 2020 Elsevier Ltd

The following reference in this paper refers to a paper that has been since retracted. 70. Zhao C, Pei SL, Cucchetti A, Tong TJ, Ma YL, Zhong JH, et al. Systematic review: benefits and harms of transarterial embolisation for treating hepatocellular adenoma. Aliment Pharmacol Ther. 2017. © 2019, The Society for Surgery of the Alimentary Tract.

Background: There has been a dramatic increase in worldwide health care spending over the last several decades. Operative procedures and perioperative care in the USA represent some of the most expensive episodes per patient. In view of both the rising cost of health care in general and the rising cost of surgical care specifically, policymakers and stakeholders have sought to identify ways to increase the value—improving quality of care while controlling (or diminishing) costs. In this context, we reviewed data relative to achieving the “value proposition” in the delivery of gastrointestinal surgical care. Methods: The National Library of Medicine online repository (PubMed) was text searched for human studies including “cost,” “quality,” “outcomes,” “health care,” “surgery,” and “value.” Results from this literature framed by the Donabedian conceptual model (identifying structures, processes, and outcomes), and the resulting impact of efforts to improve quality on costs. Results: The relationship between quality and costs was nuanced. Better quality care, though associated with better outcomes, was not always reported as concomitant with low costs. Moreover, some centers reported higher costs of surgical care commensurate with higher quality. Conversely, higher costs in health care delivery were not always linked to improved outcomes. While higher quality surgical care can lead to lower costs, higher costs of care were not necessarily associated with better outcomes. Strategies to improve quality, reduce cost, or achieve both simultaneously included regionalization of complex operations to high-volume centers of excellence, overall reduction in complications, introducing evidence-based improvements in perioperative care pathways including as enhanced recovery after surgery (ERAS), and elimination of inefficient or low-value care. Conclusions: The relationship between quality and cost following gastrointestinal surgical procedure is complex. Data from the current study should serve to highlight the various means available to improve the value proposition related to surgery, as well as encourage surgeons to become more engaged in the national conversation around the Triple Aim of better health care quality, lower costs, and improved health care outcomes. © 2020, The Society for Surgery of the Alimentary Tract.

While colorectal and hepatic resections are commonly performed through a laparoscopic approach, the safety and feasibility of total laparoscopic synchronous resections (LSR) of colorectal liver metastasis (CRLM) have not been established. In this systematic review, short- and long-term outcomes were comparable for patients undergoing LSR and open synchronous resection. LSR was safe and feasible for patients with synchronous CRLM and should be considered in well-selected patients. © 2018 Wiley Periodicals, Inc.

Advances in systemic chemotherapy have resulted in a significant increase in the reported response rates of colorectal liver metastases (CRLM) over time. Although radiologic response is usually prognostic of favorable outcomes, complete shrinkage of CRLM after chemotherapy, namely “disappearing liver metastases” (DLMs) poses significant therapeutic dilemmas. A systematic review of the literature was conducted to evaluate the existing evidence on the imaging and management of patients with DLMs using the PubMed (Medline), Embase and Cochrane library through December 21st, 2018. The following algorithm was used: “(disappearing OR vanishing OR missing OR (residual tiny)) AND ((liver OR hepatic) AND (metastasis OR metastases OR metastatic OR secondary)).” From the 225 records retrieved, 15 studies were finally deemed eligible. A total of 479 patients with DLMs with a median age of 59.5 years (range, 30–83) were identified. Median number of DLM per patient ranged from 1 to 8.8. Median size of LMs prior to chemotherapy was 1.07 cm (range 0.3–3.5). The systemic treatment used to achieve DLMs included systemic chemotherapy alone (only 2 studies) or in combination with targeted agents (11 studies). The median number of chemotherapy cycles in the included studies was 7.8 (range 6–12). Identified factors predisposing to the development of DLM were small size (

Introduction: Patients with midgut neuroendocrine tumors (MNETs) frequently present with metastatic disease at the time of diagnosis. Although combined resection of the primary MNET and liver metastases (NELM) is usually recommended for appropriate surgical candidates, primary tumor resection (PTR) in the setting of extensive, inoperable metastatic disease remains controversial. Methods: A systematic review was performed according to PRISMA guidelines utilizing Medline (PubMed), Embase, and Cochrane library—Cochrane Central Register of Controlled Trials (CENTRAL) databases until September 30, 2018. Results: Among patients with MNET and NELM, 1226 (68.4%; range, 35.5–85.1% per study) underwent PTR, whereas 567 (31.6%; range, 14.9–64.5%) patients did not. Median follow-up ranged from 55 to 90 months. Cytoreductive liver surgery was performed in approximately 15.7% (range, 0–34.8%) of patients. Pooled 5-year overall survival (OS) among the resected group was approximately 73.1% (range, 57–81%) versus 36.6% (range, 21–46%) for the non-resection group. For patients without liver debulking surgery, PTR remained associated with a decreased risk of death at 5 years compared with patients who did not have the primary tumor resected (HR 0.36, 95% CI 0.16 to 0.79, p = 0.01; I 2 58%, p = 0.12). For patients undergoing PTR, 30-day postoperative mortality ranged from 1.43 to 2%. Conclusion: PTR was safe with a low peri-operative risk of mortality and was associated with an improved OS for patients with MNET and unresectable NELM. Given the poor quality of evidence, however, strong evidenced-based recommendations cannot be made based on these retrospective single center–derived data. Future well-design randomized controlled trials will be critical in elucidating the optimal treatment strategies for patients with MNET and advanced metastatic disease. © 2019, The Society for Surgery of the Alimentary Tract.

Background: While reduction of portal venous (PV) blood flow has been described in animal models of intra-abdominal hypertension, reports on compensatory changes in hepatic arterial (HA) flow, known as the hepatic arterial buffer response are controversial. Materials and Methods: Pneumoperitoneum with helium was induced in 13 piglets. Hemodynamic measurements and pathological assessment were conducted at baseline and during the three subsequent phases: Phase A: 45 minutes with a stable intraabdominal pressure of 25 mmHg; phase B: 45 minutes with a stable intra-abdominal pressure of 40 mmHg; and phase C during which the abdomen was re-explored and reperfusion of the liver was allowed to take place. Results: Phase B pressure was significantly greater than phase A pressure in both the PV and the inferior vena cava, demonstrating a positive association between escalating intra-abdominal hypertension and the pressure in these two vessels (all p

Background: Varying definitions of resection margin clearance are currently employed among patients with colorectal cancer liver metastases (CRLM). Specifically, a microscopically positive margin (R1) has alternatively been equated with an involved margin (margin width = 0 mm) or a margin width < 1 mm. Consequently, patients with a margin width of 0–1 mm (sub-mm) are inconsistently classified in either the R0 or R1 categories, thus obscuring the prognostic implications of sub-mm margins. Methods: Six hundred thirty-three patients who underwent resection of CRLM were identified. Both R1 definitions were alternatively employed and multivariable analysis was used to determine the predictive power of each definition, as well as the prognostic implications of a sub-mm margin. Results: Five hundred thirty-nine (85.2%) patients had a margin width ≥ 1 mm, 42 had a sub-mm margin width, and 52 had an involved margin (0 mm). A margin width ≥ 1 mm was associated with improved survival vs. a sub-mm margin (65 vs. 36 months; P = 0.03) or an involved margin (65 vs. 33 months; P < 0.001). No significant difference in survival was detected between patients with involved vs. sub-mm margins (P = 0.31). A sub-mm margin and an involved margin were both independent predictors of worse OS (HR 1.66, 1.04–2.67; P = 0.04, and HR 2.14, 1.46–3.16; P < 0.001, respectively) in multivariable analysis. Importantly, after combining the two definitions, patients with either an involved margin or a sub-mm margin were associated with worse OS in multivariable analysis (HR 1.94, 1.41–2.65; P < 0.001). Conclusions: Patients with involved or sub-mm margins demonstrated a similar inferior OS vs. patients with a margin width > 1 mm. Consequently, a uniform definition of R1 as a margin width < 1 mm should perhaps be employed by future studies. © 2018, The Society for Surgery of the Alimentary Tract.

Background: The aim of this study was to review the current literature on the role of laparoscopic adrenalectomy (LA) in the treatment of primary adrenocortical carcinoma (ACC; European Network for the Study of Adrenal Tumors [ENSAT] I-III) in adults. Materials and Methods: Nonrandomized controlled trials published between January 1999 and February 2017 were identified by searching the Pubmed, EMBASE, Cochrane Library, and Google Scholar databases. Primary and secondary endpoints included surgical and pathological parameters (patients age, tumor size, ENSAT stage, type of surgical approach, and period of follow-up), surgical outcomes (operative time, estimated blood loss, length of hospital stay, conversion rate to laparotomy, R0 resection, and surgical margin's status), and oncological outcomes (rate of recurrence, disease-free survival [DFS], and overall survival [OS] rates). Results: A total of 13 studies encompassing data on 1171 patients were included in the review. Compared with open approach, LA demonstrated lower tumor size, shorter operative time, lower intraoperative blood loss, shorter postoperative hospital stay, and equivalent local recurrence rates. No significant differences were observed between groups treated with an open or laparoscopic approach for the following criteria: R0 surgical resection status, tumor overall recurrence, and postoperative DFS and OS rates. Conclusions: LA appears to be equivalent to open method for localized/locally advanced primary ACC (ENSAT I-III) in terms of R0 resection rate, overall recurrence, DFS, and OS, therefore suggesting that the extent of surgery with adequate tumor resection is the predominant endpoint, rather than the surgical approach itself. Multicenter randomized controlled trials with long follow-up time periods exploring the long-term oncological outcomes are required to determine the benefits of the laparoscopic over the open approach in adrenocortical carcinoma. © Copyright 2018, Mary Ann Liebert, Inc. 2018.

The robotic system has emerged as a new minimally invasive technology with promising results. We sought to systematically review the available literature on the safety and the oncologic outcomes of robotic liver surgery. A systematic review was conducted using Medline (PubMed), Embase and Cochrane library through November 12th, 2017. A robotic approach may be a safe and feasible surgical option for minor and major liver resections. © 2018 Wiley Periodicals, Inc.

Ruptured hepatocellular (rHCC) is a rare but life-threatening presentation that often requires acute intervention. In this systematic review we identified 67 eligible studies reporting on 4941 patients with rHCC. Here we present the treatment approaches for the management of rHCC both in the acute setting with regards to management of hemorrhage, as well long-term with regards to oncological treatment. © 2017 Wiley Periodicals, Inc.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has recently emerged as a treatment choice for patients with colorectal liver metastases (CLM) and inadequate future liver remnant (FLR). The aim of this study was to define the results of ALPPS compared with two-stage hepatectomy (TSH) for patients with CLM. Materials and methods: A meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Identification of eligible studies was performed using three distinct databases through February 2017; Medline, ClinicalTrials.gov and Cochrane library—Cochrane Central Register of Controlled Trials using a syntax including medical subject headings terms “portal vein ligation,” “PVE,” “staged hepatectomy,” “staged liver resection,” “liver resection,” “two-stage hepatectomy,” “TSH,” “in situ liver transection with portal vein ligation,” “associating liver partition and portal vein ligation for staged hepatectomy” and “ALPPS”. Results: Among the 634 records identified, 9 studies comparing ALPPS with TSH met the inclusion criteria. These studies included 657 patients with unresectable CLM (ALPPS, n = 186 vs TSH, n = 471). There was no difference in final postoperative FLR between ALPPS versus TSH (mean difference: 31.72, 95% CI: −27.33 to 90.77, p = 0.29). The kinetic growth rate was faster with the ALPPS versus TSH (mean difference 19.07 ml/day, 95% CI 8.12–30.02, p = 0.0006). TSH had a lower overall and major morbidity versus ALPPS (overall morbidity: RR: 1.39, 95% CI: 1.07–1.8, p = 0.01; I2: 58%, p = 0.01; major morbidity: RR: 1.57, 95% CI: 1.18–2.08, p = 0.002; I2: 0%, p = 0.44). Overall survival was comparable following ALPPS versus TSH. Conclusion: While ALPPS may be a suitable approach for patients, the higher morbidity and mortality should be considered when determining the operative approach for patients with extensive CLM. © 2017, Société Internationale de Chirurgie.

Objective: The relative benefit of anatomic resection (AR) versus non-anatomic resection (NAR) of HCC remains poorly defined. We sought to evaluate the available evidence on oncologic outcomes, as well as the clinical efficacy and safety of AR versus NAR performed as the primary treatment for HCC patients. Material and methods: A systematic review and meta-analysis was conducted using Medline, ClinicalTrials.gov and Cochrane library through April 15th, 2017. Only clinical studies comparing AR versus NAR were deemed eligible. Results: A total of 43 studies were considered eligible (total 12,429 patients: AR, n = 6839 (55%) versus NAR, n = 5590 (45%)). Blood loss was higher among patients undergoing AR (mean difference: +229.74 ml, 95% CI: 97.09–362.38, p = 0.0007), whereas resection margin was slightly wider following AR versus NAR (mean difference: +0.29 cm, 95% CI: 0.15–0.44, p < 0.0001). No difference was noted for perioperative complications (RR: 0.95, 95% CI: 0.81–1.11, p = 0.49) and perioperative mortality (RR: 0.91, 95% CI: 0.43–1.95, p = 0.82). AR was associated with a disease-free survival (DFS) benefit at 1- (HR: 0.79, 95% CI: 0.68–0.92, p = 0.002), 3- (HR: 0.87, 95% CI: 0.78–0.95, p = 0.004) and 5-years (HR: 0.87, 95% CI: 0.82–0.93, p < 0.0001). AR also was associated with a decreased risk of death at 5-years (HR: 0.88, 95% CI: 0.79–0.97, p = 0.01). Conclusion: Despite the high heterogeneity among studies, the data demonstrated that AR had comparable perioperative morbidity and mortality versus NAR. AR seemed to offer an advantage versus NAR in terms of DFS and OS among patients undergoing resection of HCC – especially among patients without cirrhosis. Thus, AR should be considered the preferred surgical option for patients with HCC when feasible. © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology

Objective: To examine the impact of surgical margin width on survival following R0 hepatic resection for colorectal metastases (CRLM). Summary of Background Data: Although negative resection margin is considered of paramount importance for the prognosis of patients with colorectal liver metastases, optimal resection margin width remains controversial. Methods: Eligible studies examining the association between margin status after R0 hepatic resection for CRLM and survival, including overall survival (OS) and disease-free survival (DFS) were sought using the Medline, Cochrane, and EMBASE databases. Random-effects models were used for the calculation of pooled relative risks (RRs) with their 95% confidence intervals (95% CIs). Results: Thirty-four studies were deemed eligible for inclusion representing a cohort of 11,147 hepatic resections. Wider resection margin (>1 vs 1cm resection margin at 3, 5, and 10 years. Interestingly, >1mm (vs 1mm margin is associated with better prognosis than a submillimeter margin, achieving a margin >1cm may result in even better oncologic outcomes and should be considered if possible. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Background: Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (CRLM). Following resection, up to two-thirds of patients will develop recurrence within 5-years. Genetic mutation analysis of CRLM, especially KRAS status, has been proposed as a means to guide treatment, as well as identifying patients who can derive the most survival benefit from hepatic resection. Methods: A systematic review of the literature was conducted the PubMed, Embase and Cochrane library through February 8th, 2018. The following algorithm was applied: “(colorectal OR rectal OR colon OR colonic) AND (liver OR hepatic) AND (metastasis OR metastases) AND (gene OR mutation OR KRAS OR BRAF OR SMAD4 OR RAS OR TP53 OR P53 OR APC OR PI3K OR MSI OR EGFR OR MACC1 OR microsatellite).” Results: From the 2404 records retrieved, 78 studies were finally deemed eligible; 47 studies reported mutational data on patients with resectable CRLM, whereas 31 studies reported on patients with unresectable CRLM. Mutational analyses were mostly performed on the CRLM specimen rather than the primary CRC. The vast majority of studies reported on the KRAS mutational status (88.5%, n = 69/78). Prevalence of KRAS mutations ranged from 25% to 52%. Most studies reported that RAS mutation was a negative prognostic factor for overall (OS) (n = 24) and recurrence-free (RFS) (n = 9) survival; a few reports noted no effect of RAS mutational status on OS (n = 4) or RFS (n = 6). Twelve studies reported on BRAF mutations with a prevalence of BRAF mutation ranging from 0 to 9.1% in resected CRLM specimens. BRAF mutation was strongly associated with a worse prognosis. TP53 and PIK3CA gene mutations did not affect long-term outcomes. Conclusions: The biological status of each tumor provides the basis for individualized cancer therapeutics. Data on the mutational status on CRLM should be a part of multidisciplinary discussions to help inform the therapeutic approach, type of chemotherapy, as well as timing and approach of surgical resection. © 2018 Elsevier Ltd

