Complications after free flap surgery: do we need a standardized classification of surgical complications?

Our main objective was to apply a standard classification to surgical complications after free flap surgery for reconstructions of the head and neck. We used the modified Clavien-Dindo classification in a cohort of 79 patients who were having reconstructions with jejunal free flaps simultaneously with resections of oral and oropharyngeal cancer. The most common minor complication was the need for a blood transfusion, and the most common major complication of a respiratory nature. The medical complications, and those at the recipient site and the donor site were 53/79 (67%), 44/79 (56%), and 9/79 (11%), respectively. The Clavien-Dindo classification is suitable and can easily be used to evaluate postoperative complications after free tissue transfer.

Comparison of lymphangiogenesis between primary colorectal cancer and corresponding liver metastases.

BACKGROUND: Liver metastasis (LM) is the determining factor of poor prognosis in colorectal cancer (CRC). Peripheral lymphatico-venous communications have been discussed as a potential pathway of tumor cell dissemination for the development of LMs. In the current study, we investigated the clinical impact of the lymphangiogenic activity in CRCs and their corresponding LMs. PATIENTS AND METHODS: In 47 patients with CRC, the primary tumors and the corresponding LMs were investigated. Lymphangiogenesis (LMVD), lymphovascular invasion (LVI), lymphatic vascular endothelial growth factor C expression (VEGF-C) were investigated RESULTS: A significant correlation was observed between LMVD and LVI in CRCs (p=0.001) as well as in LMs (p=0.0001). LMVD in CRC correlated significantly with that in LMVD-LMs (p=0.026) and LVI in LMs (p=0.036). Survival analysis reveilled a significant difference in disease free and overall survival between patients with and without VEGF-C expression in LMs (p=0.0019 and p=0.0101, respectively). CONCLUSION: Our data provide evidence for an important role of lymphangiogenesis in liver metastasis of CRC and provide further support for a possible role of a lymphatico-venous metastatic pathway.

Evaluation of chemotherapy-associated liver injury in patients with colorectal cancer liver metastases using indocyanine green clearance testing.

BACKGROUND: Systemic chemotherapy may render initially unresectable colorectal cancer liver metastases resectable. Histopathologic examinations of resected nontumoral liver tissue revealed chemotherapy-associated liver injuries, which was recognized to impair the function of the remnant liver. We therefore evaluated whether indocyanine green (ICG) plasma clearance helps to assess chemotherapy-induced liver damage. METHODS: Data of 101 liver resections performed between 2006 and 2008 for colorectal liver metastases were analyzed for this study. Eighteen patients had liver resection without preoperative treatment, whereas 83 patients underwent neoadjuvant chemotherapy before surgery. ICG clearance was assessed by pulse densitometry before surgery. RESULTS: Comparison of ICG retention clearances demonstrated that patients pretreated with systemic chemotherapy had a significantly lower plasma disappearance rate (ICG-PDR; 19.3 ± 5.9 vs. 23.1 ± 3.8%/min; P = 0.002) and a significantly elevated ICG retention rate at 15 min (7.9 ± 6.6 vs. 3.8 ± 1.9%; P < 0.001). The percentage of subjects with an abnormal ICG-PDR (≤18%/min) was significantly higher in the pretreated group (48.2% vs. 5.6%; P = 0.001). Patients with an ICG-PDR of ≤18 had a prolonged postoperative hospital stay and experienced four times more complications in their postoperative course. CONCLUSIONS: ICG clearance helps to identify patients with impaired liver function after neoadjuvant chemotherapy and aids in the estimation of the postoperative risk of morbidity after liver resection for colorectal liver metastases.

Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy.

BACKGROUND: Chemotherapy-induced liver injury is a considerable problem in patients undergoing surgery for colorectal liver metastases, since an increase in postoperative morbidity and mortality has been observed. We investigated whether liver damage had further implications on long-term outcome in these patients. MATERIALS AND METHODS: Liver specimens from 196 patients resected for colorectal liver metastases were evaluated for chemotherapy-associated hepatic damage in the nontumorous liver. Injury patterns were correlated with recurrence free (RFS) and overall survival (OS). Factors leading to sinusoidal injury were identified. RESULTS: Patients who developed grade 2 or 3 sinusoidal dilatation had a significantly shorter RFS (hazard ratio [HR] 2.05; 95% confidence interval [95% CI] 1.23-3.39, P = .005) and OS (HR 2.90; 95% CI 1.61-6.19, P < .001), compared to patients without this alteration. Those patients also had significantly more intrahepatic recurrences (66.7% vs 30.5%, P = .003). Other patterns of chemotherapy-associated liver damage (nonalcoholic steatohepatitis, fibrosis) were not associated with impaired survival. Factors indicating sinusoidal injury were oxaliplatin-based chemotherapy, tumor size >5 cm, and elevated alkaline phosphatase or gamma glutamyltransferase. CONCLUSIONS: Sinusoidal obstruction syndrome due to oxaliplatin-based chemotherapy may not only compromise perioperative outcome, but can lead to early recurrence and decreased survival in the long term. Strategies to prevent this condition are clearly needed.

