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ABSTRACT: PURPOSE: Systemic chemotherapy still represents the gold standard in the treatment of irresectable colorectal liver metastases. Modern anticancer agents like the monoclonal antibody cetuximab have improved the outcome of patients in clinical studies. As hepatic arterial infusion (HAI) is capable to potentially increase the anticancer effect of cytostatics, we herein studied whether HAI of cetuximab (CE) as a single agent or in combination with oxaliplatin (OX) exerts increased anticancer effects compared to the systemic application (SYS) of the drugs. METHODS: WAG/Rij rats were randomized to eight groups and underwent 10 days after subcapsular hepatic tumor implantation either HAI or SYS of CE, OX, or the combination of both agents (CE + OX). Saline-treated animals served as controls. Tumor volume was measured at days 10 and 13 using three-dimensional ultrasound. On day 13, liver and tumor tissue was sampled for histological and immunohistochemical analysis. RESULTS: In controls, the tumor volume significantly increased from day 10 to 13. Application of OX alone via HAI or SYS did not inhibit tumor growth compared to controls. SYS of CE or CE + OX did also not reduce tumor growth. In contrast, HAI of CE and CE + OX significantly inhibited tumor growth. HAI of CE significantly reduced tumor vascularization as measured by the number of platelet endothelial cell adhesion molecule-1-positive cells and significantly increased the number of apoptotic tumor cells as measured by the cellular caspase-3 expression. CONCLUSION: HAI of CE and CE + OX reduces tumor growth of colorectal rat liver metastases involving the inhibition of angiogenesis and induction of tumor cell apoptosis.
International Journal of Colorectal Disease 12/2012; · 2.38 Impact Factor
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ABSTRACT: Colorectal carcinoma is, through to its high rate of liver metastasis (mCRC), the second most cause of cancer death worldwide. Tumor resection represents the only potential cure. In cases of unresectable disease systemic chemotherapy (sCHT) remains the therapy of choice. Modern sCHT regimens including biological agents can induce tumor response that leads to curative surgery of initially unresectable mCRC. However, liver-directed therapy via hepatic arterial infusion (HAI) may produce higher response rates than sCHT. Herein we studied whether a HAI of cetuximab (CE) plus bevacizumab (BE) with or without oxaliplatin (OX) can inhibit tumor growth in a rat model. WAG/Rij rats underwent subcapsular hepatic tumor implantation. After 10 days animals received either HAI or sCHT of CE plus BE, OX or all three drugs. Saline-treated animals served as controls. Tumor growth was estimated at day 10 and 13. On day 13 liver and tumor tissue was studied histologically and immunohistochemically. In controls the tumors grew about 50 %. OX alone was not capable of inhibiting tumor growth. In contrast, CE plus BE given as HAI significantly reduced tumor growth compared to sCHT (p < 0.05). HAI of CE plus BE combined with OX yielded an even more pronounced inhibition of tumor growth. Immunohistochemistry revealed a decreased tumor cell proliferation and tumor vascularization. The present study demonstrates that HAI of CE plus BE is effective to inhibit tumor growth. This effect is even more pronounced in combination with OX. Systemic application of these agents cannot achieve comparable effects.
Clinical and Experimental Metastasis 11/2012; · 3.52 Impact Factor
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ABSTRACT: Hepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth of residual metastases, the present study analyzes the potential benefit of a parenchyma-preserving liver surgery approach.
Data from a prospectively maintained database of patients undergoing liver resection for colorectal metastases were reviewed. Evaluation of outcome was performed using the Kaplan-Meier method. Correlations were calculated between clinical-pathological variables.
One hundred sixty-three patients underwent 198 liver resections for colorectal metastases: 26 major hepatectomies, 65 minor anatomical resections, 78 non-anatomical resections, as well as 29 combinations of minor anatomical and non-anatomical procedures. Overall 1-, 3-, and 5-year survival was 93%, 62%, and 40%, respectively. Patients with repeated liver resections had a 5-year survival of 27%. Interestingly, large dissection areas were associated with a significant reduction of the 5-year survival rate (33%). Five-year survival after major hepatectomy was not significantly reduced.
