H. P. Redmond

Excisional surgery for cancer cure: therapy at a cost

Excisional surgery is one of the primary treatment modalities for cancer. Minimal residual disease (MRD) is the occult neoplastic disease that remains in situ after curative surgery. There is increasing evidence that tumour removal alters the growth of MRD, leading to perioperative tumour growth. Because neoplasia is a systemic disease, this phenomenon may be relevant to all patients undergoing surgery for cancer. In this review we discuss the published work that addresses the effects of tumour removal on subsequent tumour growth and the mechanisms by which tumour excision may alter residual tumour growth. In addition, we describe therapeutic approaches that may protect patients against any oncologically adverse effects of tumour removal. On the basis of the evidence presented, we propose a novel therapeutic paradigm; that the postoperative period represents a window of opportunity during which the patient may be further protected against the oncological effects of tumour removal.

Is human fracture hematoma inherently angiogenic

This study attempts to explain the cellular events characterizing the changes seen in the medullary callus adjacent to the interfragmentary hematoma during the early stages of fracture healing. It also shows that human fracture hematoma contains the angiogenic cytokine vascular endothelial growth factor and has the inherent capability to induce angiogenesis and thus promote revascularization during bone repair. Patients undergoing emergency surgery for isolated bony injury were studied. Raised circulating levels of vascular endothelial growth factor were seen in all injured patients, whereas the fracture hematoma contained significantly higher levels of vascular endothelial growth factor than did plasma from these injured patients. However, incubation of endothelial cells in fracture hematoma supernatant significantly inhibited the in vitro angiogenic parameters of endothelial cell proliferation and microtubule formation. These phenomena are dependent on a local biochemical milieu that does not support cytokinesis. The hematoma potassium concentration is cytotoxic to endothelial cells and osteoblasts. Subcutaneous transplantation of the fracture hematoma into a murine wound model resulted in new blood vessel formation after hematoma resorption. This angiogenic effect is mediated by the significant concentrations of vascular endothelial growth factor found in the hematoma. This study identifies an angiogenic cytokine involved in human fracture healing and shows that fracture hematoma is inherently angiogenic. The differences between the in vitro and in vivo findings may explain the phenomenon of interfragmentary hematoma organization and resorption that precedes fracture revascularization.

Provider volume and outcomes for oncological procedures.

Oncological procedures may have better outcomes if performed by high‐volume providers.

The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease.

SummarySurgical removal of a primary tumour is often followed by rapid growth of previously dormant metastases. Endotoxin or lipopolysaccharide, a cell wall constituent of Gram-negative bacteria, is ubiquitously present in air and may be introduced during surgery. BALB/c mice received a tail vein injection of 105 4T1 mouse mammary carcinoma cells. Two weeks later, animals were subjected to surgical trauma or an intraperitoneal injection of endotoxin (10 μg per animal). Five days later, animals which underwent open surgery, laparoscopy with air sufflation or received an endotoxin injection displayed increased lung metastasis compared to anaesthetic controls. These increases in metastatic tumour growth were reflected in increased tumour cell proliferation and decreased apoptosis within lung metastases. Circulating levels of the angiogenic cytokine, vascular endothelial growth factor (VEGF), were also elevated in these groups and correlated with increased plasma levels of endotoxin. Endotoxin treatment for 18 h (>10 ng ml–1) directly up-regulated VEGF production by the 4T1 tumour cells in vitro. Metastatic tumour growth in mice undergoing carbon dioxide laparoscopy, where air is excluded, was similar to anaesthetic controls. These data indicate that endotoxin introduced during surgery is associated with the enhanced growth of metastases following surgical trauma, by altering the critical balances governing cellular growth and angiogenesis.

Sulfate-Reducing Bacteria Colonize Pouches Formed for Ulcerative Colitis but Not for Familial Adenomatous Polyposis

AbstractPURPOSE: Ileal pouch-anal anastomosis remains the “gold standard” in surgical treatment of ulcerative colitis and familial adenomatous polyposis. Pouchitis occurs mainly in patients with a background of ulcerative colitis, although the reasons for this are unknown. The aim of this study was to characterize differences in pouch bacterial populations between ulcerative colitis and familial adenomatous pouches. METHODS: After ethical approval was obtained, fresh stool samples were collected from patients with ulcerative colitis pouches (n = 10), familial adenomatous polyposis (n = 7) pouches, and ulcerative colitis ileostomies (n = 8). Quantitative measurements of aerobic and anaerobic bacteria were performed. RESULTS: Sulfate-reducing bacteria were isolated from 80 percent (n = 8) of ulcerative colitis pouches. Sulfate-reducing bacteria were absent from familial adenomatous polyposis pouches and also from ulcerative colitis ileostomy effluent. Pouch Lactobacilli, Bifidobacterium, Bacteroides sp, and Clostridium perfringens counts were increased relative to ileostomy counts in patients with ulcerative colitis. Total pouch enterococci and coliform counts were also increased relative to ileostomy levels. There were no significant quantitative or qualitative differences between pouch types when these bacteria were evaluated. CONCLUSIONS: Sulfate-reducing bacteria are exclusive to patients with a background of ulcerative colitis. Not all ulcerative colitis pouches harbor sulfate-reducing bacteria because two ulcerative colitis pouches in this study were free of the latter. They are not present in familial adenomatous polyposis pouches or in ileostomy effluent collected from patients with ulcerative colitis. Total bacterial counts increase in ulcerative colitis pouches after stoma closure. Levels of Lactobacilli, Bifidobacterium, Bacteroides sp, Clostridium perfringens, enterococci, and coliforms were similar in both pouch groups. Because sulfate-reducing bacteria are specific to ulcerative colitis pouches, they may play a role in the pathogenesis of pouchitis.

