Kristoffer Watten Brudvik

Meta‐analysis of KRAS mutations and survival after resection of colorectal liver metastases

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.

Parenchymal-sparing Hepatectomy in Colorectal Liver Metastasis: Improves Salvageability and Survival.

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.

Modulation of T cell immune functions by the prostaglandin E 2 - CAMP pathway in chronic inflammatory states

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.

Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice

BackgroundThe adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E2 (PGE2) - PI-3 kinase pathways. Recent reports show that PGE2-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE2 on β-catenin homeostasis.FindingsTreatment of ApcMin/+ mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE2-induced β-catenin phosphorylation and c-Myc upregulation.ConclusionBased on our findings we suggest that PGE2 act through PKA to promote β-catenin nuclear translocation and tumor development in ApcMin/+ mice in vivo, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.

Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study

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.

Circulating tumor cells in patients with colorectal liver metastasis predict impaired survival

OBJECTIVE The aim of the study is to assess the prognostic and predictive value of circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in bone marrow (BM) in patients with colorectal liver metastasis referred to surgery. BACKGROUND A total of 194 patients were included. Treatment of the patients was decided in a multidisciplinary team. METHODS BM aspirates and blood samples were collected at surgery, or in local anesthesia in nonresectable patients. CTCs were disclosed with CellSearch System, DTC with immunocytology. RESULTS Liver resection was completed in 153 patients. Forty-one patients were nonresectable, 22 preoperatively and 19 intraoperatively. The median follow-up was 22 (range 1-61) months. Relapse was diagnosed in 103 of the resected patients. Totally, 67 patients died of cancer. CTCs were detected in 19.6% of the patients. CTC positivity was significantly higher in nonresectable (46%) than in resectable patients (11.7%), P < 0.001. 13.8% of the patients had 2 or more CTCs, 31% of the nonresectable and 9.1% of the resectable patients (P = 0.001). Patients with 2 or more CTCs experienced reduced time to relapse/progression, both analyzing all patients (P = 0.002) and analyzing resectable patients (P < 0.001). Two or more CTCs was a strong predictor of progression and mortality in all subgroups of patients, together with more than 3 liver metastases, R1 resection, and extrahepatic disease. DTCs were detected in 9.9% of the patients, but not associated with clinical outcome in resectable patients. CONCLUSIONS CTCs predict nonresectability and impaired survival. CTC analysis should be considered as a tool for decision-making before liver resection in these patients.

Definition of Readmission in 3,041 Patients Undergoing Hepatectomy

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.

Kinetics and Activation Requirements of Contact-Dependent Immune Suppression by Human Regulatory T Cells

Naturally occurring regulatory T cells (Tregs) maintain self tolerance by dominant suppression of potentially self-reactive T cells in peripheral tissues. However, the activation requirements, the temporal aspects of the suppressive activity, and mode of action of human Tregs are subjects of controversy. In this study, we show that Tregs display significant variability in the suppressive activity ex vivo as 54% of healthy blood donors examined had fully suppressive Tregs spontaneously, whereas in the remaining donors, anti-CD3/CD2/CD28 stimulation was required for Treg suppressive activity. Furthermore, anti-CD3/CD2/CD28 stimulation for 6 h and subsequent fixation in paraformaldehyde rendered the Tregs fully suppressive in all donors. The fixation-resistant suppressive activity of Tregs operated in a contact-dependent manner that was not dependent on APCs, but could be fully obliterated by trypsin treatment, indicating that a cell surface protein is directly involved. By add-back of active, fixed Tregs at different time points after activation of responding T cells, the responder cells were susceptible to Treg-mediated immune suppression up to 24 h after stimulation. This defines a time window in which effector T cells are susceptible to Treg-mediated immune suppression. Lastly, we examined the effect of a set of signaling inhibitors that perturb effector T cell activation and found that none of the examined inhibitors affected Treg activation, indicating pathway redundancy or that Treg activation proceeds by signaling mechanisms distinct from those of effector T cells.

Advances in hepatectomy technique: Toward zero transfusions in the modern era of liver surgery

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.

RAS Mutation Clinical Risk Score to Predict Survival After Resection of Colorectal Liver Metastases.

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.