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Cyclic AMP is the intracellular second messenger for a variety of immunoregulatory inflammatory mediators such as prostaglandin E2, adenosine and histamine that signal to effector T cells from monocytes, macrophages and regulatory T cells. Protein kinase A (PKA) type I localizes to lipid rafts in effector T cells during T cell activation and directly modulates proximal signal events including phosphorylation of C-terminal Src kinase (Csk), which initiates a negative signal pathway that fine-tunes the T cell activation process. The PKA-Csk immunoregulatory pathway is scaffolded by the A kinase anchoring protein ezrin, the Csk binding protein phosphoprotein associated with glycosphingolipid-enriched membrane microdomains and the linker protein ezrin/radixin/moesin binding protein of 50 kDa. This pathway is hyperactivated in chronic infections with an inflammatory component such as HIV, other immunodeficiencies and around solid tumours as a consequence of local inflammation leading to inhibition of anti-tumour immunity. LINKED ARTICLES This article is part of a themed section on Novel cAMP Signalling Paradigms. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.166.issue-2. [ABSTRACT FROM AUTHOR]

Objective: To study outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) in patients also treated for colorectal liver metastases (CLM)., Background: Colorectal cancer (CRC) frequently metastasizes to the liver and peritoneum and is associated with a poor prognosis. In selected patients, a benefit in overall survival (OS) was shown for both peritoneal metastases (PM-CRC) offered CRS-HIPEC, and CLM treated with surgical resection. However, the presence of CLM was considered a relative contraindication to CRS-HIPEC, causing a paucity of outcome data in this patient group., Methods: Patients with PM-CRC having CRS-HIPEC at a single national center between 2007 and 2023, with additional intervention for CLM, were included (previous curative treatment for extraperitoneal and extrahepatic metastases was allowed). Three groups were defined: CLM before CRS-HIPEC (pre-CRS-HIPEC), CLM resected simultaneously with CRS-HIPEC (sim-CRS-HIPEC), and CLM after CRS-HIPEC (post-CRS-HIPEC), aiming to retrospectively analyze outcomes., Results: Fifty-seven patients were included and classified as: pre-CRS-HIPEC (n = 11), sim-CRS-HIPEC (n = 29), and post-CRS-HIPEC (n = 17). Median Peritoneal Cancer Index (PCI) was 8; 13 patients had severe complications (Clavien-Dindo ≥3), and no 90-day mortality. Median OS was 48 months after CRS-HIPEC. PCI was a predictor of OS (hazard ratio: 1.11, P < 0.001). We observed no difference in short or long-term outcomes between intervention groups., Discussion: This study demonstrated that patients with CLM having CRS-HIPEC had comparable OS to reports on CRS-HIPEC only, likely explained by a low PCI. Simultaneous CLM resection did not increase the risk of severe complications., Conclusions: In this national cohort, CRS-HIPEC and CLM intervention offers long-term survival, suggesting that this treatment may be offered to selected patients with PM-CRC and CLM., Competing Interests: S.Y. is funded by the Regional Health Authority in South-Eastern Norway (grant# 2020067). The remaining authors report no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Preoperative inflammatory markers were shown to be associated with prognosis following surgery for hepato-pancreato-biliary cancer. Yet little evidence exists about their role in patients with colorectal liver metastases (CRLM). This study aimed to examine the association between selected preoperative inflammatory markers and outcomes of liver resection for CRLM., Methods: Data from the Norwegian National Registry for Gastrointestinal Surgery (NORGAST) was used to capture all liver resections performed in Norway within the study period (November 2015-April 2021). Preoperative inflammatory markers were Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS) and C-reactive protein to albumin ratio (CAR). The impact of these on postoperative outcomes, as well as on survival were studied., Results: Liver resections for CRLM were performed in 1442 patients. Preoperative GPS ≥ 1 and mGPS ≥ 1 were present in 170 (11.8%) and 147 (10.2%) patients, respectively. Both were associated with severe complications but became non-significant in the multivariable model. GPS, mGPS, CAR were significant predictors for overall survival in the univariable analysis, but only CAR remained such in the multivariable model. When stratified by the type of surgical approach, CAR was a significant predictor for survival after open but not laparoscopic liver resections., Conclusions: GPS, mGPS and CAR have no impact on severe complications after liver resection for CRLM. CAR outperforms GPS and mGPS in predicting overall survival in these patients, especially following open resections. The prognostic significance of CAR in CRLM should be tested against other clinical and pathology parameters relevant for prognosis., (© 2023. The Author(s).)

Background: High-quality surgery plays a central role in the delivery of excellent oncologic care. Benchmark values indicate the best achievable results. We aimed to define benchmark values for gallbladder cancer (GBC) surgery across an international population., Patients and Methods: This study included consecutive patients with GBC who underwent curative-intent surgery during 2000-2021 at 13 centers, across seven countries and four continents. Patients operated on at high-volume centers without the need for vascular and/or bile duct reconstruction and without significant comorbidities were chosen as the benchmark group., Results: Of 906 patients who underwent curative-intent GBC surgery during the study period, 245 (27%) were included in the benchmark group. These were predominantly women (n = 174, 71%) and had a median age of 64 years (interquartile range 57-70 years). In the benchmark group, 50 patients (20%) experienced complications within 90 days after surgery, with 20 patients (8%) developing major complications (Clavien-Dindo grade ≥ IIIa). Median length of postoperative hospital stay was 6 days (interquartile range 4-8 days). Benchmark values included ≥ 4 lymph nodes retrieved, estimated intraoperative blood loss ≤ 350 mL, perioperative blood transfusion rate ≤ 13%, operative time ≤ 332 min, length of hospital stay ≤ 8 days, R1 margin rate ≤ 7%, complication rate ≤ 22%, and rate of grade ≥ IIIa complications ≤ 11%., Conclusions: Surgery for GBC remains associated with significant morbidity. The availability of benchmark values may facilitate comparisons in future analyses among GBC patients, GBC surgical approaches, and centers performing GBC surgery., (© 2023. Society of Surgical Oncology.)

Background: The role of laparoscopy in the treatment of intrahepatic cholangiocarcinoma (ICC) remains unclear. This multicenter study examined the outcomes of laparoscopic liver resection for ICC., Methods: Patients with ICC who had undergone laparoscopic or open liver resection between 2012 and 2019 at four European expert centers were included in the study. Laparoscopic and open approaches were compared in terms of surgical and oncological outcomes. Propensity score matching was used for minimizing treatment selection bias and adjusting for confounders (age, ASA grade, tumor size, location, number of tumors and underlying liver disease)., Results: Of 136 patients, 50 (36.7%) underwent laparoscopic resection, whereas 86 (63.3%) had open surgery. Median tumor size was larger (73.6 vs 55.1 mm, p  = 0.01) and the incidence of bi-lobar tumors was higher (36.6 vs 6%, p  < 0.01) in patients undergoing open surgery. After propensity score matching baseline characteristics were comparable although open surgery was associated with a larger fraction of major liver resections (74 vs 38%, p  < 0.01), lymphadenectomy (60 vs 20%, p  < 0.01) and longer operative time (294 vs 209 min, p  < 0.01). Tumor characteristics were similar. Laparoscopic resection resulted in less complications (30 vs 52%, p  = 0.025), fewer reoperations (4 vs 16%, p  = 0.046) and shorter hospital stay (5 vs 8 days, p  < 0.01). No differences were found in terms of recurrence, recurrence-free and overall survival., Conclusion: Laparoscopic resection seems to be associated with improved short-term and with similar long-term outcomes compared with open surgery in patients with ICC. However, possible selection criteria for laparoscopic surgery are yet to be defined.

