Vascular Resections for Pancreatic Ductal Adenocarcinoma: Vascular Resections for PDAC.

BACKGROUND AND AIMS: It has become clear that vein resection and reconstruction for pancreatic ductal adenocarcinoma (PDAC) is the standard of care as supported by multiple guidelines. However, resection of large peri-pancreatic arteries remains debatable. MATERIALS AND METHODS: This review examines the current state of vascular resection with curative intent for PDAC in the last 5 years. Herein, we consider venous (superior mesenteric vein, portal vein), as well as arterial (superior mesenteric artery, celiac trunk, hepatic artery) resection or both with or without reconstruction. RESULTS: Improvement of multidrug chemotherapy has revolutionized care for PDAC that should shift traditional surgical thinking from an anatomical classification of resectability to a prognostic and biological classification. CONCLUSION: The present review gives an overview on the results of pancreatectomy associated with vascular resection, with consideration of new perspectives offered by the availability of better systemic therapies.

Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy.

BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy. METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy. RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia. CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Radiofrequency ablation of primary and metastatic malignant liver tumors.

The use of RF energy to treat unresectable liver tumors is unlikely to be curative for most patients; however, a subset of patients treated with RFA may achieve long-term disease-free survival. Longer follow-up of hepatic tumor patients treated with RFA is needed to determine long-term disease-free and overall survival rates. New metastatic tumors develop in many of these patients at an incidence rate comparable with those treated with surgical resection or cryoablation. Surgical resection remains the gold standard for treating metastatic and primary liver tumors; however, few patients are candidates for hepatic resection because of tumor size, number, location, or the presence of cirrhosis too severe to permit liver resection. Cryoablation of unresectable tumors has been an option for several years, but complications associated with the freezing of tissue can be problematic. RFA of unresectable liver tumors provides a relatively safe, highly effective method to achieve local disease control in some liver cancer patients who are not candidates for liver resection. Ongoing research and refinements in RF techniques and equipment may permit effective treatment of larger liver tumors and of malignant tumors at other body sites. Combining RFA of liver tumors with regional and/or systemic adjuvant treatments is being studied in attempts to reduce the incidence of development of new metastases and, thus, improve the overall survival rates of these patients.

Ablative techniques for hepatocellular carcinoma.

The optimal management of hepatocellular carcinoma (HCC) is resection, but this is feasible in only a minority of patients for a variety of reasons, including metastatic disease, major vascular invasion, end-stage liver disease, and poor hepatic reserve. Inoperable patients may be candidates for ablative procedures that may eradicate tumor while minimizing the loss of functioning hepatic tissue that is inevitable with surgical resection. Percutaneous ethanol injection (PEI), hepatic arterial chemoembolization, cryoablation, radiofrequency ablation (RFA), and microwave coagulation offer the potential of local tumor control and sometimes achieve long-term disease-free survival. This review will discuss the indications, anticipated benefits, and limitations of current ablative techniques and place these procedures in proper perspective as options for patients with HCC.

Cytosolic phospholipase A(2)-mediated ICAM-1 expression is calcium dependent.

BACKGROUND: Some human malignancies such as virus-related hepatocellular cancer arise in a setting of chronic inflammation. Upregulation of ICAM-1 is a seminal late event in malignant transformation following chronic inflammation. Cytosolic phospholipase A(2) (cPLA(2)) is a lipid-mediator activated by inflammatory stimuli, which has been shown to mediate ICAM-1 upregulation. As lipid mediators are known to work via calcium-dependent mechanisms in nearly all mammalian cells, we hypothesize that inflammatory-mediated ICAM-1 upregulation is dependent on both cPLA(2) and intracellular calcium. MATERIALS AND METHODS: HUVEC were chosen as a representative cell line as they emulate hepatic sinusoids and are a well-established cell model. These were grown to confluence in T-25 flasks and stimulated with TNF-alpha or LPS for 6 h. Additional groups were preincubated with AACOCF3 (a specific cPLA(2) inhibitor) or BAPTA A.M. (a specific inhibitor of intracellular Ca(2+)) prior to being exposed to inflammatory stimuli. ICAM-1 expression was determined by mean fluorescent intensity (MFI) as measured by FITC-labeled moAb to ICAM-1 via FACS. The role of intracellular Ca(2+) on cPLA(2) activity was determined by thin-layer chromatography. Groups were compared using ANOVA with Scheffe's post hoc analysis; *P < 0.05 vs control, daggerP < 0.05 vs LPS and TNF-alpha was considered significant; N > or = 4 all experimental groups. RESULTS: Both cPLA(2) and Ca(2+) inhibition significantly inhibited inflammatory upregulation of ICAM-1. Pretreatment with BAPTA A.M. attenuated HUVEC cPLA(2) activity in response to LPS. These findings suggest that appropriate molecular target suppression may prevent malignant degeneration in the presence of chronic inflammation.