Liver resection remains a safe procedure after neoadjuvant chemotherapy including bevacizumab: a case-controlled study.

OBJECTIVE: This study was conducted to analyze if the combination of Bevacizumab with standard chemotherapy increases postoperative morbidity and mortality after resection of colorectal liver metastases as compared with resection after chemotherapy alone. Parameters contributing to an increased morbidity were evaluated. SUMMARY BACKGROUND DATA: Most patients referred for colorectal liver metastases are treated with neoadjuvant chemotherapy before hepatic surgery. Targeted agents like the vascular endothelial growth factor-antagonist Bevacizumab are increasingly added to standard therapy to prolong survival; however, little is known about the consequences of this policy in the perioperative period. METHODS: One hundred-two patients treated between 2005 and 2009, who received neoadjuvant chemotherapy combined with Bevacizumab (CHT + B) were identified. A cohort of 112 patients treated without chemotherapy alone before resection served as the control group (CHT). Complications were graded within an established staging system and the therapeutic consequences were laid down. Uni- and multivariate analysis of factors contributing to postoperative complications in the CHT + B group was performed using a logistic regression model. RESULTS: Postoperative complications occurred in 45 (44%, CHT + B) and 38 (34%, CHT) patients, respectively (P = 0.216). The incidence of severe complications requiring surgical or radiologic intervention or leading to organ failure was 10.8% in the CHT + B group and 7.1% in the CHT group (P = 0.350). Increased age, low serum albumin, resection of more than 3 liver segments and synchronous bowel procedures requiring an anastomosis were associated with an increased morbidity rate in the multivariate regression analysis. No patient died in either group. CONCLUSIONS: The addition of Bevacizumab to standard chemotherapy before resection of colorectal liver metastases does not seem to increase postoperative morbidity. Caution should be given to extended resections >3 liver segments and synchronous bowel anastomoses.

Bevacizumab improves pathological response of colorectal cancer liver metastases treated with XELOX/FOLFOX.

BACKGROUND: Histological response of colorectal cancer liver metastases to chemotherapy may be graded based on the extent of tumor regression. The knowledge about the effect of bevacizumab, if given in addition to fluoropyrimidines and oxaliplatin, on tumor regression and its consequences on clinical outcome is limited. MATERIALS AND METHODS: Resected liver metastases from patients of 2 prospective nonrandomized trials (fluoropyrimidines and oxaliplatin +/- bevacizumab) were analyzed retrospectively. Histological response was analyzed according to an established tumor regression grading for colorectal cancer liver metastases. Tumor regression grades (TRGs) were correlated to progression-free and overall survival. RESULTS: Bevacizumab improved tumor regression to chemotherapy significantly. Improvement in histological response was translated into a significant prolongation of progression-free and overall survival. CONCLUSIONS: Classifying histological response based on tumor regression grades qualifies to predict the outcome of patients with colorectal cancer liver metastases. Tumor regression grading provides a standardized pathological response evaluation, against which radiologic response on chemotherapy including biologicals can be prospectively evaluated.

Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells.

The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials.

Surgery after neoadjuvant chemotherapy for colorectal liver metastases is safe and feasible in elderly patients.

