Cholangiocarcinoma: advocate an aggressive operative approach with adjuvant chemotherapy.

Cholangiocarcinoma presents many challenges. Prognosis is thought to be determined by conventional predictors of survival; margin status, pathologic criteria, stage, and comorbid disease. Ninety-four patients, 57 males and 37 females, underwent resections for cholangiocarcinoma between 1989 and 2000. Thirty-two patients (34%) had distal tumors, 10 had midduct lesions, and 52 had proximal/intrahepatic lesions. Thirty-four patients underwent pancreaticoduodenectomies, 23 bile duct resections alone, and 37 bile duct and concomitant hepatic resections. Tumor location did not influence mean survival (distal, 28 months +/- 23; midduct, 28 months +/- 21; and proximal, 31 months +/- 36). Operation undertaken did not alter survival (bile duct resection, 30 months +/- 37; pancreaticoduodenectomy, 27 months +/- 23; and concomitant bile duct/hepatic resection, 32 months +/- 32). TNM stage failed to predict survival: 5 stage I (29 months +/- 22), 12 stage II (41 months +/- 33), 12 stage III (33 months +/- 19), and 64 stage IV (27 months +/- 32). Tumor size did not influence survival: T1-2 (32 months +/- 33) versus T3-4 lesions (29 months +/- 25). Mean survival with negative margin (n = 67) was 34 months +/- 33, whereas microscopically positive (n = 13, 23.9 months +/- 25) or grossly positive (n = 14, 20.4 months +/- 20) margins were predictive of significantly shorter survival (P < 0.03). Adjuvant treatment (n = 41) was associated with significantly longer survival (40.5 months +/- 36) than those who received no further therapy (n = 53; 24 months +/- 24) (P = 0.05). TNM stage, tumor size, operation undertaken, and location were not associated with duration of survival after resection. Margin status was associated with duration of survival, though extended survival is possible even with positive margins. Advanced stage should not preclude aggressive resection. Without specific contraindications, an aggressive operative approach is advocated followed by adjuvant therapy.

Ontogeny of StAR and ACTH-R genes in ovine placenta.

It has been demonstrated that the ovine placenta secretes estrogen, progesterone and cortisol, and that plasma concentrations of estrogen and cortisol increase before birth. Among the elements important for steroid production is steroidogenic acute regulatory protein (StAR) which acutely delivers cholesterol from the outer to the inner mitochondrial membrane for rapid steroidogenesis. This study was designed to determine if StAR is present in ovine placenta, and if its expression changes during fetal development. In addition, because cortisol is secreted by the placenta, we also examined the expression of adrenocorticotropic hormone receptor (ACTH-R) to determine if it was present and if the pattern of expression changed as gestation proceeded. The mRNA levels for StAR and ACTH-R were assessed by RNase protection assay (RPA) and protein levels were measured by Western blot in placentas from pregnant ewes (100-105 days of gestation, n = 8; 120 days of gestation, n = 5; 135-142 days of gestation, n = 8). The data show that the ovine placenta expresses StAR and ACTH-R. There was a significant increase in the StAR mRNA and protein between 100 and 142 days of gestation, but there were no significant age-related changes in ACTH-R mRNA and protein levels. The data suggest that the increased steroid production by the placenta in late gestation may be related to the increased expression of StAR.

Metallothionein: the multipurpose protein.

Metallothioneins (MTs) are intracellular, low molecular, low molecular weight, cysteine-rich proteins. Ubiquitous in eukaryotes, MTs have unique structural characteristics to give potent metal-binding and redox capabilities. A primary role has not been identified, and remains elusive, as further functions continue to be discovered. The most widely expressed isoforms in mammals, MT-1 and MT-2, are rapidly induced in the liver by a wide range of metals, drugs and inflammatory mediators. In teh gut and pancreas, MT responds mainly to Zn status. A brain isoform, MT-3, has a specific neuronal growth inhibitory activity, while MT-1 and MT-2 have more diverse functions related to their thiolate cluster structure. These include involvement in Zn homeostasis, protection against heavy metal (especially Cd) and oxidant damage, and metabolic regulation via Zn donation, sequestration and/or redox control. Use of mice with altered gene expression has enhance our understanding of the multifaceted role of MT, emphasised in this review.

Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy.

The role of adjuvant chemoradiation therapy (CT/XRT) in the treatment of cholangiocarcinoma is controversial. We undertook this study to determine whether CT/XRT is appropriate after resection of cholangiocarcinomas. One hundred ninety-two patients with cholangiocarcinomas were treated from 1988 to 1999. After resection, patients were assigned a stage (TNM) and were stratified by location of the tumor as intrahepatic, perihilar, and distal tumors. Data are presented as mean +/- standard deviation. Of 192 patients 92 (48%) underwent resections of cholangiocarcinomas. Thirty-four patients had liver resections, 25 had bile duct resections, and 33 underwent pancreaticoduodenectomies. Thirty-four patients had adjuvant CT/XRT, three had adjuvant chemotherapy, four had neoadjuvant CT/XRT, and 50 had no radiation or chemotherapy. Mean survival of resected patients with adjuvant CT/XRT was 42 +/- 37.0 months and without CT/XRT it was 29 24.5 months (P = 0.07). Mean survival of patients with distal tumors receiving or not receiving CT/XRT was 41 +/- 21.8 versus 25 +/- 20.1 months, respectively, (P = 0.04). Adjuvant chemoradiation improves survival after resection for cholangiocarcinoma (P = 0.07) particularly in patients undergoing resection for distal tumors (P = 0.04). Benefits of adjuvant CT/XRT are apparent when stratified by location of cholangiocarcinomas rather than staging.

Frequency with which surgeons undertake pancreaticoduodenectomy determines length of stay, hospital charges, and in-hospital mortality.

Others have suggested that in certain technically challenging operations, outcome and experience are related. Because pancreaticoduodenectomy is a technically complex procedure, this study was undertaken to evaluate mortality, length of hospital stay, and hospital charges when compared to volume of experience. The database of the State of Florida Agency for Health Care Administration was queried for pancreaticoduodenectomies undertaken during a recent 33-month period. Length of stay, hospital charges, and in-hospital mortality were stratified by the frequency of pancreaticoduodenectomy. A total of 282 surgeons performed 698 pancreaticoduodenectomies over 33 months. Eighty-nine percent of surgeons performed one pancreaticoduodenectomy per year or less and accounted for 52% of the procedures. Overall mortality rate was 5.1%. Average hospital charges were $72,171.64. The more frequently pancreaticoduodenectomy was undertaken, the shorter the hospital stay (P = 0.025, regression analysis) and the lower the hospital charges (P = 0.008, regression analysis) and in-hospital mortality (P = 0.036, log likelihood ratio test). Surgeons who undertake pancreaticoduodenectomy more frequently have patients with shorter hospital stays, lower hospital charges, and lower in-hospital mortality rates, independent of hospital volume. Variations exist among surgeons and among different areas of the state. Data regarding cost and mortality are available for use in programs of cost and quality improvement.

Ethanol decreases zinc transfer to the fetus in normal but not metallothionein-null mice.

BACKGROUND: Ethanol causes significant teratogenicity in normal (MT+/+) but not metallothionein-null (MT-/-) fetuses. Impaired maternal fetal zinc (Zn) transfer is indicated, because ethanol significantly reduces plasma Zn concentrations in MT+/+ dams while increasing concentrations in MT-/- dams. In this study we examined maternal-fetal Zn homeostasis in response to ethanol in MT+/+ and MT-/- mice and the origins of the increase in plasma Zn in MT-/- mice. METHODS AND RESULTS: Mice were treated with saline or ethanol (0.015 ml/g intraperitoneally at 0 and 4 hr) on day 12 of gestation. An additional subcutaneous injection of 65Zn tracer was administered after the second ethanol injection before mice were killed 3 hr later. Maternal liver MT levels were not different between ethanol and saline MT+/+ mice. Both liver Zn and 65Zn levels were higher in MT+/+ mice. Plasma Zn concentrations were higher in MT-/- mice, with MT-/- ethanol-treated mice having levels greater than those of MT-/- saline-treated controls. MT+/+ ethanol-treated fetuses exhibited lower 65Zn transfer and whole Zn concentrations compared with MT+/+ and MT-/- saline and MT-/- ethanol fetuses. So we could examine changes in plasma Zn after ethanol treatment, MT+/+ and MT-/- mice were injected with 65Zn 3 days before they received ethanol treatment. Muscle and skin showed a decrease in 65Zn retention in both genotypes over 3 hr. There was a trend toward greater 65Zn release from skin and muscle at an earlier time in MT-/- mice: 24% vs. 2% decrease (MT-/- vs. MT+/+) for muscle and 28% vs. 15% decrease (MT-/- vs. MT+/+) for skin at 2 hr. CONCLUSIONS: The results show (a) that ethanol interferes with the transfer of Zn to the fetus, and that this is MT dependent, and (b) that the increase in plasma Zn seen in MT-/- mice after ethanol administration is a result of Zn release from the skin and muscle, in the absence of hepatic Zn sequestration.