Hepatocellular carcinoma (HCC) is a major contributor to the global cancer burden. Given the current limited options to treat advanced HCC, understanding the molecular basis of HCC carcinogenesis and pinpointing druggable targets will be important to identify future HCC treatments. Epigenetic modification by inhibiting histone deacetylases (HDAC) is an emerging approach with promising results in cancer treatment. In the preclinical setting, HDAC inhibitors such as valproic acid sodium, panobinostat, vorinostat, trichostatin A, sodium butyrate, belinostat and romidepsin have demonstrated antitumor efficacy via activation of classic and alternative cell death molecular cascades. Combination regimens with the tyrosine kinase inhibitor sorafenib, poly(ADP-ribose) polymerases, proteasome and mammalian target of rapamycin inhibitors have shown promise. Phase I/II clinical studies with belinostat monotherapy and the combination of resminostat with sorafenib have suggested response and survival benefits. The safety profile was favorable with manageable adverse events and a low incidence of grade 3/4 toxicity. We herein review the role and potential therapeutic impact of epigenetic regulation through histone deacetylase inhibitors (HDACi) in the treatment of HCC. © 2018 Elsevier Ltd

Recent advances in surgical techniques have broadened the indications of surgical management of liver malignancies. Intraoperative bleeding is one of the known predictors of postoperative outcomes following liver surgery, signifying the importance of vascular control during liver resection. Furthermore, preservation of future liver remnant plays a critical role in prevention of post-hepatectomy liver failure as one of the main causes of postoperative morbidity and mortality. Glissonian approach liver resection offers an effective method for vascular inflow control while protecting future liver remnant from ischemia-reperfusion injury. Several studies have demonstrated the feasibility of Glisson’s pedicle resection technique in modern liver surgery with an acceptable safety profile. Moreover, with increasing popularity of minimally invasive surgery, laparoscopic liver resection via Glissonian approach has been shown to be superior to standard laparoscopic hepatectomy. Herein, we systematically review the role of Glissonian approach hepatectomy in current practice of liver surgery, highlighting its advantages and disadvantaged over other methods of vascular control. © 2017, The Society for Surgery of the Alimentary Tract.

Colorectal liver metastases (CRLM) present an important clinical challenge in both surgical and medical oncology. Despite improvements in management, survival among patients undergoing resection of CRLM is still very variable and there is a paucity of clinical trial data and reliable biomarkers that could guide prognostic forecasts, treatment selection, and follow-up. Fortunately, recent advances in molecular biology and tumor sequencing have identified a number of critical genetic loci and proliferation markers that may hold the key to understanding the biologic behavior of CRLM; specifically, mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki-67, and the presence of microsatellite instability appear to have a decisive impact on prognosis and response to treatment in patients with CRLM. While the applicability of genetic biomarkers in everyday clinical practice remains conditional on the development of inexpensive bedside sequencing, targeted therapies, and the conduct of appropriate clinical trials, the promise of personalized treatment may be closer to realization than ever before. © 2018, The Society for Surgery of the Alimentary Tract.

Background: Margin status with resection of colorectal liver metastasis (CRLM) was an important prognostic factor in the years before the introduction of biological chemotherapy. This study examined outcomes following CRLM resection in patients who received neoadjuvant chemotherapy with or without the monoclonal antiangiogenic antibody bevacizumab. Methods: Patients who underwent surgery for CRLM at the Johns Hopkins Hospital between 2000 and 2015 were identified from an institutional database. Data regarding surgical margin status, preoperative bevacizumab administration and overall survival (OS) were assessed using multivariable analyses. Results: Of 630 patients who underwent CRLM resection, 417 (66·2 per cent) received neoadjuvant chemotherapy with (214, 34·0 per cent) or without (203, 32·2 per cent) bevacizumab. The remaining 213 (33·8 per cent) did not receive neoadjuvant chemotherapy. Univariable analysis found that positive margins were associated with worse 5-year OS than R0 resection (36·2 versus 54·9 per cent; P = 0·005). After dichotomizing by the receipt of preoperative bevacizumab versus chemotherapy alone, the prognostic value of pathological margin persisted among patients who did not receive preoperative bevacizumab (5-year OS 53·0 versus 37 per cent after R0 versus R1 resection; P = 0·010). OS was not significantly associated with margin status in bevacizumab-treated patients (5-year OS 46·8 versus 33 per cent after R0 versus R1 resection; P = 0·081), in whom 5-year survival was slightly worse (presumably reflecting more advanced disease) than among patients treated with cytotoxic agents alone. Pathological margin status was not significantly associated with 5-year OS in patients with a complete or near-complete response to chemotherapy and bevacizumab (43 versus 30 per cent after R0 versus R1 resection; P = 0·917), but this may be due to a type II error. Conclusion: The impact of margin status varied according to the receipt of bevacizumab. Bevacizumab may have a role to play in improving outcomes among patients with more advanced disease. © 2017 BJS Society Ltd Published by John Wiley & Sons Ltd

Background: The optimal tumor-free margin width remains controversial and may be inappropriate to investigate without considering differences in the underlying tumor biology. Methods: R1 resection was defined as margin clearance less than 1 mm. R0 resection was further divided into 3 groups: 1–4, 5–9, and ≥10 mm. The impact of margin width on overall survival (OS) relative to KRAS status [wild type (wtKRAS) vs. mutated (mutKRAS)] was assessed. Results: A total of 411 patients met inclusion criteria. Median patient age was 58 years (interquartile range, 49.7–66.7); most patients were male (n = 250; 60.8 %). With a median follow-up of 28.3 months, median and 5-year OS were 69.8 months and 55.1 %. Among patients with wtKRAS tumors, although margin clearance of 1–4 mm or more was associated with improved OS compared to R1 (all P 0.05). In contrast, among patients with mutKRAS tumors, all three groups of margin clearance (1–4, 5–9, and ≥10 mm) fared no better in terms of 5-year survival compared to R1 resection (all P > 0.05). Conclusions: While a 1–4 mm margin clearance in patients with wtKRAS tumors was associated with improved survival, wider resection width did not confer an additional survival benefit. In contrast, margin status—including a 1 cm margin—did not improve survival among patients with mutKRAS tumors. © 2016, Society of Surgical Oncology.

Background and Objectives: While preoperative treatment is frequently administered to CRLM patients, the impact of chemotherapy, with or without bevacizumab, on liver regeneration remains controversial. Methods: The early and late regeneration indexes were defined as the relative increase in liver volume (RLV) within 2 and 9 months from surgery. Regeneration rates of the preoperative treatment groups were compared. Results: Preoperative chemotherapy details and volumetric data were available for 185 patients; 78 (42.2%) received preoperative chemotherapy with bevacizumab (Bev+), 46 (24.8%) received chemotherapy only (Bev−), and 61 (33%) received no chemotherapy. Patients in the Bev+ and Bev− groups received similar chemotherapy cycles (4 [3-6] vs 4 [4-6]; P = 0.499). Despite the comparable clinicopathological characteristics and Resected Volume/Total Liver Volume (TLV) at surgery (P = 0.944) of both groups, Bev+ group had higher early and late regeneration (17.2% vs 4.3%; P = 0.035 and 14.0% vs 9.4%; P = 0.091, respectively). Of note, early and late regeneration rates (3.7% and 10.9% vs 6.6% and 5.5%, respectively) were comparable between the no chemotherapy and Bev− groups (all P > 0.05). In multivariable analysis —adjusted for gender, age, portal vein embolization, preoperative chemotherapy, resected liver volume, tumor number, postoperative chemotherapy, fibrosis, steatosis— bevacizumab independently predicted early liver regeneration (P = 0.019). Conclusion: Our findings suggest that preoperative bevacizumab administered along with chemotherapy was associated with enhanced volumetric restoration. Interestingly, this effect was more pronounced among patients who received oxaliplatin-based regimens and bevacizumab compared to those treated with irinotecan-based regimens and bevacizumab. © 2017 Wiley Periodicals, Inc.

Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and –L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications. © 2017 Elsevier Ltd

Background: Solid pseudopapillary tumors (SPTs) of the pancreas are a rare occurrence, not exceeding 1-2% of all exocrine pancreatic tumors. SPT was first described in 1959 as "papillary tumor of the pancreas, benign or malignant" and affects mainly young women, in their second or third decade of age. These tumors are of low malignant potential, unclear pathogenesis, grow gradually and become considerably large before causing symptoms. A typical clinical presentation is often described by affected patients and, in some cases, an SPT is an incidental finding during the time the patient undergoes medical imaging studies for other health issues. SPT is frequently located at the head or tail of the pancreas. Metastases are rare but, when present, affect predominantly the liver. Patients and Methods: We report a series of five SPT cases in female patients 13-47 years old, presenting with almost identical symptoms of upper abdominal discomfort and non-tender palpable mass. Two out of five patients also reported vomiting, nausea and poor appetite as co-existing non-diagnostic symptoms. Only one patient presented without any symptoms. Tumor location and dimensions varied. One patient underwent a pancreatoduodenectomy (Whipple's procedure), while the remaining patients underwent distal pancreatectomy with concomitant splenectomy. Results: Perioperative morbidity and mortality was zero. All five patients are disease-free at a follow-up from 3 months to 13 years. Histopathology reports supported the diagnosis of SPT and no metastatic disease was present in any of the patients. Conclusion: The overall prognosis of SPT of the pancreas is excellent due to its favorable biological features, even in the presence of distal metastasis. Although surgical resection is often curative, a close follow-up is advised in order to diagnose a possible local recurrence or distal metastasis and choose the proper therapeutic option for the patients.

