James Norman

The Role of Cytokines in the Pathogenesis of Acute Pancreatitis

BACKGROUND The systemic manifestations of acute pancreatitis are responsible for the majority of pancreatitis-associated morbidity and mortality and are now believed to be due to the actions of specific inflammatory cytokines. This report summarizes what is known about the role of cytokines in the pathogenesis of acute pancreatitis. METHODS Comprehensive literature review of experimental pancreatitis as well as all reports of cytokine involvement during clinical pancreatitis. RESULTS Several cytokines and other noncytokine inflammatory mediators are produced rapidly during pancreatitis. These mediators arise in many tissues in a predictable fashion independent of the animal model used or the underlying etiology in human disease. Preventing the activities of these mediators has a profound beneficial effect in experimental animals. CONCLUSIONS A few recently described inflammatory mediators are believed to be primarily responsible for the systemic manifestations of acute pancreatitis and its associated distant organ dysfunction. The predictable nature in which they are produced may allow for novel approaches to treating this disease. Am J Surg.

Cost-effectiveness of preoperative sestamibi scan for primary hyperparathyroidism is dependent solely upon the surgeon's choice of operative procedure.

BACKGROUND In 1991, a National Institutes of Health Consensus Panel stated that preoperative localization for primary hyperparathyroidism is not cost effective. Since then, the sestamibi scan has been applied to parathyroid disease with excellent results, even allowing unilateral exploration under local anesthesia. STUDY DESIGN A metaanalysis of the English literature over the past 10 years was performed to determine the collective sensitivity and specificity of sestamibi scanning to establish its utility in directing a unilateral procedure. The cost effectiveness of scanning all patients with sporadic primary hyperparathyroidism was examined by determining the costs of seven operative technique-dependent variables that could be reduced with a limited procedure. RESULTS The average sensitivity and specificity of sestamibi were 90.7% and 98.8%, respectively, indicating its ability to guide an accurate unilateral exploration. The analysis of 6,331 patients showed that 87% had solitary adenomas. An average cost savings of

Redefinition of Cutaneous Lymphatic Drainage With the Use of Lymphoscintigraphy for Malignant Melanoma

650 was demonstrated for a unilateral operation, which could be realized in as many as 90% (sestamibi sensitivity) of those with solitary adenomas. CONCLUSIONS A preoperative sestamibi scan is specific enough in identifying solitary adenomas to allow unilateral exploration with a < 1% failure rate. The sensitivity of this scan suggests that 78% of all patients with sporadic primary hyperparathyroidism (90% of the 87% with solitary adenomas) are candidates for unilateral exploration. This rate is significantly higher than the 51% rate at which scanning all patients becomes cost effective.

Tissue-Specific Cytokine Production During Experimental Acute Pancreatitis (A Probable Mechanism for Distant Organ Dysfunction)

Lymphoscintigraphy was performed on 82 patients with melanoma registered at the University Melanoma Clinic. From these data, precise lymphatic drainage basins could be drawn for the head, neck, shoulder, and trunk. These drawings differed significantly from the classic anatomic studies, providing a functional look at the cutaneous lymphatic drainage. This new method correlates much better with clinical experiences and demonstrates much larger areas of ambiguous drainage than previously reported. Data from the lymphoscintigrams also emphasize the individuality of cutaneous lymphatic flow. The implications of these data in planning elective node dissections for intermediate thickness melanomas are obvious, since it is estimated that up to 59% of the dissections for trunk and head and neck primary melanomas may be misdirected if based on classic anatomic studies. The data indicate that all patients with head, neck, and shoulder lesions should undergo lymphoscintigraphy to define possible drainage basins at risk for metastatic disease. Similarly, truncal lesions require scintigrams except when they are within four well-defined areas with an extremely low probability of ambiguous drainage. Lesions in these areas show very reliable and predictable drainage to a single nodal group.

Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis.

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet.Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting.Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-α (TNF-α) and interleukin-1-β (IL-1β) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models,coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P< 0.001). IL-1β and TNF-α were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle.A significant delay between pancreatic and distant organ cytokine production was always observed.It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific,correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.

