Axel Andres

Effect of Surgical Margin Status on Survival and Site of Recurrence After Hepatic Resection for Colorectal Metastases

Objective:To evaluate the influence of surgical margin status on survival and site of recurrence in patients treated with hepatic resection for colorectal metastases. Methods:Using a multicenter database, 557 patients who underwent hepatic resection for colorectal metastases were identified. Demographics, operative data, pathologic margin status, site of recurrence (margin, other intrahepatic site, extrahepatic), and long-term survival data were collected and analyzed. Results:On final pathologic analysis, margin status was positive in 45 patients, and negative by 1 to 4 mm in 129, 5 to 9 mm in 85, and ≥1 cm in 298. At a median follow-up of 29 months, the 1-, 3-, and 5-year actuarial survival rates were 97%, 74%, and 58%; median survival was 74 months. Tumor size ≥5 cm, >3 tumor nodules, and carcinoembryonic antigen level >200 ng/mL predicted poor survival (all P < 0.05). Median survival was 49 months in patients with positive margins and not yet reached in patients with negative margins (P = 0.01). After hepatic resection, 225 (40.4%) patients had recurrence: 21 at the surgical margin, 56 at another intrahepatic site, 82 at an extrahepatic site, and 66 at both intrahepatic and extrahepatic sites. Patients with negative margins of 1 to 4 mm, 5 to 9 mm, and ≥1 cm had similar overall recurrence rates (P > 0.05). Patients with positive margins were more likely to have surgical margin recurrence (P = 0.003). Adverse preoperative biologic factors including tumor number greater than 3 (P = 0.01) and a preoperative CEA level greater than 200 ng/mL (P = 0.04) were associated with an increased risk of positive surgical margin. Conclusions:A positive margin after resection of hepatic colorectal metastases is associated with adverse biologic factors and increased risk of surgical-margin recurrence. The width of a negative surgical margin does not affect survival, recurrence risk, or site of recurrence. A predicted margin of <1 cm after resection of hepatic colorectal metastases should not be used as an exclusion criterion for resection.

Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary

In many patients with advanced synchronous liver metastases from colorectal tumours, the metastases progress during treatment of the primary, precluding curative treatment. The authors have investigated a management strategy that involves high‐impact chemotherapy first, resection of liver metastases second and finally removal of the primary tumour in patients with adverse prognostic factors.

Comparison between hepatic wedge resection and anatomic resection for colorectal liver metastases

Some investigators have suggested that wedge resection (WR) confers a higher incidence of positive margins and an inferior survival compared with anatomic resection (AR) of colorectal liver metastases (CLM). We sought to investigate the margin status, pattern of recurrence, and overall survival of patients with CLM treated with WR or AR. We identified 253 consecutive patients, in a multi-institutional database from 1991 to 2004, who underwent either WR or AR. WR was defined as a nonanatomic resection of the CLM, and AR was defined as single or multiple resections of one or two contiguous Couinaud segments. Clinicopathologic factors were analyzed with regard to pattern of recurrence and survival. One hundred six WRs were performed in 72 patients and 194 ARs in 181 patients. There was no difference in the rate of positive surgical margin (8.3%), overall recurrence rates, or patterns of recurrence between patients treated with WR vs. AR. Patients who had a positive surgical resection margin were more likely to recur at the surgical margin regardless of whether they underwent WR or AR. The median survival was 76.6 months for WR and 80.8 months for AR, with 5-year actuarial survival rates of 61% and 60%, respectively. AR is not superior to WR in terms of tumor clearance, pattern of recurrence, or survival. WR should remain an integral component of the surgical treatment of CLM.