For colorectal liver metastases, minor resections offer a prolonged survival compared to major hepatectomies. As patients with stage IV colorectal disease are candidates for repeat resections, preservation of hepatic parenchyma is of increasing importance in the setting of multi-modal and repeated therapy approaches.
Langenbeck s Archives of Surgery 11/2011; 397(3):383-95. · 1.81 Impact Factor
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ABSTRACT: Unresectable colorectal liver metastases are commonly treated with systemic chemotherapy (SCT). Clinical studies on the effect of additional systemic application of bevacizumab (BE), a monoclonal antibody directed against vascular endothelial growth factor, to SCT showed a slight increase of patient survival. Herein, we studied in a rat model of colorectal liver metastasis whether a locoregional application of oxaliplatin (OX) and BE via hepatic arterial infusion (HAI) is more effective to inhibit metastatic growth compared to systemic drug application. Ten days after implantation of CC531 colorectal cancer cells into the left liver lobe of WAG/Rij rats, animals underwent either HAI or systemic intravenous application of BE (5 mg/kg body weight), OX (85 mg/m(2) body surface) or a combination of both. Sham-treated animals received saline and served as controls. Tumor volume was measured at days 10 and 13 using three dimensional ultrasound. At day 13 tumor tissue was analyzed histologically and immunohistochemically. Systemic application of OX, BE or their combination did not affect tumor volume when compared to controls. In contrast, HAI of BE and particularly the combination of BE and OX significantly reduced tumor volume. In the tumor tissue this was associated with a decrease of vascularization and cell proliferation as well as an increase of cell apoptosis, as indicated by a decreased number of PECAM-1- and PCNA-positive cells and an increased number of cleaved caspase-3-positive cells. Locoregional administration of BE, particularly in combination with OX, enhances the inhibitory effect on hepatic metastatic growth compared to systemic application of the drugs.
Clinical and Experimental Metastasis 11/2011; 29(2):91-9. · 3.52 Impact Factor
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ABSTRACT: Nightknife(©) is a novel reusable bipolar vessel sealing device. In the present study we analyzed its efficiency and quality of vessel sealing in comparison to a standard instrument (LigaSure™).
Mesenteric veins and arteries of 5 Swabian-Hall pigs were sealed by means of Nightknife and LigaSure. Thermal performance of both devices was assessed by dynamic thermography. Analysis of the sealed vessels included the determination of seal failure rates and heat-associated macroscopic tissue appearance.
The overall sealing rate of Nightknife was significantly higher than that of LigaSure (95.8% versus 87.0%; P=.012). This was associated with a more pronounced thermal spread (8.22±0.13 versus 7.12±0.10 mm; P=.012) and tissue desiccation (2.15±0.06 versus 1.86±0.07; P=.003). Moreover, sealing time (12.30±0.17 versus 7.72±0.17 seconds; P=.038) and tissue temperature (93.73°C±0.69°C versus 66.71°C±2.18°C; P=.001) were significantly higher with the use of Nightknife. Logistic regression analysis revealed that the degree of tissue desiccation correlated with the overall sealing success.
Nightknife is as appropriate as LigaSure for the successful sealing of mesenteric vessels despite significant differences in tissue alterations and sealing time between the two devices.
Journal of Laparoendoscopic & Advanced Surgical Techniques 09/2011; 21(7):659-63. · 1.40 Impact Factor
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ABSTRACT: To evaluate the influence of preoperative FOLFOX chemotherapy on CCL20/CCR6 expression in liver metastases of stage IV colorectal cancer (CRC) patients.
Using Real Time-PCR, enzyme-linked immunosorbent assay, Western Blots and immunohistochemistry, we have analyzed the expression of CCL20, CCR6 and proliferation marker Ki-67 in colorectal liver metastasis (CRLM) specimens from stage IV CRC patients who received preoperative FOLFOX chemotherapy (n = 53) and in patients who did not receive FOLFOX chemotherapy prior to liver surgery (n = 29).
Of the 53 patients who received FOLFOX, time to liver surgery was ≤ 1 mo in 14 patients, ≤ 1 year in 22 patients and > 1 year in 17 patients, respectively. In addition, we investigated the proliferation rate of CRC cells in liver metastases in the different patient groups. Both CCL20 and CCR6 mRNA and protein expression levels were significantly increased in patients who received preoperative FOLFOX chemotherapy ≤ 12 mo before liver surgery (P < 0.001) in comparison to patients who did not undergo FOLFOX treatment. Further, proliferation of CRLM cells as measured by Ki-67 was increased in patients who underwent FOLFOX treatment. CCL20 and CCR6 expression levels were significantly increased in CRLM patients who had undergone preoperative FOLFOX chemotherapy.