Involvement of p38 mitogen-activated protein kinase in the induction of tolerance to hemorrhagic and endotoxic shock.

BACKGROUND: Exposure to sublethal hemorrhage (SLH) makes rats tolerant to subsequent hemorrhagic or septic shock and is associated with altered NF-kappaB activity. The purpose of this study was to explore whether changes in p38 mitogen-activated protein (MAP) kinase activity also occur in the induction of tolerance by SLH. METHODS: Rats were made tolerant by SLH or sham operation. Twenty-four hours later rats were exposed to lipopolysaccharide (LPS) or had peritoneal macrophages (Mphi) isolated. CNI-1493, a p38 MAP kinase inhibitor, or saline was given prior to SLH. Lungs were harvested 1 h after SLH or LPS and total protein was extracted. Peritoneal Mphi were stimulated with LPS (10 microg/ml) and total protein was isolated 1 h later. Active, dually phosphorylated p38 MAP kinase was determined by Western blot. Tumor necrosis factor (TNF) was measured in Mphi supernatants by enzyme-linked immunosorbent assay (ELISA) 18 h after LPS. RESULTS: SLH activated p38 MAP kinase in the lung and this was inhibited by CNI-1493. Twenty-four hours later, lung p38 MAP kinase activity increased to the same degree in tolerant and sham rats following LPS, but much more prominently in the CNI-1493 treated rats. There was no p38 activity in peritoneal Mphi at baseline, and similar to lung p38, LPS led to increased p38 activity which was most significant in Mphi from rats that received CNI-1493 prior to SLH. TNF production by tolerant Mphi in response to LPS was significantly (P < 0.05, t test) decreased and p38 inhibition with CNI-1493 at the time of SLH reversed the inhibitory effects of tolerance on TNF production. CONCLUSIONS: TNF production by tolerant Mphi following a second insult (LPS) is attenuated despite preservation of normal p38 MAP kinase activity. However, activation of this intracellular second messenger is a necessary step in the "cellular reprogramming" that occurs during the induction of tolerance by SLH.

Maternal ethanol exposure is associated with decreased plasma zinc and increased fetal abnormalities in normal but not metallothionein-null mice.

BACKGROUND: Ethanol profoundly affects fetal development, and this is proposed to be due primarily to a transient fetal zinc (Zn) deficiency that arises from the binding of Zn by metallothionein (MT) in the maternal liver. Zn homeostasis and fetal outcome were investigated in normal (MT+/+) and metallothionein-null (MT-/-) mice in response to ethanol exposure. METHODS/RESULTS: Mice were treated with saline or ethanol (0.015 m/g intraperitoneally at 0 and 4 hr) on day 8 of gestation (Gd8), and the degree of fetal dysmorphology was assessed on Gd18. The incidence of external abnormalities was significantly increased in offspring from MT+/+ dams exposed to ethanol, where 27.4% of fetuses were affected. MT-/- ethanol-, MT+/+ saline-, and MT-/- saline-treated dams had fetuses in which the frequencies of abnormalities were 2.2, 6.4, and 6.9%, respectively. To investigate Zn homeostasis, nonpregnant mice were killed at intervals over 16 hr after ethanol injection. Liver MT concentrations in MT+/+ mice were increased 20-fold by 16 hr, with a significant elevation evident by 4 hr, whereas liver Zn levels were also significantly increased by 2 hr and maintained for 16 hr. In parallel with these changes, plasma Zn concentrations in MT+/+ mice decreased by 65%, with minimum levels of 4.5+/-0.3 micromol/liter at 8 hr. Conversely, MT-/- mice exhibited increased plasma Zn concentrations, with peak values of 20.8+/-0.3 observed at 4 hr. CONCLUSION: These findings link the teratogenic effect of ethanol to the induction of maternal MT and the limitation of fetal Zn supply from the plasma.

Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability.

BACKGROUND: Despite the advent of dialysis, survival with acute renal failure when associated with multiorgan failure is poor. The development of lung injury after shock or visceral ischemia has been shown; however, the effects of isolated renal ischemia/reperfusion injury (IRI) on the lungs are unclear. We hypothesized that isolated renal IRI could alter pulmonary vascular permeability (PVP) and that macrophages could be important mediators in this response. METHODS: Rats (N = 5 per group) underwent renal ischemia for 30 minutes, followed by reperfusion. Lung vascular permeability was evaluated by quantitation of Evans blue dye extravasation from vascular space to lung parenchyma at 1, 24, 48, or 96 hours after reperfusion. Serum was collected for blood urea nitrogen and creatinine at each time point. To examine the role of the macrophage, the macrophage pacifant CNI-1493, which inhibits the release of macrophage-derived inflammatory products, was administered in a blinded fashion during renal IRI. RESULTS: PVP was significantly (P < 0.05) increased at 24 hours and peaked at 48 hours after IRI compared with shams as well as baseline levels. PVP after IRI became similar to shams after 96 hours. This correlated with increases in blood urea nitrogen and creatinine at similar time points. At 48 hours, CNI-1493 significantly abrogated the increase in PVP compared with IRI alone. However, CNI-1493 did not alter the course of the acute renal failure. Pulmonary histology demonstrated interstitial edema, alveolar hemorrhage, and red blood cell sludging after renal IRI, which was partially attenuated by CNI-1493. CONCLUSIONS: Increased PVP develops after isolated renal IRI, and macrophage-derived products are mediators in this response. These findings have implications for understanding the mechanisms underlying respiratory dysfunction associated with acute renal failure.

Adenoma of the ampulla of Vater: a genetic condition?

The etiology of adenoma of the ampulla of Vater is not well understood. Previous authors reported the association of this neoplasm with polycystic kidney disease of two fraternal sisters. They concluded that these two conditions were somehow related. We describe a case of ampullary adenoma associated with polycystic kidney disease. This presentation raises again the question of a possible link between these two diseases.

Tolerance to shock: an exploration of mechanism.

OBJECTIVE: To determine if cross-tolerance to septic shock could be induced by a previous insult with sublethal hemorrhage (SLH) and to characterize the mechanisms involved in this induced protective response. BACKGROUND DATA: It is possible to condition animals by prior SLH such that they tolerate an otherwise lethal hemorrhage. It is also possible to condition animals with low doses of lipopolysaccharide (LPS) so that they survive a "lethal" septic insult. However, a paucity of information exists on cross-tolerance between hemorrhage and sepsis. METHODS: Rats were made tolerant by conditioning SLH or sham operation. Twenty-four hours later, tolerant and sham rats were exposed to a lethal dose of LPS. To explore the mechanism of tolerance induction, rats were given the macrophage (Mphi) inhibitor CNI-1493 or saline carrier before SLH. Survival and pulmonary vascular injury were determined after LPS. Serum tumor necrosis factor (TNF) levels and splenic Mphi TNF gene expression were measured at several time points. RESULTS: Prior SLH indeed made rats tolerant and imparted a significant survival benefit and reduction in pulmonary vascular injury after LPS. The tolerance induced by SLH was reversed by Mphi inhibition. Tolerant animals had low serum TNF levels immediately after SLH and reduced circulating TNF levels after LPS. SLH, however, did not inhibit the augmentation of TNF gene expression after LPS. CONCLUSIONS: Sublethal hemorrhage bestows protection against a lethal LPS challenge. Inhibition of the Mphi attenuated the benefit of the tolerance induced by SLH. Circulating TNF but not TNF gene after LPS is lessened by SLH. This implicates changes in Mphi intracellular signaling in induction of the tolerant state.

Induction of tolerance to hemorrhagic or endotoxic shock involves activation of NF-kappaB.