The use of liver transplantation (LT) for liver metastases attempted in the early 1990's was associated with poor perioperative outcomes and unacceptably low overall survival. Recently, there has been renewed interest in LT as a treatment option for colorectal liver metastases (CLM) in countries where organ supply is high. To date, no meticulous analysis about the efficacy, safety and outcomes of LT in CLM patients has been published. We present the first systematic review on the subject. © 2017 Wiley Periodicals, Inc.

Introduction: Colorectal liver metastases develop in 50% of patients diagnosed with colorectal cancer. Surgical resection for colorectal liver metastasis typically involves either anatomical resection (AR) or parenchymal-sparing hepatectomy (PSH). The objective of the current study was to analyze data on parenchymal versus non-parenchymal-sparing hepatic resections for CLM. Methods: A systematic review of the literature regarding parenchymal-sparing hepatectomy was performed. MEDLINE/PubMed, Cochrane, and EMBASE databases were searched for publications containing the following medical subject headings (MeSH): “Colorectal Neoplasms,” “Neoplasm Metastasis,” “Liver Neoplasms” and “Hepatectomy”. Besides, the following keywords were used to complete the literature search: “Hepatectomy,” “liver resection,” “hepatic resection,” “anatomic/anatomical,” “nonanatomic/ nonanatomical,” “major,” “minor,” “limited,” “wedge,” “CRLM/CLM,” and “colorectal liver metastasis.” Data was reviewed, aggregated, and analyzed. Results: Two thousand five hundred five patients included in 12 studies who underwent either PSH (n = 1087 patients) or AR (n = 1418 patients) were identified. Most patients had a primary tumor that originated in the colon (PSH 52.2–74.4% vs. AR 53.9–74.3%) (P = 0.289). The majority of studies included a large subset of patients with only a solitary tumor with a reported median tumor number of 1–2 regardless of whether the patient underwent PSH or AR. Median EBL was no different among patients undergoing PSH (100–896 mL) versus AR (200–1489 mL) for CLM (P = 0.248). There was no difference in median length-of-stay following PSH (6–17 days) versus AR (7–15 days) (P = 0.747). While there was considerable inter-study variability regarding margin status, there was no difference in the incidence of R0 resection among patients undergoing PSH (66.7–100%) versus AR (71.6–98.6%) (P = 0.58). When assessing overall survival, there was no difference whether resection of CLM was performed with PSH (5 years OS: mean 44.7%, range 29–62%) or AR (5 years OS: mean 44.6%, range 27–64%) (P = 0.97). Conclusion: PSH had a comparable safety and efficacy profile compared with AR and did not compromise oncologic outcomes. PSH should be considered an appropriate surgical approach to treatment for patients with CLM that facilitates preservation of hepatic parenchyma. © 2017, The Society for Surgery of the Alimentary Tract.

Background Liver transplantation to treat neuroendocrine tumors, especially in the setting of diffuse liver involvement not amenable to operative resection remains controversial. We sought to perform a systematic review of the current literature to summarize data on patients undergoing liver transplantation with neuroendocrine tumors liver metastases as the indication. Methods A systematic review was conducted in accordance to the Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines. Eligible studies were identified using 3 distinct databases through March 2017: Medline (PubMed), ClinicalTrials.gov, and Cochrane library, Cochrane Central Register of Controlled Trials using a search algorithm: “(neuroendocrine or NET) and transplantation and liver.” Results From the 1,216 records retrieved, 64 studies were eligible. Overall, 4 studies presented data from registries, namely the European Liver Transplant Registry and the United Network for Organ Transplantation/Organ Procurement and Transplantation Network databases, 3 were multicenter studies. The largest cohort of data on patients undergoing liver transplantation for neuroendocrine tumors liver metastasis indication were from single center studies comprising a total of 279 patients. Pancreas was the primary tumor site for most patients followed by the ileum. Several studies reported that more than half of patients presented with synchronous disease (55.9% and 57.7%); in contrast, metachronous neuroendocrine tumors liver metastasis ranged from 17.7% to 38.7%. Overall, recurrence after liver transplantation ranged from 31.3% to 56.8%. Reported 1-, 3-, and 5-year overall survival was 89%, 69%, and 63%, respectively. Several prognostic factors associated with worse long-term survival including transplantation >50% liver tumor involvement, high Ki67, as well as a pancreatic neuroendocrine tumors versus gastrointestinal neuroendocrine tumors tumor location. Conclusion Liver transplantation may provide a survival benefit among patients with diffuse neuroendocrine tumors metastases to the liver. However, due to high recurrence rates, strict selection of patients is critical. Due to the scarcity of available grafts and the lack of level 1 evidence, the recommendations to endorse liver transplantation for extensive liver neuroendocrine tumors metastases warrants ongoing deliberations. © 2017 Elsevier Inc.