The effect of laparotomy and laparoscopy on the establishment of spontaneous tumor metastases

Background: Surgical extirpation of solid tumors may not be entirely possible, and the consequence of surgical excision is invariably the release of tumor cells into the systemic circulation. The aim of this study was to determine whether laparotomy affects the establishment of spontaneous pulmonary metastases after excision of the primary tumor in a murine flank tumor model and to determine possible underlying immune abnormalities. Methods: An initial experiment was carried out to compare the development of gross spontaneous pulmonary metastases in the presence of a primary flank tumor and after excision of the tumor in C57/BL6 female mice. Another group of mice had flank tumors excised and were simultaneously randomized to undergo anesthetic only (control), laparoscopy, or laparotomy, after which the subsequent development of pulmonary metastases was determined. Finally, a third experiment entailed determination of natural killer cell (NK) cytotoxicity and the effect of splenic macrophages on NK cytotoxicity at days 1, 7, and 14 after tumor excision. Results: Excision of the primary tumor resulted in a significant increase in the number of pulmonary metastases in mice compared with mice that did not have tumors excised (P = .01). Both laparotomy and laparoscopy significantly increased the number of spontaneous pulmonary metastases after tumor excision compared with controls (P ≤ .01), and there was also a significant difference between laparotomy and laparoscopy groups (P = .00). NK cytotoxicity was significantly suppressed at all time points after operation in the laparotomy group compared with both the laparoscopy group and the controls (P ≤ .01). Suppression occurred after laparoscopy at 24 hours after the procedure compared with controls (P = .00); by day 7 this difference was not significant, but at day 14 there was again a significant suppression (P ≤ .03). Splenic macrophages appeared to be a suppressor to natural killer cell cytotoxicity (NKCC) in the corresponding groups and at the corresponding time points. Conclusions: The differential establishment of spontaneous metastases after tumor excision and laparotomy and, to a lesser extent, laparoscopy results in lowered host antitumor surveillance and may be mediated at least in part by the generation of splenic suppressor cells in the early postoperative period, causing a more marked and prolonged effect after laparotomy than after laparoscopy. (Surgery 1998;124:516-25.)

Role of endotoxin in mononuclear phagocyte-mediated inflammatory responses.

Lipopolysaccharide (LPS), which is derived from the cell wall of gram‐negative and some gram‐positive bacteria, plays a major role is the pathogenesis of septic shock. Initiation of these responses depends on LPS interaction with a number of immune cells, not least the mononuclear phagocyte (MP). Mononuclear phagocytes bind the LPS/lipopolysaccharide‐binding protein complex through the CD14 receptor and thus mediate the release of a wide range of inflammatory mediators. Release of these mediators is teleologically beneficial but under certain circumstances may be detrimental, resulting in the systemic inflammatory response syndrome. The development of this syndrome is not clearly understood but appears, in part, to be dependent on the ability of the host to respond to these mediators. This review evaluates the mechanisms of LPS‐MP interaction and the therapeutic strategies aimed at inhibiting this interaction. J. Leukoc. Biol. 56: 95–103; 1994.

Taurine and human nutrition.

Taurine (2-aminoethane sulphonic acid), a ubiquitous beta-amino acid not incorporated into proteins but found either free or in some simple peptides is considered as a conditionally semi-essential amino acid in man. Once thought of as no more than an innocuous end product of cysteine metabolism, taurine has in recent years generated much interest due to research findings indicating a role in numerous physiological processes. These roles are varied and include membrane stabilization, detoxification, antioxidation, osmoregulation, maintenance of calcium homeostasis, and stimulation of glycolysis and glycogenesis. Intracellular and plasma taurine levels are high and although cellular taurine is tightly regulated, plasma levels are known to decrease in response to surgical injury and numerous pathological conditions including cancer, trauma and sepsis. Decreased plasma concentrations can be restored with supplementary taurine. Although the importance of taurine as a physiological agent with pharmacological properties is now recognised, the potential advantages of dietary supplementation with taurine have not as yet been fully exploited and this is an area which could prove to be of benefit to the patient.

Exploitation of the Toll-like receptor system in cancer: a doubled- edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

The beneficial effect of taurine on the prevention of human endothelial cell death.

This study was designed to test the hypothesis that the antioxidant taurine may modulate human endothelial cell (EC) death (apoptosis versus necrosis). Sodium arsenite (80 μM) alone and in combination with tumor necrosis factor-α (25 ng/mL) caused EC apoptosis after 24 h of treatment. Taurine (.5 mg/mL) added at 0 and 6 h could significantly attenuate EC apoptosis, and maintain EC function as represented by increased intercellular adhesion molecule-1 expression and oxidative state in response to lipopolysaccharide and tumor necrosis factor-α stimulation. EC necrosis was induced by activated neutrophils (PMNs). Taurine reduced PMN-mediated EC necrosis in a dose-dependent manner. Moreover, treatment of ECs with a calcium ionophore, A23187 (1.0–4.0 ixM), resulted in both EC apoptosis and necrosis. Taurine significantly abrogated A23187-mediated intracellular calcium elevation and EC death. These data indicate that taurine, possibly through its antioxidant activity and regulation of intracellular calcium flux, can prevent EC dysfunction and cell death, which may have implications for the application of this amino acid in the amelioration of acute lung injury during systemic inflammatory response syndrome.