Background: Gene expression-based subtyping has the potential to form a new paradigm for stratified treatment of colorectal cancer. However, current frameworks are based on the transcriptomic profiles of primary tumors, and metastatic heterogeneity is a challenge. Here we aimed to develop a de novo metastasis-oriented framework., Methods: In total, 829 transcriptomic profiles from patients with colorectal cancer were analyzed, including primary tumors, liver metastases, and non-malignant liver samples. High-resolution microarray gene expression profiling was performed of 283 liver metastases from 171 patients treated by hepatic resection, including multiregional and/or multi-metastatic samples from each of 47 patients. A single randomly selected liver metastasis sample from each patient was used for unsupervised subtype discovery by nonnegative matrix factorization, and a random forest prediction model was trained to classify multi-metastatic samples, as well as liver metastases from two independent series of 308 additional patients., Results: Initial comparisons with non-malignant liver samples and primary colorectal tumors showed a highly variable degree of influence from the liver microenvironment in metastases, which contributed to inter-metastatic transcriptomic heterogeneity, but did not define subtype distinctions. The de novo liver metastasis subtype (LMS) framework recapitulated the main distinction between epithelial-like and mesenchymal-like tumors, with a strong immune and stromal component only in the latter. We also identified biologically distinct epithelial-like subtypes originating from different progenitor cell types. LMS1 metastases had several transcriptomic features of cancer aggressiveness, including secretory progenitor cell origin, oncogenic addictions, and microsatellite instability in a microsatellite stable background, as well as frequent RAS/TP53 co-mutations. The poor-prognostic association of LMS1 metastases was independent of mutation status, clinicopathological variables, and current subtyping frameworks (consensus molecular subtypes and colorectal cancer intrinsic subtypes). LMS1 was also the least heterogeneous subtype in comparisons of multiple metastases per patient, and tumor heterogeneity did not confound the prognostic value of LMS1., Conclusions: We report the first large study of multi-metastatic gene expression profiling of colorectal cancer. The new metastasis-oriented subtyping framework showed potential for clinically relevant transcriptomic classification in the context of metastatic heterogeneity, and an LMS1 mini-classifier was constructed to facilitate prognostic stratification and further clinical testing., (© 2021. The Author(s).)

Importance: Portal vein embolization (PVE) has been implemented in patients with extensive colorectal liver metastases to increase the number of patients able to undergo liver resection. Liver transplant could be an alternative in selected patients with extensive liver-only disease, and we have recently shown promising survival outcomes., Objective: To compare overall survival (OS) among patients with colorectal cancer and high liver metastasis tumor load who were treated with liver transplant or with PVE and liver resection., Design, Setting, and Participants: This comparative effectiveness research study assessed 50 patients with colorectal cancer liver metastases who were previously enrolled in liver transplant studies between November 2006 and August 2019 at Oslo University Hospital in Norway. Those patients were compared with a retrospective cohort of 53 patients in the Oslo University Hospital PVE database from March 2006 through November 2015 with similar selection criteria who underwent PVE and liver resection., Main Outcomes and Measures: The OS among patients with high tumor load after liver transplant was compared with that among patients with high tumor load who underwent PVE and liver resection. High tumor load was defined as 9 or more metastatic tumors or a diameter of 5.5 cm or longer for the largest liver lesion., Results: In the PVE cohort of 53 patients, the median age was 61.8 years (range, 34.3-71.3 years), and 36 patients (68%) were men. The 5-year OS rate among 38 patients who underwent liver resection after PVE was 44.6%. The 5-year OS rate for patients with high tumor load was 33.4% for those who underwent liver transplant and 6.7% for those who underwent PVE. Among patients with high tumor load and left-sided primary tumors, the 5-year OS rate was 45.3% for those receiving a liver allograft and 12.5% for those treated with PVE and liver resection., Conclusions and Relevance: Patients with nonresectable disease, an extensive liver tumor load, and left-sided primary tumors had long OS after liver transplant, exceeding the survival outcome for those patients treated with PVE and liver resection.

Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co-mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAF V600 , and TP53 in 441 liver lesions from 171 patients treated by partial hepatectomy for metastatic colorectal cancer. CNAs were profiled in 232 tumors from 67 of the patients. Mutations and high-level amplifications of cancer-critical genes, the latter including ERBB2 and EGFR, were predominantly homogeneous within patients. RAS/BRAF V600E and TP53 co-mutations were associated with a poor patient outcome (hazard ratio, HR, 3.9, 95% confidence interval, CI, 1.3-11.1, P = 0.012) in multivariable analyses with clinicopathological variables. The genome-wide CNA burden and intrapatient intermetastatic CNA heterogeneity varied within the mutation groups, and the CNA burden had prognostic associations in univariable analysis. Combined prognostic analyses of RAS/BRAF V600E /TP53 mutations and CNAs, either as a high CNA burden or high intermetastatic CNA heterogeneity, identified patients with a particularly poor outcome (co-mutation/high CNA burden: HR 2.7, 95% CI 1.2-5.9, P = 0.013; co-mutation/high CNA heterogeneity: HR 2.5, 95% CI 1.1-5.6, P = 0.022). In conclusion, DNA copy number profiling identified genomic and prognostic heterogeneity among patients with resectable colorectal liver metastases with co-mutated RAS/BRAF V600E /TP53., (© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Purpose: Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer., Experimental Design: We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing ( n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients., Results: Three drug-response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2-5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS -mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression., Conclusions: Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression-based predictive signatures to guide experimental therapies., (©2020 American Association for Cancer Research.)