BACKGROUND: Tolerance to hemorrhagic or endotoxic shock can be induced by prior sublethal hemorrhage (SLH). The purpose of this study was to explore whether alterations in signal transduction pathways involving NF-kappaB occur in macrophages (Mphi) following induction of tolerance by SLH. METHODS: Using a model of SLH previously shown in our lab to impart a survival benefit to subsequent hemorrhagic or endotoxic shock, rats (n = 30) were conditioned by SLH. Peritoneal Mphi were harvested 24 h after conditioning and stimulated with lipopolysaccharide (LPS) (10 microg/mL). Nuclear and cytosolic proteins were isolated 1 h later for determination of NF-kappaB activation by gel-shift assay and IkappaB-alpha by Western blot. TNF mRNA gene expression was measured 4 h after LPS stimulation by reverse transcription/polymerase chain reaction (RT/PCR). TNF protein levels were measured in cellular supernatants by enzyme-linked immunosorbent assay (ELISA) 18 h after LPS. RESULTS. LPS stimulation of sham Mphi increased NF-kappaB activation with corresponding loss of its inhibitor IkappaB-alpha. In contrast, IkappaB-alpha was not detectable following conditioning, and conditioned Mphi had NF-kappaB activation at baseline which increased minimally with LPS stimulation. LPS increased TNF gene expression and significantly increased protein production by both sham and conditioned Mphi, but this increase was greater in the sham-conditioned group. CONCLUSIONS: The ability of Mphi from animals made tolerant by SLH to produce TNF in vitro is conserved. Nevertheless, these same Mphi exhibit alterations in TNF gene induction and expression as well as signal transduction, specifically, changes in IkappaB-alpha and NF-kappaB activation. This suggests a role for activation of NF-kappaB in the induction of tolerance.

Sublethal hemorrhage blunts the inflammatory cytokine response to endotoxin in a rat model.

BACKGROUND: Tolerance to lipopolysaccharide (LPS) induced by previous hemorrhage in mice is associated with a blunted interleukin 1 (IL-1) response, suggesting down-regulation of the cytokine cascade as a possible protective mechanism. This study was undertaken to determine whether prehemorrhage induces attenuation of the cytokine response to sepsis beyond IL-1 in a rat model and whether this response occurs at the level of gene transcription. METHODS: Sprague-Dawley rats underwent sublethal hemorrhage, lethal intraperitoneal endotoxin, or sublethal hemorrhage with delayed lethal endotoxin. Animals were killed 12 hours after LPS injection or 24 hours after hemorrhage. IL-1 and tumor necrosis factor (TNF) mRNA levels were determined on total splenic RNA using reverse-transcriptase polymerase chain reaction, and serum cytokine levels were determined using enzyme-linked immunosorbent assay. RESULTS: Animals that received LPS alone mounted an IL-1 and TNF response (RNA and protein) much higher than animals subjected to hemorrhage alone. TNF and IL-1 gene expression and protein levels in prehemorrhaged animals that received LPS, however, were significantly lower than those of animals that received LPS alone. CONCLUSION: Hemorrhage induces early IL-1 and TNF gene expression, which blunts their subsequent expected increase after endotoxic challenge. These findings validate previously documented immune-modulated protective effects of the first insult in a two-hit model.

Transient human gene therapy: a novel cytokine regulatory strategy for experimental pancreatitis.

OBJECTIVE: The purpose of this study was to evaluate the ability to transfect a murine pancreas with a human cytokine regulatory gene (interleukin-10 [IL-10]) and examine the duration of transgene expression, its effect on the normal pancreas, and its antiinflammatory effect during acute pancreatitis. SUMMARY BACKGROUND DATA: Interleukin-1beta and tumor necrosis factor-alpha are known detrimental mediators during the progression of acute pancreatitis, and blockade of either cytokine results in decreased severity of pancreatitis and improved survival. Although gene therapy has been proposed as a method to deliver protein-based therapy during a number of conditions, no means of effectively transfecting the pancreas without inducing injury has been developed. METHODS: A plasmid-human IL-10 construct (pMP6-hIL-10) complexed with cationic liposomes was administered by single intraperitoneal injection to healthy mice. Effective transfection (reverse transcriptase-polymerase chain reaction for hIL-10 mRNA), transfected cell type (in situ polymerase chain reaction for hIL-10 DNA), and the effect on the normal pancreas were determined. Additional animals were transfected to determine the effects of this regulatory gene on the severity of pancreatitis. RESULTS: Nearly 80% of all pancreatic cells expressed human DNA that was subsequently transcribed into mRNA through day 14. The transfection event had no effect on amylase, lipase, or pancreatic histologic appearance. Successful transfection could attenuate subsequently induced pancreatitis (all parameters p < 0.05). CONCLUSIONS: Transient transfection of a human IL-10 gene can be accomplished into all cell types of murine pancreata using a plasmid/ liposome vector. The DNA is effectively transcribed into intact mRNA and does not cause inflammation or acinar cell damage. Transfer of this cytokine regulatory gene decreases the severity of pancreatitis, demonstrating a benefit of gene therapy during this acute inflammatory process.