Secretory phospholipase A2 activity correlates with postinjury multiple organ failure.

UNLABELLED: Postinjury multiple organ failure (MOF) may result from overwhelming systemic hyperinflammation. Secretory phospholipase A2 (sPLA2) produces many inflammatory lipid mediators, and levels have been correlated with both the severity of patient injury and postinjury mortality. The objective of this study was to characterize the plasma activity of sPLA2 type IIa in severely injured patients and to determine whether the activity of this enzyme correlates with the subsequent development of MOF. PATIENTS: Seventeen severely injured patients at known risk for MOF had blood sampled on postinjury days 0, 1, 2, 3, and 5. DESIGN: sPLA2 activity was sequentially measured and correlated with MOF scores. RESULTS: Six patients (35%) developed MOF. In comparison with non-MOF patients, MOF patients had elevated sPLA2 activity beginning 36 hrs postinjury (MOF sPLA2, 2.4 +/- 0.97, vs. non-MOF sPLA2, 0.86 +/- 0.16 active units (AU); p < .05) and continuing over the ensuing 5 days. To rule out the possibility that stored blood components required for patient resuscitation was the source of sPLA2, the sPLA2 was measured in packed red blood cells, platelet concentrates, and fresh frozen plasma over the routine storage time. None of the products tested had elevated levels of sPLA2 compared with fresh plasma from healthy adult volunteers. CONCLUSIONS: We conclude that increased sPLA2 activity is associated with the development of postinjury MOF.

Limitations of size as a criterion in the evaluation of adrenal tumors.

BACKGROUND: Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers. METHODS: We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy. RESULTS: The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas. CONCLUSIONS: Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

The excluding effects of sucrose on a protein chemical degradation pathway: methionine oxidation in subtilisin.

The conformational stabilization of proteins by sucrose has been previously attributed to a preferential exclusion mechanism. The present study links this mechanism to stability against a chemical degradation pathway for subtilisin. Oxidation of a methionine residue adjacent to the active site to the sulfoxide form compromises subtilisin's enzymatic activity. In the presence of hydrogen peroxide and borate buffer, a borate-hydrogen peroxide complex binds to subtilisin's active site prior to the formation of methionine sulfoxide. Sucrose decreases the oxidation rate by limiting the accessibility of the complex to the methionine at the partially buried active site. The stabilization mechanism of sucrose is based on shifting the equilibrium of transiently expanding native conformations of subtilisin to favor the most compact states. Enzymatic parameter determination (kcat, KM) and hydrogen-deuterium exchange measurements confirm the limited conformational mobility of the enzyme in the presence of sucrose. Further support for limited mobility as the cause of oxidation inhibition by sucrose comes from the findings that neither viscosity nor possible interactions of sucrose with hydrogen peroxide, hydroxyl radicals, or borate can adequately explain the inhibition. The volume exclusion of sucrose from subtilisin is used to estimate the extent by which the native state of subtilisin must expand in solution to allow oxidation. The surface area of the oxidation-competent state is ca. 3.9% greater than that of the native state.

Cardiopulmonary bypass renders patients at risk for multiple organ failure via early neutrophil priming and late neutrophil disability.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response syndrome (SIRS) and these patients are recognized to be at increased risk for delayed infectious complications. We have documented that circulating neutrophils (PMNs) from patients manifesting SIRS have evidence of early postinjury priming for cytotoxicity. Consequently, we hypothesized that CPB would result in early postoperative PMN hyperresponsiveness (priming). MATERIALS AND METHODS: Six patients (mean age 50 +/- 2.9 years) who underwent CPB for CABG had sequential blood samples obtained perioperatively. PMNs were isolated and superoxide anion (O(-)(2)) generation (nmol O(-)(2)/3.75 x 10(5) PMNs/min) was measured by reduction of cytochrome c after exposure to fMLP, C5a, or PMA; elastase release (% total PMN elastase content) was measured by cleavage of AAPV-pNA after exposure to fMLP or C5a. RESULTS: PMNs were activated for increased elastase release 6 h after initiation of CPB. Significant PMN priming for O(-)(2) production was discovered at 3, 6, and 12 h following CPB and for elastase release at 3 and 6 h after CPB. At 2 to 3 days after CPB, O(-)(2) generation was significantly less than that of the preoperative control. Neutrophil primability with PAF was detected at 6 h after CPB. A similar defect in PAF-primable O(-)(2) production was seen 2 and 3 days post-CPB. Direct PMN interrogation with the receptor-independent activator PMA revealed loss of integrity of the NADPH oxidase at 2 and 3 days following CPB. CONCLUSIONS: A vulnerable window exists between 3 and 12 h after CPB when PMNs are primed for enhanced cytotoxicity via O(-)(2) production and elastase release. Paradoxically, PMN oxidase integrity becomes deficient 48 h post-CPB, while protease degranulation remains intact. These events render the bypass patient at risk for multiple organ failure via both early PMN-mediated tissue injury and delayed infectious complications.

Release of anti-inflammatory mediators after major torso trauma correlates with the development of postinjury multiple organ failure.

BACKGROUND: Soluble tumor necrosis factor receptor (sTNFr) and interleukin-1 receptor antagonist (IL-1ra) have been identified as endogenous inhibitors of TNF-alpha and IL-1beta. While TNF-alpha and IL-1beta levels are not systematically elevated in postinjury patients who developed multiorgan failure (MOF), their involvement at the tissue level has been suggested. Our study hypothesis was that levels of sTNFr-I and IL-1ra would discriminate patients at risk for postinjury MOF. METHODS: Serial plasma levels of sTNFr and IL-1ra were measured in 29 trauma patients at high risk for postinjury MOF. RESULTS: sTNFr-I levels were higher in MOF compared with non-MOF patients at 12, 84, and 132 hours postinjury. MOF patients also had higher IL-1ra values 36, 60, 84, and 132 hours postinjury. CONCLUSIONS: Anti-inflammatory mechanisms are activated after trauma. Since increased levels of sTNFr and IL-1ra correlate with postinjury MOF, they may contribute to our understanding of the pathogenesis as well as prediction of outcome. High levels of antagonists to TNF-alpha and IL-1beta suggest tissue level involvement of these cytokines in postinjury hyperinflammation.

ICAM-1-CD18 interaction mediates neutrophil cytotoxicity through protease release.

