Necrosis and glioblastoma: a friend or a foe? A review and a hypothesis

OBJECTIVE: Two main forms of cell death are encountered in biology: apoptosis (i.e., programmed cell death) and necrosis (i.e., accidental cell death). Because necrosis and apoptosis can lead to cell removal, one might intuit that they are both desirable in cancer treatment. However, in the setting of glioblastoma multiforme, a malignant brain tumor for which the presence of necrosis is an important diagnostic feature, clinical studies indicate that as the degree of necrosis advances, the patient's prognosis worsens. Despite the apparent importance of this form of cell death, the mechanism of development of necrosis in glioblastomas remains unelucidated. The purpose of this article is to try to resolve this dilemma by hypothesizing the mechanism of necrosis formation in these tumors. METHODS: On the basis of an extensive review of the literature, we present a hypothesis for the mechanism of necrosis formation in glioblastoma multiforme. RESULTS: One of the many possible pathways leading to necrosis formation may involve increased tumor cell secretion of tumor necrosis factor. Procoagulation and antiapoptotic mechanisms resulting from certain pathways could prevent the completion of tumor necrosis factor-induced apoptosis and could promote necrosis as the final mode of cell death. Such a hypothesis would explain the inverse correlation that exists between tumor necrosis and the survival of patients with glioblastomas, because the hypoxia that results from procoagulation selects for tumor cells that are more aggressive and more resistant to apoptosis-inducing therapies. CONCLUSION: A complete understanding of the series of events surrounding necrosis development in glioblastomas that is evidence-based is likely to provide targets for future therapies. On the basis of the potential mechanisms of development of necrosis described in this article, we postulate that effective therapies may have to be directed against the pathways that result in the formation of necrosis.     

Aprotinin; friend or foe? A review of recent medical literature

Recent articles published in peer review journals have questioned the safety of using aprotinin in patients having heart surgery. Also, evidence has been published to suggest an increase in renal events in patients given aprotinin when compared to those where tranexamic acid was used. The present review will focus principally on the first of these articles in relation to previously published data and experience.     

Evidence-based practice: friend or foe?

Chiropractic is an increasingly-recognised health profession and systematic reviews of the effectiveness of manipulation for back pain are responsible for much of that recognition. Establishement on this basis, however demands that the profession learns to operate in the new clinical culture of evidence based practice if it is to progress. This calls for changes in emphases in education for self-monitoring through clinical adit. Evidence based practice can remain a positive factor in the future role of chiropractic provided that the profession and its educators invest meaningfully in arrangements which will allow them to respond to the evidence as it emerges.     

Pain and the immune system: friend or foe?

When tissue is destroyed, pain arises. Tissue destruction as well as wound healing are associated with an inflammatory reaction. This leads to activation of nociceptors ("pain receptors") which can cross-communicate with the inflammatory infiltrate. The following review will concentrate on pain-exaggerating (hyperalgesic) and pain-ameliorating (analgesic) mediators which arise from immune cells or the circulation during the inflammation. In the early stages of inflammation endogenous hyperalgesic mediators are produced, including the proinflammatory cytokines IL-1, IL-6 and TNF-alpha, nerve growth factor as well as bradykinin and prostaglandins. Simultaneously, analgesic mechanisms are activated. Opioid peptides such as endorphins, enkephalins and dynorphins are produced by immune cells and can be released locally in the inflamed tissue on stimulation with IL-1 or corticotropin releasing factor. Analgesia is elicited by binding of the opioid peptides to receptors on peripheral sensory neurons. During the course of an inflammatory process, peripheral opioid-mediated analgesia increases. In parallel, antiinflammatory cytokines such as IL-4, IL-10, IL-13 and IL-1ra are produced and reduce hyperalgesic effects of the proinflammatory cytokines initially produced. Inflammatory pain, therefore, is the result of an interplay between hyperalgesic and analgesic mediators. Drugs such as immunosuppressants influencing this interplay may also impair endogenous hyperalgesic and analgesic mechanisms.     

Regional anesthesia in cardiac surgery: a friend or a foe?

Escalating costs and change in the profile of patients presenting for cardiac surgery requires modification of perioperative management strategies. Regional anesthesia has played an integral part of many fast-track anesthesia protocols across North America and Europe. This review suggests that for patients undergoing coronary artery bypass graft surgery, the risk-to-benefit ratio is in favor of epidural and spinal anesthesia, provided there are no specific contraindications and the guidelines for the use of regional techniques in cardiac surgery are followed. Patients managed with regional techniques seem to benefit from superior postoperative analgesia, shorter postoperative ventilation, reduced incidence of supraventricular arrhythmia, and lower rates of perioperative myocardial infarction. The results of this analysis suggest that for each episode of neurologic complication, 20 myocardial infarctions and 76 episodes of atrial fibrillation would be prevented, thus, we would consider the regional anesthesia and analgesia to be an effective strategy that improves perioperative morbidity. However, other treatment modalities such as the addition of calcium channel blockers, aspirin, and beating heart surgery, are also suggested to be beneficial in cardiac surgical patients and may impose less risk than the use of regional techniques. We believe that the results presented in this review are encouraging enough to permit continued investigation. A prospective, randomized, controlled multicenter trial needs to be adequately powered to answer important clinical questions and allow for a long-term follow-up.