Small bowel transplantation: An overview

Small bowel transplantation (SBT) would, in theory, be the treatment of choice for patients suffering from the short bowel syndrome. Although SBT has been done with a considerable degree of success in some centers [36,145], it is by no means an established or widely applicable therapy for those with short bowel syndrome. The small bowel is unique among vascularized organ grafts because it not only elicits a vigorous rejection reaction but is also capable of inducing graft-versus-host disease (GVHD). Rejection of the graft does not only lead to loss of function but also to bacterial translocation. The risk of fatal sepsis is aggravated by the immunosuppression given to prevent rejection. Here, the history of SBT is described, and recent developments in experimental and clinical SBT, as well as future prospects for this theoretically optimal treatment modality for patients dependent on total parenteral nutrition (TPN) for life, are outlined

Tumour growth stimulation after partial hepatectomy can be reduced by treatment with tumour necrosis factor α

This study investigated whether partial hepatectomy enhances the growth of experimental liver metastases of colonic carcinoma in rats and whether treatment with recombinant human tumour necrosis factor (TNF) α can reduce this increased growth. Resection of 35 or 70 per cent of the liver was performed in inbred WAG rats, with sham-operated controls (five to eight animals per group). Immediately after surgery 5·105 CC531 colonic tumour cells were injected into the portal vein. After 28 days the animals were killed and the number of liver metastases counted. A 35 per cent hepatectomy induced a significant increase in the median number of liver metastases (28 versus 3 in controls), whereas a 70 per cent resection provoked excessive growth, consistently leading to more than 100 liver metastases and a significantly increased wet liver weight in all animals. TNF-α was given intravenously to rats following 70 per cent hepatectomy or sham operation in a dose of 160 μg/kg three times per week. This had only a marginal effect on tumour development in sham-operated rats but was very effective following partial hepatectomy (median 45 liver metastases). These observations confirm previous findings that surgical metastasectomy may act as a ‘double-edged sword’ by provoking outgrowth of dormant tumour cells and suggest that adjuvant treatment with TNF-α may be of benefit in patients undergoing resection of metastases

Blood transfusions and local tumor recurrence in colorectal cancer. Evidence of a noncausal relationship

OBJECTIVE. The authors analyzed the effect of blood transfusions on the pattern of colorectal cancer recurrence. BACKGROUND. Retrospective studies suggest that blood transfusions are associated with a poor prognosis in patients who undergo operations for colorectal malignancies. In a previously published, randomized trial, it was investigated whether autologous blood transfusions could overcome this putative detrimental effect. However, this did not appear to be the case. METHODS. In the current study, the authors analyzed the patterns of recurrence in 420 patients who underwent curative operations for colorectal cancer. RESULTS. Patients who did not require transfusions (N = 143) had significantly better disease-free survival than those who did need transfusions (N = 277); percentages at 4 years were 73% and 59%, respectively (p = 0.001). No difference was found between both groups in comparing cumulative percentages of patients having metastases; percentages at 4 years were 25% in the group that did not undergo transfusion and 27% in the transfused group. The percentage of cases having local recurrence, however, was significantly increased (p = 0.0006) in the transfused group as compared with the group that did not undergo transfusion; percentages at 4 years were 20% and 3%, respectively. The groups of patients receiving only allogeneic, only autologous, or both types of transfusions all had a significantly higher incidence of local recurrence than the patients who did not receive transfusions, but no differences were found between these three groups. CONCLUSIONS. These findings suggest that the association between blood transfusions and prognosis in colorectal cancer is a result of the circumstances that necessitate transfusions, leading to the development of local recurrences, but not of distant metastases

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

the feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment

Injection of recombinant tumor necrosis factor directly into liver metastases: an experimental and clinical approach

__Abstract__ Systemic treatment with tumor necrosis factor (TNF) is associated with side-effects, limiting its clinical use in the treatment of malignancies. To investigate the feasibility of other routes of administration experimental and clinical studies were started to establish the toxicity and antitumor activity of TNF after intratumoral (i.t.) injection. In a rat model for colon adenocarcinoma, tumor fragments, implanted subcutaneously or under the hepatic capsule, were treated with TNF injected i.v. or i.t. A dosage of 40 μg/kg was lethal when given i.v., but not i.t. Injection of TNF (40 μg/kg) directly into the tumor resulted in inhibition of tumor growth in the subcutaneous as well as subhepatic tumor model. A phase I study was started in patient

Reduction of peritoneal trauma by using nonsurgical gauze leads to less implantation metastasis of spilled tumor cells

OBJECTIVES: To evaluate whether infliction of peritoneal trauma would promote tumor cell adherence to damaged peritoneal surfaces; to investigate whether peritoneal damage could promote tumor growth of extraperitoneal tumors; and to evaluate whether the amount of trauma correlated with the degree of tumor cell adherence and local and distant tumor growth. BACKGROUND DATA: After potentially curative resection of colorectal carcinoma, the most common site for recurrence is locoregional. We previously demonstrated that surgical trauma induces a cascade of events leading to adhesion formation. The same mechanisms may be responsible for improved tumor cell adherence and growth facilitation in early local recurrence. METHODS: A reproducible rat model was used in which peritoneal damage was inflicted by standardized rubbing of the peritoneum with surgical gauzes of different texture. In the first experiment, tumor cell adherence and growth at traumatized and nontraumatized peritoneal sites were assessed semiquantitatively 3 weeks after perioperative intra-abdominal injection of CC-531 tumor cells. In the second experiment, the effect of peritoneal trauma on ectopic tumor growth was investigated (CC-531 implanted under the renal capsule). In the final experiment, we evaluated how soon after peritoneal traumatization tumor cell adhesion and growth-promoting factors were active and whether they could be passively transferred to naive nontraumatized abdominal cavities. RESULTS: A significant correlation between the amount of peritoneal trauma and the degree of tumor take at damaged peritoneal surfaces was found (p < or = 0.018). Tumor take at remote peritoneal sites not directly traumatized was also significantly higher after severe trauma than after moderate trauma of the peritoneum (p < or = 0.005). In addition, a significant correlation between the degree of peritoneal trauma and the growth of ectopic tumors under the renal capsule was observed (p < or = 0.009). The final experiment demonstrated that within a few hours after infliction of peritoneal trauma, tumor growth-promoting effects could be passively transferred to naive recipients. CONCLUSIONS: Surgical trauma is an important factor in the promotion of local recurrence. The enhancing effect of trauma is not restricted to the inflicted site but rather has a generalized character. Avoidance of unnecessary surgical trauma by using gentle techniques and materials is therefore indicated

Scavenging of reactive oxygen species leads to diminished peritoneal tumor recurrence

Previously, we demonstrated that RBCs inhibit the recurrence of perioperatively spilled tumor cells. The aim of this study was to identify on which RBC component(s) the inhibitory effect is based. By using a cell-seeding model in rats, the effect of RBC-related antioxidant scavengers [hemoglobin, catalase, and superoxide dismutase (SOD)] on peritoneal tumor recurrence was investigated. i.p. injection of hemoglobin caused 45% more tumor load (P < 0.0001). At least 40% inhibition of tumor recurrence was achieved with the use of catalase or SOD (P < 0.05). Combining SOD and catalase did not lead to additional inhibition of tumor recurrence. Inhibition of the overwhelmin

In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour

Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorbicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 μmol/l, while intratumoral CsA levels amounted to 3.6 μmol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting