Richard L. Marquet

Blood Transfusions and Prognosis in Colorectal Cancer

BACKGROUND Blood transfusions may adversely affect the prognosis of patients treated surgically for cancer, although definite proof of this adverse effect has not been reported. METHODS We carried out a randomized trial to investigate whether the prognosis in patients with colorectal cancer would be improved by a program of autologous blood transfusion as compared with the current practice of allogeneic transfusion. Patients in the autologous-transfusion group were required to donate two units of blood before surgery. RESULTS A total of 475 patients were evaluated. We found no significant difference in prognosis between the allogeneic-transfusion group (236 patients) and the autologous-transfusion group (239 patients); colorectal cancer-specific survival rates at four years were 67 percent and 62 percent, respectively (P = 0.39). Among the 423 patients who underwent curative surgery, 66 percent of those in the allogeneic-transfusion group and 63 percent of those in the autologous-transfusion group had no recurrence of colorectal cancer at four years (P = 0.93). We also found that the risk of recurrence was significantly increased in patients who received blood transfusions, either allogeneic or autologous, as compared with patients who did not require transfusions; the relative rates of recurrence were 2.1 (P = 0.01) and 1.8 (P = 0.04), respectively; these rates did not differ significantly from each other. CONCLUSIONS The use of autologous blood as compared with allogeneic blood for transfusion does not improve the prognosis in patients with colorectal cancer. Regardless of their type, transfusions are associated with poor prognosis, probably because of the circumstances that necessitate them.

Impact of gas(less) laparoscopy and laparotomy on peritoneal tumor growth and abdominal wall metastases

OBJECTIVE A tumor model in the rat was used to study peritoneal tumor growth and abdominal wall metastases after carbon dioxide (CO2) pneumoperitoneum, gasless laparoscopy, and laparotomy. SUMMARY BACKGROUND DATA The role of laparoscopic resection of cancer is under debate. Insufflation of the peritoneal cavity with CO2 is believed to be a causative factor in the development of abdominal wall metastases after laparoscopic resection of malignant tumors. METHODS In the solid tumor model, a lump of 350-mg CC-531 tumor cells was placed intraperitoneally in rats having CO2 pneumoperitoneum (n = 8), gasless laparoscopy (n = 8), or conventional laparotomy (n = 8). After 20 minutes, the solid tumor was removed through a laparoscopic port or through the laparotomy. In the cell seeding model, 5 x 10(5) CC-531 cells were injected intraperitoneally before CO2 pneumoperitoneum (n = 12), gasless laparoscopy (n = 12), or laparotomy (n = 12). All operative procedures lasted 20 minutes. After 6 weeks, in the solid tumor model and after 4 weeks in the cell seeding model, tumor growth was scored semiquantitatively. All results were analyzed using the analysis of variance. RESULTS In the solid tumor model, peritoneal tumor growth in the laparotomy group was greater than in the CO2 pneumoperitoneum group (p < 0.01). Peritoneal tumor growth in the CO2 group was greater than in the gasless group (p < 0.01). The size of abdominal wall metastases was greater at the port site of extraction of the tumor than at the other port sites (p < 0.001). In the cell seeding model, peritoneal tumor growth was greater after laparotomy in comparison to CO2 pneumoperitoneum (p < 0.02). Peritoneal tumor growth in the CO2 group was greater than in the gasless group (p < 0.01). The port site metastases in the CO2 group were greater than in the gasless group (p < 0.01). CONCLUSIONS The following conclusions can be made: 1) that direct contact between solid tumor and the port site enhances local tumor growth, 2) that laparoscopy is associated with less intraperitoneal tumor growth than laparotomy, and 3) that insufflation of CO2 promotes tumor growth at the peritoneum and is associated with greater abdominal wall metastases than gasless laparoscopy.

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 naïve 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 naïve 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.