Cytokine activation through sublethal hemorrhage is protective against early lethal endotoxic challenge.

OBJECTIVES: To determine the immunologic consequences of nonlethal hemorrhage on subsequent exposure to lipopolysaccharide (LPS) and to determine the role of interleukin 1 beta (IL-1) specifically in mediating the response to LPS with and without prior hemorrhage. DESIGN: Prospective, randomized, controlled experimental trial. PARTICIPANTS: Male BALB/c mice and transgenic mice deficient in IL-1 converting enzyme. INTERVENTIONS: Animals were subjected to hemorrhage (by cardiac puncture), LPS challenge by intraperitoneal injection, or hemorrhage followed 24 hours later by LPS challenge. Mortality was assessed every 4 hours for 96 hours following hemorrhage or LPS exposure. Serum IL-1 levels were determined 24 hours after exposure to hemorrhage and LPS. SETTING: University of South Florida Core General Surgery Research Facility, Tampa. MAIN OUTCOME MEASURES: Mortality and serum IL-1 levels. RESULTS: Hemorrhage alone resulted in complete survival, whereas LPS alone resulted in near-complete (95%) mortality. Hemorrhage, when given 24 hours before LPS challenge, afforded significant protection compared with LPS alone (67% survival vs 5% survival; P < .001). Serum IL-1 levels 24 hours after exposure to LPS were significantly lower in prehemorrhaged mice than in those receiving LPS alone. Transgenic mice incapable of producing biologically active IL-1 were further protected, demonstrating near-complete (95%) survival following hemorrhage and LPS challenge. CONCLUSIONS: Cytokine activation through nonlethal hemorrhage attenuates subsequent IL-1 response to early immunologic challenge. Such immune suppression appears to be protective early on and is supported by the near-complete immunity to LPS in animals incapable of producing biologically active IL-1.

Decreased mortality of severe acute pancreatitis after proximal cytokine blockade.

OBJECTIVE: This 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 DATA: Previous studies 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. METHODS: A 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/microL 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-1ra 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-alpha, IL-1ra, pancreatic wet weight, and blind histopathologic grading. RESULTS: The 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 p < 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. CONCLUSIONS: Early 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 accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.

Analysis of residual cancer after diagnostic breast biopsy: an argument for fine-needle aspiration cytology.

BACKGROUND: Diagnostic breast biopsy (DxBx) requires an effective strategy for successful treatment of breast cancer by lumpectomy or mastectomy. Clearance of margins is required to achieve local control. METHODS: We reviewed 844 malignant diagnostic biopsies. The strategy was to perform DxBx on all nonpalpable lesions and fine-needle aspiration (FNA) on all palpable lesions. When FNA was equivocal, DxBx was performed. After positive DxBx, either the biopsy cavity or FNA-positive breast mass was excised, and margins were documented with touch preparation cytology analysis (TPC) and frozen section (FS) as necessary to achieve negative margins. RESULTS: Outside institutions referred 430 excisional biopsies. Two hundred twenty-five (52.3%) were found to have residual cancer at surgical excision. Our institution performed 414 biopsies: 169 were performed on nonpalpable lesions in which 58% had residual tumor at resection; 245 were diagnosed by FNA of palpable lesions. Residual disease was found in 12 (5%). CONCLUSIONS: Of patients who undergo DxBx, > 50% have residual breast cancer. It is recommended that (a) FNA be performed on all palpable masses or DxBx of nonpalpable masses; when cancer is diagnosed, proceed to surgical excision. (b) When lumpectomy is the option, margins should be reexcised and intraoperatively evaluated with TPC and FS at the time of axillary dissection.