Background: The prevalence and clinical implications of genetic heterogeneity in patients with multiple colorectal liver metastases remain largely unknown. In a prospective series of patients undergoing resection of colorectal liver metastases, the aim was to investigate the inter-metastatic and primary-to-metastatic heterogeneity of mutations in KRAS, NRAS, BRAF, and PIK3CA and their prognostic impact., Patients and Methods: We analyzed the mutation status among 372 liver metastases and 78 primary tumors from 106 patients by methods used in clinical routine testing, by Sanger sequencing, by next-generation sequencing (NGS), and/or by droplet digital polymerase chain reaction. The 3-year cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method., Results: Although Sanger sequencing indicated inter-metastatic mutation heterogeneity in 14 of 97 patients (14%), almost all cases were refuted by high-sensitive NGS. Also, heterogeneity among metastatic deposits was concluded only for PIK3CA in 2 patients. Similarly, primary-to-metastatic heterogeneity was indicated in 8 of 78 patients (10%) using Sanger sequencing but for only 2 patients after NGS, showing the emergence of 1 KRAS and 1 PIK3CA mutation in the metastatic lesions. KRAS mutations were present in 53 of 106 patients (50%) and were associated with poorer 3-year CSS after liver resection (37% vs. 61% for KRAS wild-type; P = .004). Poor prognostic associations were found also for the combination of KRAS/NRAS/BRAF mutations compared with triple wild-type (P = .002)., Conclusion: Intra-patient mutation heterogeneity was virtually undetected, both between the primary tumor and the liver metastases and among the metastatic deposits. KRAS mutations separately, and KRAS/NRAS/BRAF mutations combined, were associated with poor patient survival after partial liver resection., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Surgery combined with perioperative chemotherapy has become standard of care in patients with resectable colorectal liver metastases. However, poor outcome is expected for a significant subgroup. The clinical implications of inter-metastatic heterogeneity remain largely unknown. In a prospective, population-based series of patients undergoing resection of multiple colorectal liver metastases, the aim was to investigate the prevalence and prognostic impact of heterogeneous response to neoadjuvant chemotherapy., Materials and Methods: Radiological response to treatment was evaluated in a lesion-specific manner in 2-5 metastases per patient. Change of lesion diameter was evaluated and response/progression was classified according to three different size thresholds; 3, 4 and 5 mm. A heterogeneous response was defined as progression and response of different metastases in the same patient., Results: In total, 142 patients with 585 liver metastases were examined with the same radiological method (MRI or CT) before and after neoadjuvant treatment. Heterogeneous response to treatment was seen in 16 patients (11%) using the 3 mm size change threshold, and this group had a 5-year cancer-specific survival of 19% compared to 49% for patients with response in all lesions (p = 0.003). Cut-off values of 4-5 mm were less sensitive for detecting a heterogeneous response, but the survival difference was similar and significant., Conclusion: A subgroup of patients with multiple colorectal liver metastases had heterogeneous radiological response to neoadjuvant chemotherapy and poor prognosis. The evaluation of response pattern is easy to perform, feasible in clinical practice and, if validated, a promising biomarker for treatment decisions., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Surgeons are exploring the use of molecular biomarkers in patients with colorectal liver metastases (CLM) to improve preoperative prognostication and selection. This is important because surrogate markers of tumor biology remain insufficient to predict clinical outcomes. In the current literature, there is agreement for the association between RAS and BRAF mutations and poor long-term outcome after hepatectomy. While this knowledge is gradually being implemented in the clinical work-up of patients, their limitations and implications have yet to be fully understood. Recent data indicate that combinations of coexisting mutations may refine the molecular scoring into footprints of good and bad. This already complex information must be interpreted in light of recent understanding of clonal heterogeneity and genetic diversity of colorectal cancer and CLM. In the clinical settings, it is important to approach new insight into molecular biomarkers with caution. However, it is likely that in the future, genomic analysis will determine which patient is amenable to surgery or not, the timing of surgery versus other modalities, as well as how to approach the metastases technically. Here we review current knowledge about molecular biomarkers in the treatment of CLM and the limitations to consider at the translation to clinical practice.

Background: Todani type 1 and 4 choledochal cysts are associated with a risk of developing cholangiocarcinoma. Resection is usually recommended, but data for asymptomatic Western adults are sparse. The aim of this study was to investigate diagnostic interpretation and attitudes towards resection of bile ducts for choledochal cysts in this subgroup of patients across northern European centres., Methods: Thirty hepatopancreatobiliary centres were provided with magnetic resonance cholangiopancreatograms and asked to discuss the management of six cases: asymptomatic non-Asian women, aged 30 or 60 years, with variable common bile duct (CBD) dilatations and different risk factors in the setting of a multidisciplinary team (MDT). The Fleiss κ value was calculated to estimate overall inter-rater agreement., Results: For all case scenarios combined, 83·3 and 86·7 per cent recommended resection for a CBD of 20 and 26 mm respectively, compared with 19·4 per cent for a CBD of 13 mm ( P  < 0·001). For patients aged 30 and 60 years, resection was recommended in 68·5 and 57·8 per cent respectively ( P  = 0·010). There was a trend towards recommending resection in the presence of a common channel, most pronounced in the 60-year-old patient. High amylase levels in the CBD aspirate led to recommendations to resect, but only for the 13-mm CBD dilatation. There were no differences related to centre size or region. MDT discussion was associated with recommendations to resect. Inter-rater agreement was 73·3 per cent (κ = 0·43, 95 per cent c.i. 0·38 to 0·48)., Conclusion: The inter-rater agreement to resect was intermediate, and the recommendation was dependent mainly on the diameter of the CBD dilatation., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Associated liver partition and portal vein ligation in staged hepatectomy (ALPPS) is an alternative resection method to portal vein embolization (PVE) in patients with small future liver remnants (FLR) but has been associated with early tumor recurrences., Methods: Twenty-four patients with colorectal liver metastases (CRLM) patients from the randomized multicenter LIGRO trial comparing outcome of ALPPS (n = 13) vs PVE (n = 11) were included in the study. Mutational analyses of the KRAS, NRAS, BRAF, PIC3CA and TP53 genes of the metastases were performed in 21 patients and correlated to early tumor recurrence., Results: Within 12 months, 13 patients experienced recurrences (6 in TSH group and 7 in ALPPS group). Nine of 13 patients with recurrences had mutations in the TP53 gene, while 3 of 8 patients without recurrence carried the same mutation. Only sporadic cases of the other mutations studied were identified., Conclusions: ALPPS did not appear to be associated with higher rate of rapid recurrences than PVE following radical resection of colorectal liver metastases. Mutations in genes associated with negative oncologic outcome after surgical resection most likely play a role for tumor recurrences in these patients., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Up to half of patients with a gastrointestinal stromal tumor (GIST) will present with metastatic disease, most commonly involving the liver. Prior to the introduction of tyrosine kinase inhibitors, treatment options were limited for patients with metastatic GIST to the liver resulting in dismal survival rates. However, with the advent of effective systemic chemotherapy and continued advancements in both surgical and local adjunctive therapy options, significant improvements in survival have been achieved. In this review, the authors characterize the evolution of the treatment approach for metastatic GIST to the liver, including the roles of both surgical resection and adjunctive therapies in today's practice., Competing Interests: None declared., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Improved outcome after liver resections have been reported in several series, but outcomes from national cohorts are scarce. Our aim was to evaluate nationwide practice and short-term outcomes after liver surgery in a universal healthcare system., Methods: A complete 5-year cohort of all liver resections from the Norwegian Patient Registry (NPR). Short-term outcomes were aggregated length of stay (a-LoS), reoperation and 90-day mortality., Results: Of 2118 liver resections, 605 (28.6%) were major, median age was 65 years and 1184 (55%) were male. Most common indication was metastatic disease (n = 1554; 73.4%) and primary malignancy (n = 328; 15.3%). Laparoscopy was performed in 513 (33.9%) of minor and 37 (6.1%) of major liver resections and increased over time to 39.1% of minor resections in 2016. Median a-LoS was 12 days for major resections, 8 days for open minor and 3 days for laparoscopic minor resections. Reoperation was reported for 159 (7.4%) and 90-day mortality for 44 (2.1%). Primary malignancy, male gender, elderly patients and major resections were associated with poorer outcome., Conclusions: In a national cohort, laparoscopy is used for a substantial proportion of minor resections and was associated with reduced a-LoS. Risk factors for reoperation and mortality were male gender, increased age and major resection for primary malignancy.

Objective: To determine the impact of RAS mutation status on the traditional clinical score (t-CS) to predict survival after resection of colorectal liver metastases (CLM)., Background: The t-CS relies on the following factors: primary tumor nodal status, disease-free interval, number and size of CLM, and carcinoembryonic antigen level. We hypothesized that the addition of RAS mutation status could create a modified clinical score (m-CS) that would outperform the t-CS., Methods: Patients who underwent resection of CLM from 2005 through 2013 and had RAS mutation status and t-CS factors available were included. Multivariate analysis was used to identify prognostic factors to include in the m-CS. Log-rank survival analyses were used to compare the t-CS and the m-CS. The m-CS was validated in an international multicenter cohort of 608 patients., Results: A total of 564 patients were eligible for analysis. RAS mutation was detected in 205 (36.3%) of patients. On multivariate analysis, RAS mutation was associated with poor overall survival, as were positive primary tumor lymph node status and diameter of the largest liver metastasis >50 mm. Each factor was assigned 1 point to produce a m-CS. The m-CS accurately stratified patients by overall and recurrence-free survival in both the initial patient series and validation cohort, whereas the t-CS did not., Conclusions: Modifying the t-CS by replacing disease-free interval, number of metastases, and CEA level with RAS mutation status produced an m-CS that outperformed the t-CS. The m-CS is therefore a simple validated tool that predicts survival after resection of CLM.

Purpose: No consensus exists on the optimal anticoagulation therapy after pancreatoduodenectomy with venous resection (PDVR). The aim of the study was to analyze perioperative outcomes of patients receiving low- vs high-dose anticoagulation therapy and to identify risk factors for postpancreatectomy hemorrhage in patients undergoing PDVR., Methods: Retrospective study of patients undergoing PDVR at a tertiary referral center between January 2006 and April 2017. Patients were investigated according to the dose of postoperative anticoagulation given (low- or high-dose low-molecular-weight heparin). Uni- and multivariate analysis were performed to assess risk factors for postpancreatectomy hemorrhage., Results: A total of 141 patients underwent PDVR. Low-dose anticoagulation was given to 45 (31.9%) patients. Operative time (428 min vs 398 min, p = 0.025) and the use of interposition grafts (27% vs 11%, P = 0.033) were significantly higher in the high-dose group. There was no difference in the rate of early portal vein thrombosis (4.4% vs 4.2%, p = 0.939) or postpancreatectomy hemorrhage (13.3% vs 16.7%, p = 0.611) between the low- and high-dose groups. On multivariate analysis, serum bilirubin ≥ 200 μmol/L and clinically relevant postoperative fistula were the only factors associated with postpancreatectomy hemorrhage (OR 10.28, 95% CI 3.51-30.07, P < 0.001, and OR 6.39, 95% CI 1.59-25.74, P = 0.009)., Conclusion: Preoperative hyperbilirubinemia and clinically relevant postoperative fistula are risk factors for postpancreatectomy hemorrhage after PDVR. Rates of postpancreatectomy hemorrhage did not differ between patients receiving high- vs low-dose low-molecular-weight heparin.

Background: The aim of this study was to determine the frequency and indications for unplanned readmission and outpatient examination after acute appendectomy., Methods: Adults who underwent acute appendectomy from 2008-2013 were included in the study and events occurring within 90-days from discharge recorded., Results: A total of 710 patients underwent surgery. The appendix was removed in 622 patients and post-discharge contact occurred in 99 (15.9%): readmission in 60 (9.6%), outpatient examination in 39 (6.3%). The main reasons for post-discharge contact were infection (n = 25; intraabdominal, n = 16; superficial) and abdominal pain of uncertain cause (n = 25). Use of prophylactic antibiotics was associated with lower rates of contact, 8.5% versus 20.9% (p = 0.006), respectively. Removal of non-inflamed appendix was borderline associated with higher rates of contact, 21.7% versus 8.0% (if left in-situ; p = 0.058), respectively., Conclusions: A substantial number of patients underwent readmission or outpatient examination within 90-days after appendectomy in the current study. The procedure is common and attempts to prevent readmissions are important. Correct use of antibiotics and not removing a non-inflamed appendix may be key points., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The aim of the current study was to investigate survival after resection of colorectal liver metastases (CLM) in octogenarians. The survival of octogenarian patients was compared to the survival of the national population of octogenarians and the survival of sexagenarians, the latter representing the average-age patient undergoing resection of CLM., Methods: Octogenarian and sexagenarian were defined as person 80-89 and 60-69 years of age, respectively. Survival analyses of patients who underwent resection of CLM between 2002 and 2014 were performed. Data from Statistics Norway were used to estimate the survival of the age-matched national population of octogenarians (ageM-Octo) and the age-matched national population of sexagenarians (ageM-Sexa)., Results: During the study period, 59 octogenarians underwent resection of CLM. The majority of patients underwent a minor liver resection (n=50). In octogenarians, the 5-year survival was 32.5% and 66.3% [difference, 33.8 percentage points (pp)] in patients and ageM-Octo, respectively. The 10-year survival was 14.1% and 31.2% (difference, 17.1 pp) in patients and ageM-Octo, respectively. In sexagenarians, the 5-year survival was 50.9% and 96.2% (difference, 45.3 pp) in patients and ageM-Sexa, respectively. The 10-year survival was 35.7% and 90.3% (difference, 54.6 pp) in patients and ageM-Sexa, respectively. The 5-year cancer-specific survival and 5-year recurrence-free survival (RFS) after resection of CLM in octogenarians were 43.1% and 32.9%, respectively., Conclusions: After resection of CLM, the survival was poorer in octogenarians than in sexagenarians. However, the difference between the survival curves of patients and their age-matched population was smaller in octogenarians. In practice, this finding may indicate a greater benefit of resection in the elderly than the survival rates alone would suggest., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Background: The aim of this study was to determine the prognostic value of embryonic origin in patients undergoing resection after chemotherapy for colon cancer liver metastases (CCLM)., Methods: We identified 725 patients with primary colon cancer and known RAS mutation status who underwent hepatic resection after preoperative chemotherapy for CCLM (1990 to 2015). Survival after resection of CCLM from midgut origin (n = 238) and hindgut origin (n = 487) was analyzed. Predictors of pathologic response and survival were determined. Prognostic value of embryonic origin was validated with a separate cohort of 252 patients with primary colon cancer who underwent resection of CCLM without preoperative chemotherapy., Results: Recurrence-free survival (RFS) and overall survival (OS) after hepatic resection were worse in patients with midgut origin tumors (RFS rate at 3 years: 15% vs 27%, P < 0.001; OS rate at 3 years: 46% vs 68%, P < 0.001). Independent factors associated with minor pathologic response were midgut embryonic origin [odds ratio (OR) 1.55, P = 0.010], absence of bevacizumab (OR 1.42, P = 0.034), and mutant RAS (OR 1.41, P = 0.043). Independent factors associated with worse OS were midgut embryonic origin [hazard ratio (HR) 2.04, P < 0.001], carcinoembryonic antigen value ≥5 ng/mL at hepatic resection (HR 1.46, P = 0.0021), synchronous CCLM (HR 1.45, P = 0.012), and mutant RAS (HR 1.43, P = 0.0040). In the validation cohort, patients with CCLM of midgut origin had a worse 3-year OS rate (55% vs 78%, P = 0.003)., Conclusions: Compared with CCLM from hindgut origin, CCLM from midgut origin are associated with worse pathologic response to chemotherapy and worse survival after resection. This effect appears to be independent of RAS mutation status.