Port-site metastases

AbstractBackground: Port-site metastases after laparoscopic procedures in patients with digestive malignancies have evoked concern. The pathogenesis of port-site metastases remains unclear. Two experiments in rats were performed to determine the impact of both tissue trauma and leakage of CO2 along trocars (chimney effect) in the development of port-site metastases. Methods: Experiment I: Ten WAG rats had four 5-mm incisions in all abdominal quadrants. The incisions on the right side were crushed to induce tissue trauma. After inserting 5-mm trocars in all incisions, a pneumoperitoneum was created, and CC-531 tumor cells were injected intraperitoneally. CO2 was insufflated for 20 min. Experiment II: Ten WAG rats had 5-mm incisions in the left and right abdominal upper quadrant. A 5-mm trocar was inserted in the incision in the left upper quadrant, and a 2-mm trocar was inserted in the incision in the right upper quadrant. After insufflating the abdomen, CC-531 tumor cells were injected intraperitoneally. Total leakage of CO2 along the trocar in the right quadrant was 10 liters. After 4 weeks, in both experiments, the tumor deposits at the trocar sites were assessed. Statistical analysis was performed by the Wilcoxon matched-pairs test. Results: Experiment I: The median weight of tumor deposits at the trocar sites without induced tissue trauma was 22 mg. At the traumatic port sites, median weight of tumor deposits was 316 mg (p= 0.007). Experiment II: The median weight of tumor deposits at the leaking trocar sites was 478 mg and at the control sites 153 mg (p= 0.009). Conclusion: Tissue trauma at trocar sites and leakage of CO2 along a trocar appear to promote implantation and growth of tumor cells at port sites.

Laparoscopic surgery in the rat. Beneficial effect on body weight and tumor take.

AbstractBackground: The ability of laparoscopic techniques to treat malignant disease is controversial. We developed a rat model to assess metabolic and oncological effects of laparoscopic surgery. Methods: Experiment I. The postoperative body weight in 10 rats having laparoscopic bowel resection (group I), 10 rats having open bowel resection (group II) and 5 rats having anesthesia only (group III) was determined. Experiment II. Tumor take was scored in 11 rats having laparoscopic bowel resection (group IV), 11 rats having open bowel resection (group V), 6 rats having CO2 pneumoperitoneum without bowel resection (group VI) and 6 rats having anesthesia only (group VII). All rats had CC531 cancer cells injected intraperitoneally postoperatively. Results: Experiment I. Body weight loss in group I compared to group II (p<0.036). Rats of group III lost no weight postoperatively. Experiment II. Tumor take was less in the subcutis (p=0.005), parietal peritoenum (p<0.001) and bowel anastomosis (p=0.021) in group IV compared to group V. Tumor take was significantly greater at all sites except for subcutis in group VI compared to VII (all p<0.022). Conclusions: Laparoscopic surgery is associated with less postoperative weight loss and less tumor take compared to open surgery. CO2 insufflation appears to increase tumor take.

Interleukin-6: Historical background, genetics and biological significance

Interleukin-6 (IL-6) is a pleiotropic cytokine previously known as B cell stimulatory factor (BSF-2), interferon-beta 2 (IFN-beta 2), 26-kDa protein, and hepatocyte stimulating factor (HSF). The name IL-6 was proposed when the nucleotide sequences of the cDNAs for these proteins had been determined and the molecules were found to be identical. IL-6 production can be induced by a wide variety of agents in a wide range of cells, although IL-6 gene expression seems to be regulated in a tissue and stimulus specific manner. At least 3 different signal pathways regulate IL-6 gene expression, emphasizing its multiply inducible nature. The currently known activities of IL-6 include regulatory functions in hematopoiesis, immune reactions and acute phase responses. IL-6 appears to be a key member of the IL family; however, it is still poorly understood how IL-6 interacts with other lymphokines within the network. The anti-viral activity of IL-6 seems to be negligible. Elevated IL-6 levels have been found in diseases like rheumatoid arthritis, multiple myeloma and systemic lupus erythematosus. The abnormal expression and dysregulation of IL-6 in certain disorders may be a typical feature of this cytokine, making it the first cytokine that may be directly related to pathogenesis.