Postoperative adhesions remain one of the more challenging issues in surgical practice. Although peritoneal adhesions occur after every abdominal operation, the density, time interval to develop symptoms, and clinical presentation are highly variable with no predictable patterns. Numerous studies have investigated the pathophysiology of postoperative adhesions both in vitro and in vivo. Factors such as type and location of adhesions, as well as timing and recurrence of adhesive obstruction remain unpredictable and poorly understood. Although the majority of postoperative adhesions are clinically silent, the consequences of adhesion formation can represent a lifelong problem including chronic abdominal pain, recurrent intestinal obstruction requiring multiple hospitalizations, and infertility. Moreover, adhesive disease can become a chronic medical condition with significant morbidity and no effective therapy. Despite recent advances in surgical techniques, there is no reliable strategy to manage postoperative adhesions. We herein review the pathophysiology and clinical significance of postoperative adhesions while highlighting current techniques of prevention and treatment. © 2017, The Society for Surgery of the Alimentary Tract.

Introduction: There is limited evidence characterizing the impact of glycemic alterations on short-term outcomes among patients undergoing resection of colorectal liver metastases (CRLM). Methods: Hyperglycemia was defined as a glucose value >125 mg/dl according to WHO definition. The impact of early postoperative hyperglycemia on short-term postoperative outcomes was assessed. Results: The mean postoperative glucose value was 128 mg/dl; 30 (9.8 %) patients had normal fasting glucose (125 mg/dl). A postoperative complication occurred in 101 patients (morbidity, 33.1 %); among patients who experienced a complication, an infectious complication was most common (38.6 %). After controlling for clinical factors, patients with hyperglycemia had an increased risk of overall complications [odds ratio (OR) 4.11; 95 % confidence interval (CI) 1.96–8.62, P < 0.001]. This was the case for both patients with and without diabetes (P < 0.05). Patients with hyperglycemia on the day of surgery were also at an increased risk of infections [OR 9.17; 95 % CI 2.26–37.13, P = 0.002] and had a longer hospital stay (normal glucose, 4 days vs. glucose 100–125 mg/dl, 4 days vs. glucose >125 mg/dl, 5 days, P < 0.001). Conclusions: Early postoperative hyperglycemia was associated with adverse outcomes in patients with and without diabetes who underwent resection of CRLM. Perioperative glucose evaluation may be an important quality target. © 2016, The Society for Surgery of the Alimentary Tract.

Exosomes are nanovesicles that may play a role in intercellular communication by acting as carriers of functional contents such as proteins, lipids, RNA molecules and circulating DNA from donor to recipient cells. In addition, exosomes may play a potential role in immunosurveillance and tumor pathogenesis and progression. Recently, research has increasingly focused on the role of exosomes in hepatocellular carcinoma (HCC), the most common primary liver malignancy. We herein review data on emerging experimental and clinical studies focused on the role of exosomes in the pathogenesis, diagnosis, progression and chemotherapy response of patients with HCC. Beyond their diagnostic value in HCC, exosomes are involved in different mechanisms of HCC tumor pathogenesis and progression including angiogenesis and immune escape. Moreover, exosomes have been demonstrated to change the tumor microenvironment to a less tolerogenic state, favoring immune response and tumor suppression. These results underline a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. Future studies will need to further elucidate the exact role and reliability of exosomes as screening, diagnostic and treatment targets in patients with HCC. © 2017 Elsevier Ltd

Colorectal cancer is one of the leading causes of mortality in the Western world. Half of patients with colorectal cancer will develop liver-metastatic (CLM) disease, with fewer than 30% having surgically resectable disease at diagnosis. It is well established in the literature that major hepatectomy offers a high rate of R0 resection, however, with concommitant increased rates of mortality and morbidity. Emerging literature during the past two decades has demonstrated the potential superiority of parenchymal-sparing hepatectomy (PSH) in treating CLM disease in terms of oncological outcomes, survival and re-operation in cases of recurrence (salvageability). To date, no data regarding the evaluation of quality of life and cost after PSH have been published. PSH seems to be correlated with less mortality and morbidity, which can be translated in lower re-admission rates, better quality of life and, therefore, reduced relevant cost. Prospective studies and clinical trials evaluating the multiple beneficial role of a PSH surgical strategy in CLM disease are mandatory to support or reject the emerging belief that PSH could be the gold standard of treatment of CLM disease.

Background/Aims: The impact of tumor biology on prognosis in patients with colorectal liver metastasis (CRLM) has been the topic of intense research. Specifically, the presence of BRAF mutations has been recently associated with adverse long-term outcomes. We examined the existing literature on the prognostic implications of BRAF mutations in patients with CRLM. Materials and Methods: A structured review of the literature was performed between 5/1/2016 and 6/1/2016 using the PubMed database. Original research articles published between 1/1/2010 and 4/01/2016 were considered eligible. The primary end-points were overall survival (OS)/disease-specific survival (DSS) and recurrence-free survival (RFS) among patients with BRAF mutated CRLM who underwent resection. Results: Eight studies were included. All studies reported on OS/DSS, while 6 reported on RFS. BRAF mutant status was a strong independent predictor of both worse OS/DSS and RFS in 7 and 4 studies, respectively. Conclusion: BRAF-mutant lesions are consistently associated with poor prognosis. Consequently, the indications of CRLM resection in this patient group should be reconsidered.