Background: Laparoscopic total extraperitoneal repair (TEP) of inguinal hernia has been associated with higher rates of recurrence compared to open methods. The aim of the present study was to determine independent risk factors for recurrence within 2 years after TEP., Methods: This was a single-centre prospective cohort study with consecutive inclusion of patients undergoing inguinal hernia repair from 2010 to 2014. Systematic follow-up was conducted 6 months and 2 years postoperatively. Risk factors for recurrence after 2 years were analysed in univariate and multivariate analyses., Results: A total of 1194 patients underwent TEP for inguinal or femoral hernia in the study period, of which 1047 were eligible for analyses. After 2 years, 56 (5.3%) patients had presented with recurrence. The following factors were associated with recurrence in univariate analyses: body mass index (BMI) >30 (HR 3.64; p = 0.011), medial vs. lateral hernia (HR 2.37; p = 0.004), repair of recurrent hernia vs. primary repair (HR 2.12; p = 0.049), and length of stay >1 day (HR 1.77; p = 0.043). In multivariate analyses, factors independently associated with recurrence after 2 years were BMI >30 (HR 3.74; p = 0.026) and medial vs. lateral hernia (HR 2.39; p = 0.004)., Conclusion: The recurrence rate after TEP is higher than reported after open hernia repair. Attempts to decrease the rate should be persuaded. Good surgical technique with precise dissection and correct placement of the mesh, especially in medial hernias and obese patients, may be key points to improve outcomes after TEP.

Aim: There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified 'liver-first' approach., Method: This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short-term surgical outcome, overall survival and recurrence-free survival are reported., Results: Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty-four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7-116) and 60 (range 31-156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien-Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence-free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent., Conclusion: The modified liver-first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases., (Colorectal Disease © 2017 The Association of Coloproctology of Great Britain and Ireland.)

Objective: The aim of this study was to analyse the survival impact of primary tumor nodal status (N0/N+) in patients with resectable colorectal liver metastases (CLM), and to determine the value of circulating and disseminated tumor cells (CTCs/DTCs) in this setting., Methods: In this prospective study of patients undergoing resection of CLM from 2008 to 2011, peripheral blood was analyzed for CTCs using the CellSearch System ® , and bone marrow was sampled for DTC analyses just prior to hepatic resection. The presence of one or more tumor cells was scored as CTC/DTC-positive. Following resection of the primary tumor, the lymph nodes (LNs) were examined by routine histopathological examination., Results: A total of 140 patients were included in this study; 38 patients (27.1%) were negative at the primary colorectal LN examination (N0). CTCs were detected in 12.1% of all patients; 5.3% of patients in the N0 group and 14.7% of patients in the LN-positive (N+) group (p = 0.156), with the LN-positive group (N+) consisting of both N1 and N2 patients. There was a significant difference in recurrence-free survival (RFS) when analysing the N0 group versus the N+ group (p = 0.007) and CTC-positive versus CTC-negative patients (p = 0.029). In multivariate analysis, CTC positivity was also significantly associated with impaired overall survival (OS) [p = 0.05], whereas DTC positivity was not associated with survival., Conclusion: In this cohort of resectable CLM patients, 27% had primary N0 colorectal cancer. Assessment of CTC in addition to nodal status may contribute to improved classification of patients into high- and low-risk groups, which has the potential to guide and improve treatment strategies.

Precision surgery involves improving patient selection to ensure that surgical intervention that is proven to benefit on a population level is the optimal treatment for each individual patient. For patients with colorectal liver metastases (CRLM), existing prognostic scoring systems rely on well-recognised histopathological features such as size and number of lesions. Advances in preoperative imaging algorithms mean that increasingly low volume disease can be detected, improving assessment of these factors. In addition, novel imaging modalities mean that underlying tumour biology and metabolic behaviour during therapy can be assessed. Molecular analysis of tumours can provide crucial prognostic information, with the critical role of RAS/RAF mutations in prognosis well recognised. The optimal source of tissue for this level of analysis is debated, with good concordance between primary and metastatic lesions for some recognised prognostic factors but marked discrepancies for a variety of other relevant mutations. As well as mutational heterogeneity between primary and metastatic lesions, heterogeneity within tumours and dynamic changes in tumour biology over time present a significant challenge in assessing tumour for prognostic biomarkers. Circulating tumour cells offer one potential method of longitudinal tumour analysis, but are limited by current technologies. This review article summarises some of the key advances in prognostication for patients with resectable colorectal liver metastases, as well as highlighting the potential limitations of such an approach., (Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: RAS mutations are associated with limited overall survival after resection of colorectal liver metastases. Our aim was to determine criteria for considering hepatectomy for patients with RAS mutant colorectal liver metastases., Methods: Of 1,163 patients who underwent liver resection for colorectal liver metastases during 2005-2014, all patients operated on with curative intent who had known RAS mutation status were included. Factors associated with overall survival were determined using multivariate analysis., Results: A total of 524 patients met the inclusion criteria; 212 (40%) had mutated RAS. Mutations were located on codon 12 in 128 patients (60%) and codon 13 in 29 (14%). At median follow-up of 38 months, median overall survival was 72.6 months for wild-type RAS and 50.9 months for mutated RAS (P < .001). Median overall survival for patients with codon 12 and 13 mutations was 51.9 and 50.9 months, respectively (P = .839), significantly worse than for patients with wild-type RAS (P = .005, and P = .038 for codon 12 and 13, respectively). For patients with RAS mutation, factors associated independently with worse overall survival were node-positive primary tumor, tumor >3 cm, and >7 cycles of preoperative chemotherapy. Major and 2-stage hepatectomy were not associated independently with overall survival. Median overall survival was 57, 41, and 21.5 months for patients with 1, 2, and 3 risk factors, respectively. There were no 4-year survivors in the highest-risk group., Conclusion: Patients with multiple risk factors had poor overall survival after curative resection of RAS mutant colorectal liver metastases. For such patients, hepatectomy may be ill advised, and alternative therapies or further systemic therapy should be considered., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The relationship between RAS mutation status and outcome for patients undergoing repeat hepatectomy (RH) for recurrent colorectal liver metastases (CLM) has not been defined., Objective: The objective of this study was to evaluate the relationship between RAS mutation status and outcome in patients undergoing RH for CLM., Methods: All patients who underwent RH for CLM with known RAS mutation status between January 2005 and November 2014 were identified, and the outcomes of patients with and without RAS mutations were compared., Results: Ninety-eight patients underwent RH, of whom 34 (35 %) harbored a RAS mutation. Wild-type (WT) and mutant RAS groups had similar clinicopathologic characteristics. Median recurrence-free survival (RFS) for patients with WT and mutant RAS was 12.2 and 6.1 months, respectively (p = 0.03). Median overall survival (OS) for the WT and mutant RAS patients were 42.5 and 26.6 months, respectively (p < 0.01). On multivariate analysis, RAS mutations [hazard ratio (HR) = 1.69, p = 0.04] were associated with worse RFS, while multiple tumors (HR = 1.92, p = 0.045) and RAS mutations (HR = 2.11, p = 0.02) predicted worse OS., Conclusion: Patients with recurrent CLM that harbor RAS mutations have worse RFS and OS than patients with WT RAS, and RAS mutations are independently associated with worse RFS and OS. RAS mutation status should be determined prior to RH, as it may impact treatment decisions.