This chemokine/receptor up-regulation could lead to increased proliferation/migration through an autocrine mechanism which might be used by surviving metastatic cells to escape cell death caused by FOLFOX.
World Journal of Gastroenterology 07/2011; 17(26):3109-16. · 2.47 Impact Factor
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ABSTRACT: Delayed gastric emptying (DGE) is still a common postoperative complication after pancreaticoduodenectomy (PD). Because different reconstruction techniques after PD and the influence of motilin receptor expression are controversially discussed, the present study analyzed the influence of a total orthotopic reconstruction technique on DGE after PD.
Data from patients undergoing PD and reconstruction using a total orthotopic technique were reviewed, and correlations between DGE and clinico-pathological variables were analyzed. Motilin receptor expression was measured within the duodenum, jejunum, and terminal ileum.
Three hundred seven patients received orthotopic reconstruction using a single jejunal loop. DGE grade B or C could be observed in 16.6% of the patients. DGE was significantly associated with the severity of a postoperative pancreatic fistula, the need for a reoperation, wound infections, and vascular complications. Furthermore, these parameters correlated significantly with the grade of DGE. The density of motilin receptor expression decreased significantly behind the duodenum in aboral direction.
The orthotopic reconstruction after PD is the shortest distance without resection of a jejunal segment, preserves the greatest length of jejunum and thus the highest density of motilin receptors, and should therefore be recommended to reduce the incidence of DGE after PD.
Journal of Gastrointestinal Surgery 07/2011; 15(7):1158-67. · 2.83 Impact Factor
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ABSTRACT: Wound infections after abdominal surgery are still frequent types of nosocomial infections. Suture materials might serve as a vehicle for mechanical transport of bacteria into the surgical wound. To reduce bacterial adherence to surgical sutures, triclosan-coated polyglactin 910 suture materials with antiseptic activity (Vicryl plus®) were developed. The aim of this prospective non-randomized clinical pathway driven study was to ascertain if the use of Vicryl plus® reduced the number of wound infections after transverse laparotomy.
Between October 2003 and October 2007, 839 operations were performed using a transverse abdominal incision. In the first time period, a PDSII® loop suture was used for abdominal wall closure. In the second time period, we used Vicryl plus®. Risk factors were collected prospectively to compare the two groups.
Using a PDSII® loop suture for abdominal wall closure in the first time period, 9.2% of the patients developed wound infections. In the second time period, using Vicryl plus®, the number of wound infections decreased to 4.3% (p < 0,005). Both groups were comparable regarding risk factors despite no other changes in protocols of patient care.
Antiseptic-coated loop Vicryl suture for abdominal wall closure can be superior to PDSII sutures in respect to the development of wound infections after a two-layered closure of transverse laparotomy.
Langenbeck s Archives of Surgery 04/2011; 396(6):845-50. · 1.81 Impact Factor
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ABSTRACT: Liver insufficiency after major hepatectomy still represents a serious challenge in liver surgery. Although some previous studies indicate that erythropoietin (EPO) and its analogue darbepoetin-alpha (DPO) may improve liver function and liver regeneration, little is known on their effect on tumor growth after hepatectomy. Because EPO may promote tumor progression, we herein studied the effect of DPO on tumor growth after major hepatectomy.
CT26.WT colorectal cancer cells were implanted into the left liver lobe of BALB/c mice. Animals underwent 50% hepatectomy (Phx) and received 10 microg/kg DPO-treatment. Additional Phx animals received only saline treatment. Nonhepatectomized animals with DPO-treatment or saline treatment served as controls. One week after hepatectomy angiogenic blood vessel formation, leukocyte-endothelial cell interaction, tumor cell proliferation, apoptotic cell death, and tumor growth were studied using intravital fluorescence microscopy, histology, Immunohistochemistry, and Western blot analysis.
