Bergthor Björnsson

The role of microRNA-200 in progression of human colorectal and breast cancer.

The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200–ZEB–E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMT-markers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 – ZEB – E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

In Situ Split of the Liver When Portal Venous Embolization Fails to Induce Hypertrophy: A Report of Two Cases

Introduction. Associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been reported as an efficient alternative to portal vein embolization (PVE) to induce growth of the future liver remnant (FLR). This method combines portal vein ligation with splitting of the liver parenchyma. Although shown to be efficient in introducing growth of the FLR and allowing for resection of the deportalized part of the liver one to two weeks after the first operation, this approach carries a significant mortality. Presentation of Case. ALPPS was applied to two elderly patients where PVE failed to stimulate sufficient growth of the FLR. In both cases, subsequent growth of the FLR allowed for successful resection of the liver lesions. The postoperative course was uneventful for both patients. Discussion. In both cases, the growth of the FLR was similar to what was previously reported when ALPPS has been performed, both patients underwent radical resections that would probably not have been safe after only the PVE. Conclusion. ALPPS used as rescue technique when PVE fails to stimulate sufficient growth of the FLR can be expected to deliver similar results as ALPPS “Up front”. These cases also suggest that ALPPS is applicable to the elderly population.

Role of associating liver partition and portal vein ligation for staged hepatectomy in colorectal liver metastases: A review

Colorectal cancer is the third most common cancer in the Western world. Approximately half of patients will develop liver metastases, which is the most common cause of death. The only potentially curative treatment is surgical resection. However, many patients retain a to small future liver remnant (FLR) to allow for resection directly. There are therefore strategies to decrease the tumor with neoadjuvant chemotherapy and to increase the FLR. An accepted strategy to increase the FLR is portal vein occlusion (PVO). A concern with this strategy is that a large proportion of patients will never be operated because of progression during the interval between PVO and resection. ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a new procedure with a high resection rate. A concern with this approach is the rather high frequency of complications and high mortality, compared to PVO. In this review, it is shown that with ALPPS the resection rate was 97.1% for CRLM and the mortality rate for all diagnoses was 9.6%. The mortality rate was likely lower for patients with CRLM, but some data were lacking in the reports. Due to the novelty of ALPPS, the indications and technique are not yet established but there are arguments for ALPPS in the context of CRLM and a small FLR.

Associating liver partition and portal vein ligation for staged hepatectomy in patients with colorectal liver metastases - Intermediate oncological results

BACKGROUND Colorectal liver metastases (CRLM) not amenable for resection have grave prognosis. One limiting factor for surgery is a small future liver remnant (FLR). Early data suggests that associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) effectively increases the volume of the FLR allowing for resection in a larger fraction of patients than conventional two-stage hepatectomy (TSH) with portal vein occlusion (PVO). Oncological results of the treatment are lacking. The aim of this study was to assess the intermediate oncological outcomes after ALPPS in patients with CRLM. MATERIAL AND METHODS Retrospective analysis of all patients with CRLM operated with ALPPS at the participating centres between December 2012 and May 2014. RESULTS Twenty-three patients (16 male, 7 female), age 67 years (28-80) were operated for 6.5 (1-38) metastases of which the largest was 40 mm (14-130). Six (27.3%) patients had extra-hepatic metastases, 16 (72.7%) synchronous presentation. All patients received chemotherapy, 6 cycles (3-25) preoperatively and 16 (70%) postoperatively. Ten patients (43%) were rescue ALPPS after failed PVO. Severe complications occurred in 13.6% and one (4.5%) patient died within 90 days of surgery. After a median follow-up of 22.5 months from surgery and 33.5 months from diagnosis of liver metastases estimated 2 year overall survival was 59% (from surgery) and 73% (from diagnosis). Liver only recurrences (n = 8), were treated with reresection/ablation (n = 7) while lung recurrences were treated with chemotherapy. CONCLUSION The overall survival, rate of severe complications and perioperative mortality associated with ALPPS for patients with CRLM is comparable to TSH.