Objective: The aim of this study was to validate clinical risk scores in patients underwent laparoscopic resection of colorectal liver metastases (CLM) with 5 years follow-up or more, and assess 5- and 10-year actual survival in this group., Methods: A total of 516 laparoscopic liver resections were performed in 406 patients with CLM between February 1998 and September 2015. A follow-up of 5 and 10 years could be assessed in 144 and 29 patients, respectively. The Fong score, pre- and postoperative Basingstoke Predictive Index (BPI), Nordlinger score, and Iwatsuki score were validated., Results: Five- and ten-year cancer-related actual survival was 54% and 32%, respectively. The Fong score, pre- and postoperative BPI and the Nordlinger score divided patients into risk groups with significant difference in survival between the groups. However, predicted 5-year survival rates were lower than the actual 5-year survival (mean difference in 17%,13%, 20%, and 30%, respectively)., Conclusion: The Fong score, pre- and postoperative BPI and the Nordlinger score systems can be used to predict survival for laparoscopically operated patients in the era of multimodal-treatment after adjusting of survival rates. The actual five- and 10-year survival after laparoscopic resection of CLM is similar to results previously published for open liver resection. J. Surg. Oncol. 2016;114:757-763. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Extensive surgery is associated with greater mortality for elderly patients. For gastric adenocarcinoma (GA), it is unclear whether the benefit of an extended lymphadenectomy in this population outweighs the associated risks. This study aimed to determine the impact of lymphadenectomy on postoperative outcomes and survival for the elderly., Objective: To determine the impact of lymphadenectomy on postoperative outcomes and survival for elderly., Methods: From a cohort of 19 centers, patients who underwent resection of GA with curative intent between 1997 and 2010 were included in this study. Lymphadenectomy was defined according to the total number of lymph nodes in the surgical specimen (limited, <15; intermediate, 15-25; extended, >25). Postoperative outcomes and survival were compared between elderly (≥75 years) and younger patients and regarding the extent of lymphadenectomy for the elderly., Results: Of 1348 patients, 386 were elderly. The elderly presented with a higher American Society of Anesthesiologist (ASA) score (ASA 3-4: 45 vs. 16.5 %; p < 0.001) as well as greater postoperative morbidity (45 vs. 37 %; p = 0.009) and mortality (8 vs. 2.5 %; p < 0.001) despite less aggressive treatment including less neoadjuvant chemotherapy (5 vs. 20 %; p < 0.001) and adjuvant chemotherapy (7 vs. 44 %; p < 0.001), fewer total gastrectomies (41.5 vs. 60 %; p < 0.001), and less extended lymphadenectomy (38 vs. 48.5 %; p < 0.001). Among the elderly patients, limited lymphadenectomy (n = 116), intermediate lymphadenectomy (n = 125), and extended lymphadenectomy (n = 145) were comparable with respect to tumor stage, perioperative treatment, morbidity, and mortality. For the elderly patients, overall survival (OS) was 30.8 months, and disease-specific survival (DSS) was 63.9 months. The extent of the lymphadenectomy did not have an impact on OS or DSS for the elderly patients., Conclusion: The expected benefit in terms of long-term survival did not justify an extended lymphadenectomy for elderly patients.

Background: In patients undergoing resection of colorectal liver metastases (CLM), resection margin status is a significant predictor of survival, particularly in patients with suboptimal response to preoperative therapy. RAS mutations have been linked to more invasive and migratory tumor biology and poor response to modern chemotherapy., Objective: The aim of this study was to evaluate the relationship between RAS mutation and resection margin status in patients undergoing resection of CLM., Methods: Patients who underwent curative resection of CLM from 2005 to 2013 with known RAS mutation status were identified from a prospectively maintained database. A positive margin was defined as tumor cells <1 mm from the parenchymal transection line., Results: The study included 633 patients, of whom 229 (36.2 %) had mutant RAS. The positive margin rate was 11.4 % (26/229) for mutant RAS and 5.4 % (22/404) for wild-type RAS (p = 0.007). In multivariate analysis, the only factors associated with a positive margin were RAS mutation (hazard ratio [HR] 2.439; p = 0.005) and carcinoembryonic antigen level 4.5 ng/mL or greater (HR 2.060; p = 0.026). Among patients presenting with liver-first recurrence during follow-up, those with mutant RAS had narrower margins at initial CLM resection (median 4 mm vs. 7 mm; p = 0.031). A positive margin (HR 3.360; p < 0.001) and RAS mutation (HR 1.629; p = 0.044) were independently associated with worse overall survival., Conclusion: RAS mutations are associated with positive margins in patients undergoing resection of CLM. Tumors with RAS mutation should prompt careful efforts to achieve negative resection margins.

Purpose: Regular use of aspirin (acetylsalicylic acid) is associated with reduced incidence and mortality of colorectal cancer (CRC). However, aspirin as primary prevention is debated because of the risk of hemorrhagic adverse effects. Aspirin as secondary prevention may be more justified from a risk-benefit perspective. We have examined the association between aspirin use after the diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS)., Materials and Methods: An observational, population-based, retrospective cohort study was conducted by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with data on their aspirin use (The Norwegian Prescription Database). These registries cover more than 99% of the Norwegian population and include all patients in an unselected and consecutive manner. Exposure to aspirin was defined as receipt of aspirin prescriptions for more than 6 months after the diagnosis of CRC. Multivariable Cox-proportional hazard analyses were used to model survival. The main outcome measures of the study were CSS and OS., Results: A total of 23,162 patients diagnosed with CRC were included, 6,102 of whom were exposed to aspirin after the diagnosis of CRC (26.3%). The median follow-up time was 3.0 years. A total of 2,071 deaths (32.9%, all causes) occurred among aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01)., Conclusion: Aspirin use after the diagnosis of CRC is independently associated with improved CSS and OS., (© 2016 by American Society of Clinical Oncology.)

Background: Portal vein embolization (PVE) reduces the risks of hepatic insufficiency after major hepatectomy for small predicted liver remnant. The extent of liver hypertrophy after PVE depends on various clinical factors. We sought to develop a nomogram for predicting the increase in the volume of segments 2 and 3 after right PVE (RPVE)., Method: In 360 patients who underwent RPVE from 1998 through 2013, clinicopathologic data were analyzed, including body mass index (BMI), diabetes, aspirin use, viral hepatitis status, preoperative albumin level, total bilirubin level, prothrombin time, platelet count, type of liver neoplasm, preoperative chemotherapy, previous laparotomy or hepatectomy, segment 4 embolization, two-stage hepatectomy, and liver volumes before and after PVE. Multivariate linear regression analysis was used to identify variables predicting the degree of hypertrophy of segments 2 and 3., Results: Multivariate regression analysis revealed that BMI (p = 0.002), previous hepatectomy (p = 0.03), RPVE in the setting of two-stage hepatectomy (p < 0.001), and segment 4 embolization (p = 0.003) independently predicted the degree of hypertrophy of segments 2 and 3. Based on the fitted model, a nomogram was constructed., Conclusion: The constructed nomogram predicts the degree of hypertrophy of segments 2 and 3 after RPVE and can be used in clinical decision making for patients undergoing right hepatectomy.