Phx significantly enhanced the growth of liver metastases. This was associated with an increase of tumor capillary density and tumor cell proliferation. In nonhepatectomized animals, DPO only slightly affected metastatic growth. In hepatectomized animals, however, DPO significantly enhanced the Phx-induced stimulation of tumor growth. This was associated with an increased tumor capillary density, a decreased leukocyte-endothelial cell interaction, and a reduced cleaved caspase-3 expression of the CT26.WT cells.
: Our data indicate that DPO significantly enhances the hepatectomy-induced stimulation of colorectal liver metastatic growth by increasing neovascularization, suppressing intratumoral leukocyte recruitment, and reducing tumor cell apoptosis. Thus, EPOs may not be used in patients undergoing hepatectomy for malignant tumor resection.
Annals of surgery 07/2010; 252(1):131-41. · 7.90 Impact Factor
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ABSTRACT: A 70-year-old male patient presented with abdominal pain, acute renal failure, and fever 2 years after laparoscopic cholecystectomy. During the surgical drainage of the abscess formation on the patient's right flank, a huge gallstone was found in the retroperitoneum. The patient was dismissed from the hospital 11 days after admission with normal lab panel and restored renal function.
Langenbeck s Archives of Surgery 03/2010; 395(3):285-7. · 1.81 Impact Factor
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ABSTRACT: Therapy of unresectable hepatic metastases may include tumor necrosis factor (TNF)-alpha treatment. Because of its serious systemic side effects, TNF-alpha is only used in isolated hepatic perfusion. This, however, is a technically demanding procedure with a substantial mortality rate. The infusion of TNF-alpha via the hepatic artery without hepatic isolation would be less invasive. Systemic side effects, however, have not been studied yet. Therefore, we evaluated in pigs the effects of TNF-alpha hepatic artery infusion (HAI) on systemic hemodynamics, inflammation, and organ injury.
Animals were randomized in three groups. In group 1, HAI was performed with 0.9% NaCl (n = 6). In group 2, 20 microg/kg TNF-alpha (n = 6), and in group 3, 40 microg/kg TNF-alpha (n = 6) were added. HAI was performed over 15 min, followed by 120 min of observation. Finally, 250 ml hydroxyethylstarch (HAES; 6%) was administered for resuscitation and hemodynamics were analyzed for another 30 min.
Hepatic artery TNF-alpha infusion did not cause complications such as bleeding, cardiac depression, pulmonary dysfunction, or SIRS. TNF-alpha induced a 30% decrease of MAP and systemic vascular resistance, as well as a rise in heart rate and endexspiratory pCO(2). TNF-alpha also moderately (10-20%) lowered the cardiac preload and induced a metabolic acidosis, which, however, could easily be controlled. TNF-alpha HAI did not induce liver toxicity, and all hemodynamic changes normalized either spontaneously within the 120-min observation period, or, at least, after HAES resuscitation.
TNF-alpha-based HAI, which may represent a minimally invasive alternative to isolated hepatic perfusion, can be performed without early systemic hemodynamic complications.
International Journal of Colorectal Disease 11/2009; 25(4):523-32. · 2.38 Impact Factor
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ABSTRACT: A 49-year-old woman presented with acute abdominal pain in the right iliac fossa in our emergency department. Pain was abrupt in onset and severely colicky in nature. Abnormal laboratory values included a C-reactive protein of 75 mg/L and a CA-125 of 70.3 U/mL. White blood cell count was normal. Abdominal computed tomography (CT) scan revealed an inhomogeneous mass of 9.5 x 3.5 x 5.5 cm in diameter close to the appendix vermiformis and the sigmoid colon. Because of the clinical symptoms of an acute abdomen an explorative laparotomy was performed. Intraoperatively a pedunculated tumor beginning at the serosa of the sigmoid colon was found. The appendix was unremarkable. The macroscopic aspect as well as the backtable incision of the tumor was suspicious of an intraperitoneal liposarcoma. Rapid section and histopathologic examination revealed necrotic fat tissue without any malignancy. The patient was discharged from the hospital 7 days after the operation with normal laboratory parameters and without further complication. When epiploic appendagitis is evident as a big tumor mass in addition to clinical symptoms of an acute abdomen and elevated tumor markers, surgical exploration is mandatory.
International surgery 96(2):117-9. · 0.36 Impact Factor