BACKGROUND: Surgery for colorectal liver metastases is part of the endeavor to cure metastatic colorectal cancer (mCRC). Neoadjuvant chemotherapy increases progression free survival in resectable patients. The safety and feasibility of this concept has not been investigated in elderly patients. METHODS: We performed a comparative analysis of data from 244 patients who were resected for colorectal liver metastases between 1999 and 2004 at our institution. Seventy patients were aged 70 or older; they form the basis of this analysis. RESULTS: Twenty-nine patients received neoadjuvant chemotherapy (oxaliplatin-based chemotherapy (XELOX), 19; 5-fluorouracil (5-FU), 10) prior to surgery. XELOX was associated with higher response rates to chemotherapy (CR + PR: XELOX 68% vs. 5-FU 0%, P = 0.001), and responding patients had a better overall (OS, P < 0.001) and recurrence free survival (RFS, P < 0.001) compared to others. Response to neoadjuvant chemotherapy was the only factor on multivariate analysis predicting longer OS and RFS (P = 0.01 and P = 0.001). CONCLUSION: Neoadjuvant chemotherapy can be administered safely in patients older than 70 years and appears to be effective in prolonging long-term outcome. Patients responding to neoadjuvant treatment have a significantly better prognosis after liver resection.

Influence of hepatic resection margin on recurrence and survival in intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare disease in the Western world, hence little is known about its optimal surgical management. We analyzed whether hepatic resection margin is a prognostic factor for local or distant recurrence and survival in patients resected with curative intent. METHODS: Seventy-four patients underwent potentially curative surgery for ICC at our institution from 1994 to 2007. Demographic, and tumor- and surgery-related details including hepatic resection margin were recorded, patients were followed up for recurrence and survival. All patients were resected using modern dissection devices (CUSA or Waterjet). RESULTS: Fifty-nine patients (80%) underwent R0 resection, 15 (20%) had a resection margin greater than 10 mm (wide margin, WM) and 38 (51%) between 1 and 10 mm (close margin, CM). In 14 patients (19%), hepatic resection margin was involved on histological examination; perioperative mortalities were excluded from analysis (n = 7). Forty-seven patients developed recurrence (WM, CM, and R1): hepatic recurrence was observed in 40%, 58%, and 50% of patients; extrahepatic spread occurred in 27, 16, and 14%; and 33, 26, and 36% had no recurrence of disease so far (P = 0.755). There was no difference between groups regarding local versus disseminated hepatic recurrence. Median recurrence free survival was 11.4 months (WM), 9.8 months (CM), and 9.9 months (R1), respectively (P = 0.880). Median overall survival was 27.2 months (WM), 29.7 months (CM), and not reached in the R1 group, (P = 0.350). CONCLUSION: Hepatic resection margin seems to play a minor role in the prognosis of ICC as long as complete tumor clearance can be achieved with a modern liver dissection technique.

Adequate preoperative staging rarely leads to a change of intraoperative strategy in patients undergoing surgery for colorectal cancer liver metastases.

BACKGROUND: Diagnostic tools used prior to hepatic surgery have significantly advanced during the last decade. We investigated the value of preoperative staging on detection of additional resectable hepatic lesions in metastatic colorectal cancer patients. METHODS: One hundred ninety-four consecutive resections for colorectal liver metastases between January 2002 and December 2005 were prospectively analyzed. Data on imaging (multidetector computed tomography [MDCT] and magnetic resonance imaging [MRI]) were compared to intraoperative findings by intraoperative sonography and bimanual palpation together with histopathological examination. Univariate and multivariate analysis of factors influencing recurrence was performed. RESULTS: In 16 (8.2%) resections, additional lesions were detected intraoperatively. In 11 cases (5.7%), these were small (<1 cm) and subcapsular. Detection of additional tumors was associated with shorter median recurrence free survival (5.4 vs. 13.4 months; P < .001) even though all lesions were resected and risk of recurrence was stratified by the Fong score. Patients treated with neoadjuvant chemotherapy did not generally have an increased risk of additional tumors; however, intraoperative detection of new lesions was associated with inferior outcome in this subgroup (median RFS 4.6 vs. 18.3 months in responders, P < .001). CONCLUSION: Preoperative imaging with contrast-enhanced MDCT and MRI is efficient and very seldom leads to changes in intraoperative strategy. Patients exhibiting additional resectable hepatic lesions upon surgery have a high risk for early recurrence and should be monitored closely during follow-up.

Activated mammalian target of rapamycin is an adverse prognostic factor in patients with biliary tract adenocarcinoma.

PURPOSE: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. EXPERIMENTAL DESIGN: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. RESULTS: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR-positive tumors as compared with patients with p-mTOR-negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). CONCLUSIONS: Patients with BTA and p-mTOR-positive tumors have a significantly shorter overall survival than patients with p-mTOR-negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.