Background: In patients with bilateral colorectal liver metastases (CLM) not resectable in 1 operation, 2-stage hepatectomy is the standard surgical approach. The objective of this study was to determine factors associated with safety and efficacy of 2-stage hepatectomy., Study Design: The study included all 109 patients for whom 2-stage hepatectomy for CLM was planned during 2003 to 2014. The RAS mutation status and other clinicopathologic factors were evaluated for association with major complications and survival using multivariate analysis., Results: Two-stage hepatectomy was completed in 89 of 109 patients (82%). Reasons for dropout after the first stage were disease progression (n = 12), insufficient liver growth (n = 5), and complications after first stage or portal vein embolization (n = 3). More than 6 cycles of preoperative chemotherapy were associated with failure to proceed to the second stage (p = 0.009). Rates of major complications (26% vs 6%; p < 0.001) and 90-day mortality (7% vs 0%; p = 0.006) were higher after the second stage. The cumulative rate of major complications was 15% (n = 29). Factors independently associated with major complications were rectal primary tumor, metachronous CLM, and more than 1 lesion resected at first stage. At median follow-up of 29.5 months, 3-year (68% vs 6%; p < 0.001) and 5-year overall survival rates (49% vs 0%; p < 0.001) were better after 2-stage hepatectomy completion than noncompletion. Factors independently associated with poor overall survival were rectal primary tumor (p = 0.044), more than 5 CLMs (p = 0.043), need for chemotherapy after first stage (p = 0.046), and RAS mutation (p < 0.001)., Conclusions: The RAS mutation independently predicts the oncologic efficacy of 2-stage hepatectomy and may help guide patient selection for this aggressive surgical strategy., (Copyright © 2016 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Perioperative blood transfusions suppress immunity and increase hospital costs. Despite multiple improvements in perioperative care, rates of transfusion during/after hepatectomy are reported to range from 25 to 50%. The purpose of this study was to determine the current risk factors for perihepatectomy transfusion by assessing the impact of recent technical advances in liver surgery on transfusion rates., Methods: Using our prospectively maintained hepatobiliary tumor database from a high-volume center, a modern cohort of 2,249 hepatectomies (2004-2013) were identified. Patient and operative characteristics were compared between 2 time periods, 2004-2008 (n = 1,139) and 2009-2013 (n = 1,110). Throughout the study interval, transfusions were given based on clinical assessment and not triggered by laboratory thresholds., Results: Compared with the early cohort, the recent cohort had more patients with an American Society of Anesthesiologists score of ≥ 3 (79 vs 74%), preoperative chemotherapy (73 vs 68%), and a lesser median preoperative hemoglobin (12.9 vs 13.1 mg/dL) and platelet (215,000 vs 243,000) values (all P < .001). Despite these adverse risk factors, with an increasing use of the 2-surgeon resection technique (63 vs 50%), estimated blood loss (309 vs 394 mL), transfusion rates (6 vs 15%), and duration of stay (7.0 vs 8.4 days) were decreased (all P < .001) with no change in overall morbidity or mortality. Multivariate analysis of the recent cohort determined that the independent risk factors associated with transfusion were preoperative anemia and >350 mL of blood loss. The only independent factor associated with less transfusion was use of the 2-surgeon technique for hepatic parenchymal transection., Conclusion: With the exception of patients with moderate to severe preoperative anemia requiring major hepatectomy, recent technical advances have decreased significantly the need for transfusion in liver surgery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To investigate prognostic impact of parenchymal-sparing hepatectomy (PSH) for solitary small colorectal liver metastasis (CLM)., Background: It is unclear whether PSH confers an oncologic benefit through increased salvageability or is a detriment through increasing recurrence rate., Methods: Database of 300 CLM patients with a solitary tumor (≤ 30 mm in size) was reviewed from 1993 to 2013. A total of 156 patients underwent PSH and 144 patients underwent right hepatectomy, left hepatectomy, or left lateral sectionectomy (non-PSH group)., Results: The rate of PSH increased over the study period (P < 0.01). PSH did not impact negatively on overall (OS), recurrence-free, and liver-only recurrence-free survival, compared with non-PSH (P = 0.53, P = 0.97, and P = 0.69, respectively). Liver-only recurrence was observed in 22 patients (14%) in the PSH and 25 (17%) in the non-PSH group (P = 0.44). Repeat hepatectomy was more frequently performed in the PSH group (68% vs 24%, P < 0.01). Subanalysis of patients with liver-only recurrence revealed better 5-year overall survival from initial hepatectomy and from liver recurrence in the PSH than in the non-PSH group [72.4% vs 47.2% (P = 0.047) and 73.6% vs 30.1% (P = 0.018), respectively]. Multivariate analysis revealed that non-PSH was a risk of noncandidacy for repeat hepatectomy (hazard ratio: 8.18, confidence interval: 1.89-45.7, P < 0.01)., Conclusions: PSH did not increase recurrence in the liver remnant but more importantly improved 5-year survival in case of recurrence (salvageability). PSH should be the standard approach to CLM to allow for salvage surgery in case of liver recurrence.

Background: Previous studies by different authors have reported their readmission rates after pancreatectomy as either “30 days from discharge” or “90 days from surgery.” The objective of this study was to determine which of these definitions captures the most surgery-related complications., Methods: A prospectively maintained database at a high volume center was queried to identify all individuals who underwent pancreatectomy between 2000 and 2012 for any diagnosis. The data was analyzed at 30 days after discharge and 90 days after operation. The optimal timing for complication reporting was defined as the time point that maximized the capture of surgery-related readmissions and direct major surgical complications while minimizing the capture of disease (cancer)-related readmissions., Results: There were 1123 patients included during the study time period. The median age was 63 years old, and 55.6% were male. Operations included 833 (74.2%) pancreaticoduodenectomies, 257 (22.9%) distal pancreatectomies, 18 (1.6%) total pancreatectomies, and 15 (1.3%) central pancreatectomies. Surgery-related readmissions occurred in 248 (22%) individuals, while readmission related to malignant disease progression occurred in 25 (2%) individuals. The 30 days from discharge definition captured 184 surgery-related readmissions and 1 disease-related readmission (sensitivity 0.74, specificity 0.96). The 90 days from surgery definition captured 215 surgery-related readmissions and 1 disease-related readmission (sensitivity 0.87, specificity 0.96). Major surgical complication was the only independent factor associated with readmission not captured by the 30 days from discharge definition (p = 0.002, HR 3.94, 95% CI 1.44–12.22)., Conclusion: The 90 days from surgery definition was superior to the 30 days from discharge definition, especially with regards to readmission related to major surgical complications.