Scandinavian multicenter study on the safety and feasibility of the associating liver partition and portal vein ligation for staged hepatectomy procedure

BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has emerged as an additional tool to increase the size of the future liver remnant (FLR) in the settings of advanced tumor burden in the liver. Initial reports have indicated high feasibility but also high mortality and morbidity. The aim of this study was to assess the initial experience with ALPPS in Scandinavia regarding feasibility, morbidity, and mortality. MATERIALS AND METHODS We conducted a retrospective analysis of all patients who underwent ALPPS since its introduction at 3 Scandinavian hepatobiliary centers. RESULTS Thirty-six patients were identified, 21 male and 15 female. Median age was 67 years (22-83). Colorectal liver metastases (n = 25) were the most common indication for ALPPS followed by hepatocellular carcinoma (n = 4), cholangiocarcinoma (n = 4), and other (n = 3). Median growth of the FLR between the operations was 67% (-17 to 238) in 6 (5-13) days. All patients completed the second operation, and 71% of the resections were R0. Although the total percentage of patients with complication(s) was 92%, only 4 patients (11%) had a grade 3b complication according to the Clavien-Dindo classification, and no other severe complications were noted. There was no in-hospital mortality, but 1 (2.8%) patient died within 90 days of operation. CONCLUSION ALPPS is a highly feasible method to stimulate FLR growth in patients with colorectal liver metastases as well as primary hepatobiliary malignancies. The treatment can be carried out with relative safety.

Laparoscopic distal pancreatectomy for adenocarcinoma of the pancreas

Since the first report on laparoscopic distal pancreatectomy (LDP) appeared in the 1990s, the procedure has been performed increasingly frequently to treat both benign and malignant lesions of the pancreas. Many earlier publications have shown LDP to be a good alternative to open distal pancreatectomy for benign lesions, although this has never been studied in a prospective, randomized manner. The evidence for the use of LDP to treat adenocarcinoma of the pancreas is not as well established. The purpose of this review is to evaluate the current evidence for LDP in cases of pancreatic adenocarcinoma. We conducted a review of English language publications reporting LDP results between 1990 and 2013. All studies reporting results in patients with histologically proven pancreatic adenocarcinoma were included. Thirty-nine publications were found and included in the results for a total of 309 cases of pancreatic adenocarcinoma (potential double publications were not eliminated). Most LDP procedures are performed in selected cases and generally involve smaller tumors than open distal pancreatectomy (ODP) procedures. Some of the papers report unselected cases and include procedures on larger tumors. The number of lymph nodes harvested using LDP is comparable to the number obtained with ODP, as is the frequency of R0 resections. Current data suggest that similar short term oncological results can be obtained using LDP as those obtained using ODP.

How much liver needs to be transected in ALPPS? A translational study investigating the concept of less invasiveness.

BACKGROUND ALPPS induces rapid liver hypertrophy after stage‐1 operation, enabling safe, extended resections (stage‐2) after a short period. Recent studies have suggested that partial transection at stage‐1 might be associated with a better safety profile. The aim of this study was to assess the amount of liver parenchyma that needs to be divided to achieve sufficient liver hypertrophy in ALPPS. METHODS In a bi‐institutional, prospective cohort study, nonfibrotic patients who underwent ALPPS with complete (n = 22) or partial (n = 23) transection for colorectal liver metastases were analyzed and compared with an external ALPPS cohort (n = 23). A radiologic tool was developed to quantify the amount of parenchymal transection. Liver hypertrophy and clinical outcome were compared between both techniques. The relationship of partial transection and hypertrophy was investigated further in an experimental murine model of partial ALPPS. RESULT The median amount of parenchymal transection in partial ALPPS was 61% (range, 34–86%). The radiologic method correlated poorly with the intraoperative surgeons estimation (rS = 0.258). Liver hypertrophy was equivalent for the partial ALPPS, ALPPS, and external ALPPS cohort (64% vs 60% vs. 64%). Experimental data demonstrated that partial transection of at least 50% induced comparable hypertrophy (137% vs 156%) and hepatocyte proliferation compared to complete transection. CONCLUSION The study provides clinical and experimental evidence that partial liver partition of at least 50% seems to be equally effective in triggering volume hypertrophy as observed with complete transection and can be re recommended as less invasive alternative to ALPPS.

Conventional, but not remote ischemic preconditioning, reduces iNOS transcription in liver ischemia/reperfusion

AIM To study the effects of preconditioning on inducible nitric oxide synthase (iNOS) and interleukin 1 (IL-1) receptor transcription in rat liver ischemia/reperfusion injury (IRI). METHODS Seventy-two male rats were randomized into 3 groups: the one-hour segmental ischemia (IRI, n = 24) group, the ischemic preconditioning (IPC, n = 24) group or the remote ischemic preconditioning (R-IPC, n = 24) group. The IPC and R-IPC were performed as 10 min of ischemia and 10 min of reperfusion. The iNOS and the IL-1 receptor mRNA in the liver tissue was analyzed with real time PCR. The total Nitrite and Nitrate (NOx) in continuously sampled microdialysate (MD) from the liver was analyzed. In addition, the NOx levels in the serum were analyzed. RESULTS After 4 h of reperfusion, the iNOS mRNA was significantly higher in the R-IPC (ΔCt: 3.44 ± 0.57) group than in the IPC (ΔCt: 5.86 ± 0.82) group (P = 0.025). The IL-1 receptor transcription activity was reduced in the IPC group (ΔCt: 1.88 ± 0.53 to 4.81 ± 0.21), but not in the R-IPC group, during reperfusion (P = 0.027). In the MD, a significant drop in the NOx levels was noted in the R-IPC group (12.3 ± 2.2 to 4.7 ± 1.2 μmol/L) at the end of ischemia compared with the levels in early ischemia (P = 0.008). A similar trend was observed in the IPC group (11.8 ± 2.1 to 6.4 ± 1.5 μmol/L), although this difference was not statistically significant. The levels of NOx rose quickly during reperfusion in both groups. CONCLUSION IPC, but not R-IPC, reduces iNOS and IL-1 receptor transcription during early reperfusion, indicating a lower inflammatory reaction. NOx is consumed in the ischemic liver lobe.

Risk Adjustment in ALPPS Is Associated With a Dramatic Decrease in Early Mortality and Morbidity

Objective: To longitudinally assess whether risk adjustment in Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) occurred over time and is associated with postoperative outcome. Background: ALPPS is a novel 2-stage hepatectomy enabling resection of extensive hepatic tumors. ALPPS has been criticized for its high mortality, which is reported beyond accepted standards in liver surgery. Therefore, adjustments in patient selection and technique have been performed but have not yet been studied over time in relation to outcome. Methods: ALPPS centers of the International ALPPS Registry having performed ≥10 cases over a period of ≥3 years were assessed for 90-day mortality and major interstage complications (≥3b) of the longitudinal study period from 2009 to 2015. The predicted prestage 1 and 2 mortality risks were calculated for each patient. In addition, questionnaires were sent to all centers exploring center-specific risk adjustment strategies. Results: Among 437 patients from 16 centers, a shift in indications toward colorectal liver metastases from 53% to 77% and a reverse trend in biliary tumors from 24% to 9% were observed. Over time, 90-day mortality decreased from initially 17% to 4% in 2015 (P = 0.002). Similarly, major interstage complications decreased from 10% to 3% (P = 0.011). The reduction of 90-day mortality was independently associated with a risk adjustment in patient selection (P < 0.001; OR: 1.62; 95% CI: 1.36–1.93) and using less invasive techniques in stage-1 surgery (P = 0.019; OR: 0.39; 95% CI: 0.18–0.86). A survey indicated risk adjustment of patient selection in all centers and ALPPS technique in the majority (80%) of centers. Conclusions: Risk adjustment of patient selection and technique in ALPPS resulted in a continuous drop of early mortality and major postoperative morbidity, which has meanwhile reached standard outcome measures accepted for major liver surgery.

Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis

BACKGROUND Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. MATERIAL AND METHODS Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. RESULTS Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC [759 (84) μM] and the IRI [732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. CONCLUSIONS IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.