‘Liver First’ Approach in the Treatment of Colorectal Cancer with Synchronous Liver Metastases

Background: In patients with synchronous colorectal liver metastases, an approach reversing the traditional therapeutic order – i.e. starting with chemotherapy first, doing the liver surgery second, and performing the colorectal surgery last – is theoretically appealing as it avoids the risk of metastatic progression during treatment of the primary tumor. The present series updates on a previously reported pilot experience. Patients and Methods: 35 patients with advanced synchronous colorectal metastases and nonobstructive colorectal tumors were treated with the reversed approach. Data were collected in a prospective database. Results: The median number of metastases was 6, the median size of the largest metastasis was 6 cm. Five patients could not complete the program (one death from sepsis during chemotherapy, 3 cases of progressive disease under treatment, and one case of vanishing liver metastases). The remaining 30 patients responded and underwent R0 liver resections with no major complications. One patient needed a Hartmann’s procedure for obstruction after a first-step hepatectomy, and 1 patient had a rectal anastomotic leak. Median survival was 44 months. Overall survival rates of the 30 patients who completed the program at 1, 2, 3, 4 and 5 years were 100, 89, 60, 44 and 31%. Conclusions: The reverse approach appeared feasible and safe, with operability and survival rates better than expected for patients with similar severity. Potential problems, in particular regrowth of vanishing metastases and primary tumors, chemotherapy-associated liver damage, and large bowel obstruction, can be minimized by careful multidisciplinary selection, planning and execution.

A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study.

Background:Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. Methods:The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. Results:A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). Conclusions:Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed.

The Fas pathway is involved in pancreatic beta cell secretory function.

Pancreatic β cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in β cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates β cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a β cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient β cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased β cell mass. Up-regulation of FLIP enhanced NF-κB activity via NF-κB-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.

Improved Long-Term Outcome of Surgery for Advanced Colorectal Liver Metastases: Reasons and Implications for Management on the Basis of a Severity Score

BackgroundThe outcome of liver resection for colorectal liver metastases (CRLM) appears to be improving despite the fact that surgery is offered to patients with more-severe disease. To quantify this assumption and to understand its causes we analyzed a series of patients on the basis of a standardized severity score and changes in management occurring over the years.MethodsPatients’ characteristics, operative data, chemotherapies and follow-up were recorded. CRLM severity was quantified according to Fong’s clinical risk score (CRS), modified to take into account the presence of bilateral liver metastases. Three periods were analyzed, in which different indications, surgical strategies and uses of chemotherapy were applied: 1984–1992, 1993–1998, and 1999–2005.ResultsBetween January 1984 and December 2005, 210 liver resections were performed in 180 patients (1984–1992, 43 patients; 1993–1998, 42 patients; 1999–2005, 95 patients). CRLM severity increased throughout the time periods, as did the use of neoadjuvant chemotherapies, repeat resections, and multistep procedures. While the disease-free survival did not improve over time, the 1-, 3- and 5-year overall survival rate increased from 85%, 30%, and 23% in the first period, to 88%, 60%, and 34% in the second period, and to 94%, 69%, and 46% in the third period.ConclusionsAnalysis according to the CRS showed that despite the fact that patients had more severe disease, the overall survival improved over the years, mainly thanks to more aggressive treatment of recurrent disease. Management of advanced CRLM should, from the start, take into account the likelihood of secondary procedures.

Treatment of fulminant liver failure by transplantation of microencapsulated primary or immortalized xenogeneic hepatocytes

Abstract:  Background:  The aim of this study was to evaluate in vitro and in vivo functions of isolated hepatocytes after immortalization, cryopreservation, encapsulation and xenotransplantation into mice with fulminant liver failure (FLF).

Dangerous halo after neoadjuvant chemotherapy and two-step hepatectomy for colorectal liver metastases

Bilobar colorectal metastases are a therapeutic challenge and require a multidisciplinary approach. The aim of this study was to describe the clinical and histological outcomes of patients having neoadjuvant chemotherapy and two‐step hepatectomy with right portal vein occlusion for advanced bilateral colorectal metastases.

Preliminary Single-Center Canadian Experience of Human Normothermic Ex Vivo Liver Perfusion: Results of a Clinical Trial.

After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver function compared with standard static cold storage (SCS). We present a preliminary single‐center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3–22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent‐to‐treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.