Background: The presence of circulating tumor cells (CTCs) is negatively associated with survival after resection of colorectal liver metastases (CLM). The current study aimed to determine the prognostic value of CTCs and disseminated tumor cells (DTCs) at the time of surgery and the prognostic value of CTCs at follow-up assessment, for patients scheduled to undergo two-stage hepatectomy with portal vein embolization (PVE) for CLM., Methods: Samples were collected at surgery (blood and bone marrow) and at follow-up assessment (blood) for the period 2008 through 2011. In this study, CTCs were detected with the CellSearch system, and DTCs were detected using standard immunocytochemical analysis., Results: Of 24 patients, 18 completed both stages, and no patients were lost to follow-up. The median overall survival (OS) was 37 months, and the median recurrence-free survival (RFS) was 7 months. At surgery, CTCs were found in nine patients (38 %), and their presence was associated with reduced OS (p < 0.001) and RFS (p = 0.006). Follow-up CTC status was available for 11 patients. All eight patients with positive CTC status experienced recurrence. Two of three patients with negative CTC status remained recurrence free. In seven patients (32 %), DTCs were detected but were not associated with OS or RFS., Conclusions: The presence of CTCs at surgery is associated with worse OS and RFS for patients undergoing two-stage hepatectomy with PVE for CLM. Analysis of CTCs should be explored further for their potential to assist in treatment decisions and monitoring for CLM patients.

Background: In patients with advanced colorectal cancer, KRAS mutation status predicts response to treatment with monoclonal antibody targeting the epithelial growth factor receptor (EGFR). Recent reports have provided evidence that KRAS mutation status has prognostic value in patients with resectable colorectal liver metastases (CLM) irrespective of treatment with chemotherapy or anti-EGFR therapy. A meta-analysis was undertaken to clarify the impact of KRAS mutation on outcomes in patients with resectable CLM., Methods: PubMed, Embase and Cochrane Library databases were searched systematically to identify full-text articles reporting KRAS-stratified overall (OS) or recurrence-free (RFS) survival after resection of CLM. Hazard ratios (HRs) and 95 per cent c.i. from multivariable analyses were pooled in meta-analyses, and a random-effects model was used to calculate weight and overall results., Results: The search returned 355 articles, of which 14, including 1809 patients, met the inclusion criteria. Eight studies reported OS after resection of CLM in 1181 patients. The mutation rate was 27.6 per cent, and KRAS mutation was negatively associated with OS (HR 2.24, 95 per cent c.i. 1.76 to 2.85). Seven studies reported RFS after resection of CLM in 906 patients. The mutation rate was 28.0 per cent, and KRAS mutation was negatively associated with RFS (HR 1.89, 1.54 to 2.32)., Conclusion: KRAS mutation status is a prognostic factor in patients undergoing resection of colorectal liver metastases and should be considered in the evaluation of patients having liver resection., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Background: We investigated outcomes by primary tumor type in patients who underwent resection of liver metastases from gastrointestinal stromal tumors (GIST), leiomyosarcomas, and other sarcomas., Method: Our institutional liver database was used to identify patients who underwent resection from 1998 through 2013. Histopathological, clinical, and survival data were analyzed., Results: One hundred forty-six patients underwent resection of liver metastases from GIST (n = 49), leiomyosarcomas (n = 47), or other sarcomas (n = 50). The 5-year overall survival (OS) rates in patients with GIST, leiomyosarcomas, and other sarcomas were 55.3, 48.4, and 44.9%, respectively, and the 10-year OS rates were 52.5, 9.2, and 23.0%, respectively. The 5-year recurrence-free survival (RFS) rate was better for GIST (35.7%; p = 0.003) than for leiomyosarcomas (3.4%) and other sarcomas (21.4%). Lung recurrence was more common for leiomyosarcomas (36% of patients; p < 0.0001) than for other sarcomas (12%) and GIST (2%). For GIST, the findings support a benefit of imatinib regarding the 5-year RFS rate compared to resection alone (47.1 vs. 9.5%; p = 0.013). For leiomyosarcoma, primary tumor location did not affect the 5-year RFS rate (intraabdominal 14.5%; other location 0%; p = 0.182)., Conclusion: Liver metastases from GIST, leiomyosarcomas, and other sarcomas should be assessed separately as their survival and recurrence patterns are different. This is especially important for GIST, for which imatinib is now available.

Background: Readmission rates of 9.7% to 15.5% after hepatectomy have been reported. These rates are difficult to interpret due to variability in the time interval used to monitor readmission. The aim of this study was to refine the definition of readmission after hepatectomy., Study Design: A prospectively maintained database of 3,041 patients who underwent hepatectomy from 1998 through 2013 was merged with the hospital registry to identify readmissions. Area under the curve (AUC) analysis was used to determine the time interval that best captured unplanned readmission., Results: Readmission rates at 30 days, 90 days, and 1 year after discharge were 10.7% (n = 326), 17.3% (n = 526), and 31.9% (n = 971) respectively. The time interval that best accounted for unplanned readmissions was 45 days after discharge (AUC, 0.956; p < 0.001), during which 389 patients (12.8%) were readmitted (unplanned: n = 312 [10.3%]; planned: n = 77 [2.5%]). In comparison, the 30 days after surgery interval (used in the ACS-NSQIP database) omitted 65 (26.3%) unplanned readmissions. Multivariate analysis revealed the following risk factors for unplanned readmission: diabetes (odds ratio [OR] 1.6; p = 0.024), right hepatectomy (OR 2.1; p = 0.034), bile duct resection (OR 1.9; p = 0.034), abdominal complication (OR 1.8; p = 0.010), and a major postoperative complication (OR 2.4; p < 0.001). Neither index hospitalization > 7 days nor postoperative hepatobiliary complications were independently associated with readmission., Conclusions: To accurately assess readmission after hepatectomy, patients should be monitored 45 days after discharge., (Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Advances in multidisciplinary care are changing the prognostic impact of colorectal lung metastases. Resection of colorectal liver metastases (CLM) may benefit patients with synchronous lung metastases even when lung metastases are not resected. The aim of this study was to investigate the survival of patients undergoing complete resection of CLM in the setting of unresected lung metastases., Patients and Methods: We compared survival among 98 patients who underwent resection of CLM with unresected lung metastases, 64 who received only chemotherapy for limited colorectal liver and lung metastases, and 41 who underwent resection of both liver and lung metastases. Prognostic factors were investigated in the patients who underwent resection of CLM only., Results: The 3-year/5-year overall survival (OS) rates of patients with CLM resection only (42.9 %/13.1 %) were better than those of patients treated with chemotherapy only (14.1 %/1.6 %; p < 0.01) but worse than those of patients with resection of liver and lung metastases (68.9 %/56.9 %; p < 0.01). Multivariate analysis of patients with CLM resection only revealed that KRAS mutation [hazard ratio (HR) 2.10; 95 % confidence interval (CI) 1.21-3.64; p < 0.01] and rectal primary tumor (HR 1.72; 95 % CI 1.02-2.88; p = 0.04) were independent predictors of worse OS. Survival of patients without these risk factors was similar to that of patients with curative metastasectomy., Conclusions: Complete resection of metastases remains the primary goal of treatment for stage IV colorectal cancer. Resection of CLM without resection of lung metastases is associated with an intermediate survival between that of patients treated with palliative and curative intent and should be considered in selected patients.