Background and Objectives: The prognostic impact of primary colorectal cancer (CRC) location following resection of colorectal liver metastasis (CRLM) remains largely unknown. We sought to characterize the prognostic implications of primary tumor location among patients who underwent curative-intent hepatectomy for CRLM. Methods: Tumors of the cecum, ascending, and transverse colon were defined as right-sided; tumors of the sigmoid flexure, descending, and sigmoid colon were defined as left-sided. Clinicopathologic and long-term survival data were collected and assessed using univariable and multivariable analyses. Results: About 475 patients who underwent CRLM resection at a single institution were included; most patients had left-sided tumors (n = 284). Median and 5-year RFS was 20.2 months and 28.0%, respectively. Patients who had a left-sided primary tumor had a shorter RFS compared with patients who had a right-sided tumor (P = 0.01). Although site of and time to recurrence did not differ between the two groups (P > 0.05), patients with right-sided primary tumors were more likely to recur with advanced disease (i.e., ≥4 recurrent lesions) (P < 0.01). In turn, patients with right-sided tumors had both worse OS (P = 0.03) and worse survival after recurrence (P = 0.01). Conclusion: While patients with right-sided tumors experienced longer RFS, when these patients did recur following CRLM resection, disease extent was more advanced. In turn, OS following recurrence was shorter among patients with right-sided CRC. J. Surg. Oncol. 2016;114:803–809. © 2016 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal neoplastic process, largely due to the presence of disseminated disease at presentation. As such, evidence-based management of metastatic disease is integral to patient care in such circumstances. This review aimed to summarize the current state of knowledge regarding the potential effectiveness of liver metastasectomy in the setting of PDAC. Methods: A structured review of the literature was performed from April to May 2016, using the PubMed database. Relevant original research articles and systematic reviews/meta-analyses published between 1990 and 2015 were considered eligible. The primary endpoint was overall survival in patients undergoing resection for PDAC and liver metastasectomy. Studies reporting on fewer than 10 patients were excluded. Results: Ultimately, eight studies met our inclusion criteria. Their results suggest that hepatic metastasectomy for PDAC is a safe procedure, with a potential survival benefit for carefully selected patients, particularly those with metachronous metastases. Nonetheless, small sample sizes and inconsistent use of appropriate controls preclude generalization of these findings. Conclusion: Multi-institutional prospective studies are required to fully delineate the potential therapeutic utility and operative indications of liver metastasectomy in the setting of modern interdisciplinary management of PDAC. © 2016 Royal Australasian College of Surgeons

Introduction: The interplay of tumor biology and surgical margin status after resection for colorectal liver metastasis (CRLM) remains controversial. Consequently, we sought to determine the impact of surgical margin status on overall survival (OS) stratified by KRAS mutational status. Materials and Methods: Four hundred eighty-five patients with known KRAS mutational status were identified. Clinicopathologic and long-term survival data were collected and assessed. Results: On pathology, most patients (n = 380; 78.3 %) had an R0 margin, while 105 (21.7 %) had an R1. Roughly two thirds of tumors were KRAS wild type (wtKRAS) (n = 307, 63.3 %), while 36.7 % (n = 178) had KRAS mutations (mutKRAS). Median and 5-year OS of the entire cohort was 65.8 months and 53.8 %, respectively. An R1 resection was associated with worse 5-year OS compared with R0 (42.4 % vs. 57.1 %; hazard ratio (HR) 1.82, 95 % CI 1.28–2.57; P = 0.001). After controlling for KRAS status, the survival benefit associated with an R0 resection persisted only among patients with wtKRAS tumors (HR 2.16, 95 % CI 1.42–3.30; P < 0.001). In contrast, surgical margin had no impact on OS among patients with mutKRAS tumors (5-year OS R0, 40.7 % vs. R1, 46.7 %; HR 1.34, 95 % CI 0.73–2.48; P = 0.348). Conclusion: The impact of margin status differed by KRAS mutation status. An R0 margin only provided a survival benefit to patients with wtKRAS tumors. Tumor biology and not surgical technique determined prognosis. © 2016, The Society for Surgery of the Alimentary Tract.

Background: The Italian Liver Cancer (ITA.LI.CA) prognostic system for patients with hepatocellular carcinoma (HCC) has recently been proposed and validated. We sought to explore the relationship among the ITA.LI.CA prognostic variables (ie tumour stage, functional score based on performance status and Child-Pugh score, and alpha-fetoprotein), treatment selection and survival outcome in HCC patients. Patients and Methods: We analysed 4,867 consecutive HCC patients undergoing six main treatment strategies (liver transplantation, LT; liver resection, LR; ablation, ABL; intra-arterial therapy, IAT; Sorafenib, SOR; and best supportive care, BSC) and enrolled during 2002-2015 in a multicenter Italian database. In order to control pretreatment imbalances in observed variables, a machine learning methodology was used and inverse probability of treatment weights (IPTW) was calculated. An IPTW-adjusted multivariate survival model that included ITA.LI.CA prognostic variables, treatment period and treatment strategy was then developed. The survival benefit of HCC treatments was described as a hazard ratio (95% confidence interval), using BSC as a reference value and as predicted median survival. Results: After the IPTW, the six treatment groups became well balanced for most baseline characteristics. In the IPTW-adjusted multivariate survival model, treatment strategy was found to be the strongest survival predictor, irrespective of ITA.LI.CA prognostic variables and treatment period. The survival benefit of different therapies over BSC was: LT=0.19 (0.18-0.20); RES=0.40 (0.37-0.42); ABL 0.42 (0.40-0.44); IAT=0.58 (0.55-0.61); SOR=0.92 (0.87-0.97). This multivariate model was then used to predict median survival for each therapy within each ITA.LI.CA stage. Conclusion: The concept of therapeutic hierarchy was established within each ITA.LI.CA stage.