Extracorporeal perfusion for the treatment of acute liver failure

OBJECTIVE AND SUMMARY BACKGROUND DATA Because of the shortage of available donor organs, death rates from liver failure remain high. Therefore, several temporary liver-assisting therapies have been developed. This article reviews various approaches to temporary liver support as well as immunologic and metabolic developments toward a solution for this problem. METHODS A literature review was performed using Medline and additional library searches to obtain further references. Only articles with a well-defined aim of study and methodology and a clear description of the outcome of the experiments were included. CONCLUSIONS Renewed interest has developed in old and new methods for an extracorporeal approach to the treatment of acute liver failure. Although temporary clinical improvement has been established, further research is needed to achieve a successful long-term clinical outcome. New developments in the field of genetic modification and tissue engineering await clinical application in the near future.

Impact of temperature and humidity of carbon dioxide pneumoperitoneum on body temperature and peritoneal morphology.

BACKGROUND The insufflation of cold gas during laparoscopic surgery exposes patients to the risk for hypothermia. The objectives of this study were to investigate whether heating or humidification of insufflation gas could prevent peroperative hypothermia in a rat model, and to assess whether the peritoneum was affected by heating or humidification of the insufflation gas. METHODS Rats were exposed to insufflation with either cold, dry carbon dioxide CO2 (group I); cold, humidified CO2 (group II); warm, dry CO2 (group III); or warm, humidified CO2 (group IV); another group underwent gasless laparoscopy (group V). Core temperature and intraperitoneal temperature were registered in all animals during 120 minutes. Specimens of the parietal peritoneum were taken directly after desufflation and 2 and 24 hours after the procedure. All specimens were analyzed with scanning electron microscopy (SEM). RESULTS During the 120-minute study period, core temperature and intraperitoneal temperature were significantly reduced in groups I, II, and III. In the animals that underwent warm, humidified insufflation (group IV) and the gasless controls (group V), intraoperative hypothermia did not develop. At SEM, retraction and bulging of mesothelial cells and exposure of the basal lamina were seen in the four insufflation groups (groups I-IV) and also in the gasless controls (group V). CONCLUSION Insufflation with cold, dry CO2 may lower the body temperature during laparoscopic surgery. Hypothermia can be prevented by both heating and humidifying the insufflation gas. Changes of the peritoneal surface occur after CO2 insufflation, despite heating or humidifying, and also after gasless surgery.

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

ObjectiveThe authors analyzed the effect of blood transfusions on the pattern of colorectal cancer recurrence. BackgroundRetrospective 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. MethodsIn the current study, the authors analyzed the patterns of recurrence in 420 patients who underwent curative operations for colorectal cancer. ResultsPatients 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. ConclusionsThese 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.

Effect of inflammatory cytokines and growth factors on tumour cell adhesion to the peritoneum.

In this experimental study, the effect of inflammatory cytokines and growth factors on tumour cell adhesion to the peritoneum was investigated. A reproducible in vitro assay was developed to study the adhesion of CC531 colon carcinoma cells to an autologous monolayer of rat mesothelial cells. Tumour cell adhesion to mesothelium pre‐incubated with interleukin‐1β (IL‐1β) and epidermal growth factor (EGF) resulted in at least 60% more tumour cell adhesion at maximal stimulation (p≤0.001). Transforming growth factor‐β (TGF‐β) pre‐incubation resulted in minor, though significant stimulation of cell adhesion (maximal 16%, p<0.05). The effect of IL‐1β was time‐ and dose‐dependent. No mesothelial cell proliferation took place after pretreatment with IL‐1β, indicating that enhanced adhesion was not based on an increase in the number of mesothelial cells. Pretreatment with EGF stimulated mesothelial cell growth as measured by DNA analysis. This effect on cell growth and adhesion was dose‐dependent. Additional blocking experiments with anti‐IL‐1β resulted in statistically significant inhibition of IL‐1β‐stimulated tumour cell adhesion (p≤0.01), demonstrating the specificity of this effect. Interferon‐γ (IFN‐γ), tumour necrosis factor‐α (TNF‐α), IL‐6, and insulin‐like growth factor (IGF‐I) pre‐incubation had no effect on tumour cell adhesion. These results prove that IL‐1β and EGF are significant promoting factors in tumour cell adhesion to mesothelium in vitro and may therefore account for tumour recurrence in the peritoneum in vivo. Copyright