Decreased mortality of severe acute pancreatitis after proximal cytokine blockade

BACKGROUND Fulminant acute pancreatitis is a disease of complex origin that results in activation of several of the proinflammatory cytokines. Because interleukin-1 (IL-1) is an integral early component of the acute inflammatory process, the use of an IL-1 receptor antagonist (IL-1ra) was investigated in experimental acute pancreatitis to determine the therapeutic potential of proximal cytokine blockade and to further establish the role of inflammatory cytokines in the pathogenesis of acute pancreatitis. METHODS IL-1ra was administered in escalating doses either before or after acute edematous, necrotizing pancreatitis was induced in adult male mice by injection of cerulein. The severity of pancreatitis was quantified by serum amylase, lipase, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels, pancreatic wet weight, and blinded histologic grading. RESULTS Administration of medium (10 mg/kg) and high (100 mg/kg) doses of IL-1ra either before or after the induction of pancreatitis significantly decreased the expected rise in pancreatic wet weight, lipase, IL-6, and TNF-alpha (all, p < 0.01). Serum amylase was significantly reduced when IL-1ra was administered in either dosage before (p < 0.05), but not after, induction of pancreatitis. Pancreatic edema, necrosis, and inflammatory cell infiltrate were significantly diminished (p < 0.05) by histologic grading in all animals receiving medium or high doses of IL-1ra. Low doses of IL-1ra (1.0 mg/kg) had modest effects if given before, but no effect if given after, induction of pancreatitis. CONCLUSIONS The proinflammatory cytokines IL-6 and TNF-alpha are elevated during experimental acute pancreatitis and correlate well with the severity of local pancreatic destruction. Blockade of the cytokine cascade at the level of the IL-1 receptor before or soon after induction of pancreatitis significantly attenuates the rise in these cytokines and is associated with decreased severity of pancreatitis and reduced intrinsic pancreatic damage.

Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis

ObjectiveThis study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. Summary Background DataPrevious studes have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known. MethodsA lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received 100/μ L normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time 0; IL-1ra late mice received IL-1 ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-α, IL-1ra, pancreatic wet weight, and blind histopathologic grading. ResultsThe 10-day mortality in the untreated control group was 73%. Early and late IL-1ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). Interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. ConclusionsEarly or late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is

Lymphoscintigraphy in malignant melanoma

BACKGROUND Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host. METHODS With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily. RESULTS Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockade (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters. CONCLUSIONS Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.

New Approaches to Acute Pancreatitis: Role of Inflammatory Mediators

The development and rationale for the use of lymphoscintigraphy in the preoperative evaluation of patients with malignant melanoma being considered for elective lymph node dissection is reviewed. This overview is updated by an analysis of 135 patients with early stage malignant melanoma involving the head, neck, shoulders, and trunk at Moffitt Cancer Center and Research Institute at the University of South Florida (Tampa, FL). High discordancy rates (overall, 41%) were seen between drainage patterns predicted from historical anatomical guidelines and those revealed by the lymphoscintigraphic examination. The high discordancy rate was most pronounced in the head (64%) and the neck (73%). Surgical management was changed in 33% of the patients, overall. A preoperative lymphoscintigram is recommended for all patients with melanoma with head, neck, and truncal lesions evaluated for elective lymph node dissection as the lymphatic drainage patterns are often unpredictable and variable.

The use of lymphoscintigraphy in melanoma of the head and neck

Regardless of whether the initiating event is alcohol, gallstones or some other less common cause, acute pancreatitis progresses in a predictable manner eventually leading to failure of multiple unrelated organs. Very quickly following the inciting event, a local inflammatory process is initiated which results in the local production of inflammatory mediators. Virtually all patients with acute pancreatitis will experience some symptoms related to this local inflammation, with some resolving completely at this point. Most patients will go on to develop a systemic hyperinflammatory state expressed as the development of fever, tachycardia, tachypnea, and mild acid-base disturbances. Although this systemic hyperinflammatory state is usually mild, occasionally it may be very severe resulting in overt distant organ failure. With a more thorough understanding of the inflammatory mediators responsible for this hyperinflammatory state, many new therapeutic approaches are on the horizon.