Interaction of the beta2-integrin complex on the polymorphonuclear neutrophil (PMN) with intercellular adhesion molecule-1 (ICAM-1) has been implicated in PMN-mediated cytotoxicity. This study examined interaction of the CD11a, CD11b, and CD18 subunits of the beta2-integrin with ICAM-1, transfected into Chinese hamster ovarian (CHO) cells to avoid effects of other adhesion molecules. Incubation of quiescent PMNs with wild-type and ICAM-1-transfected CHO cells produced nominal cell lysis. Similarly, when phorbol myristate acetate (PMA)-activated PMNs were incubated with wild-type CHO cells, minimal cytotoxicity was produced. However, when ICAM-1-transfected CHO cells were incubated with PMA-activated PMNs, 40% cell lysis occurred. Blockade with a monoclonal antibody (MAb) to ICAM-1 or MAbs to CD11a, CD11b, or CD18 reduced PMN-mediated cytotoxicity to baseline. To examine the role of adhesion in cytotoxicity, we studied beta2-integrin-mediated PMN adhesion to ICAM-1-transfected CHO cells and found that MAbs for CD11a, CD11b, and CD18 all abrogated PMN cytotoxicity despite disparate effects on adhesion. To assess the role of CD18, beta2-integrin subunits were cross-linked, and CD18 alone mediated protease release. Moreover, ICAM-1 was immunoprecipitated from transfected CHO cells and incubated with PMNs. This soluble ICAM-1 provoked elastase release, similar to PMA, which could be inhibited by MAbs to CD18 but not MAbs to other beta2-integrin subunits. In addition, coincubation with protease inhibitors eglin C and AAPVCK reduced PMN-mediated cytotoxicity to control levels. Finally, ICAM-1-transfected CHO cells were exposed to activated PMNs from a patient with chronic granulomatous disease that caused significant cell lysis, equivalent to that of PMNs from normal donors. Collectively, these data suggest that ICAM-1 provokes PMN-mediated cytotoxicity via CD18-mediated protease release.

Nitric oxide attenuates platelet-activating factor priming for elastase release in human neutrophils via a cyclic guanosine monophosphate-dependent pathway.

BACKGROUND: Nitric oxide (NO) has proven benefits in treating adult respiratory distress syndrome (ARDS). The protective mechanism remains unclear, but cyclic guanosine monophosphate (cGMP)-dependent signal transduction pathways have been suggested. Our laboratory has implicated polymorphonuclear neutrophil (PMN) priming and subsequent activation in the pathogenesis of postinjury ARDS and has shown that NO inhibits superoxide anion production from activated PMNs. More recently, the pivotal role of elastase in PMN-mediated tissue injury has been emphasized. Consequently, our study hypothesis was that NO attenuates platelet-activating factor (PAF) priming for elastase release through a cGMP-dependent pathway in human PMNs. METHODS: PMNs isolated from human volunteers were preincubated with the NO donor 3-morpholinosydnonimine hydrochloride (SIN-1; 10(-6) to 10(-2) mol/L), cGMP (10(-3) mol/L), or the cell-permeable cGMP analog dibutyryl-cGMP (10(-3) mol/L) for 10 minutes. The cells were then primed with platelet-activating factor (PAF) 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (200 nmol/L), which was followed by N-formyl-methionyl-leucyl-phenylalanine (fMLP) activation (1 mumol/L). Elastase release was measured by the cleavage of N-methoxysuccinyl-Ala-Ala-Pro-Val p-nitroanilide (AAPV-pNA). RESULTS: NO (through SIN-1) significantly attenuated elastase release from PAF-primed PMNs in a dose-dependent manner. Cell-permeable dibutyryl-cGMP attenuated PMN elastase release similar to NO, but cGMP (not cell-permeable) had no effect. CONCLUSIONS: NO attenuates elastase release from PAF-primed PMNs through an intracellular cGMP-dependent signal transduction pathway. These findings may partially explain the beneficial effects of NO in the treatment of postinjury ARDS and add to our knowledge of the complex intracellular pathways involved in NO/PMN interactions.

Lipid mediators up-regulate CD11b and prime for concordant superoxide and elastase release in human neutrophils.

BACKGROUND: The pathogenesis of multiple organ failure after injury is believed to involve priming and activation of the inflammatory cascade, and the polymorphonuclear neutrophil (PMN) appears to be an integral effector. Characterization of the primed PMN is evolving. Because much research has focused on the respiratory burst, the synergistic role of cytotoxic proteases, especially elastase, has been largely ignored. In addition, CD11b has been identified as pivotal in PMN-mediated tissue injury. Our hypothesis is that the well-recognized postinjury mediators platelet-activating factor (PAF) and leukotriene B4 (LTB4) prime PMNs for the concordant release of elastase and superoxide (O2-) as well as for CD11b up-regulation. METHODS: Human PMNs were isolated and then incubated with PAF or LTB4 before N-formyl-methionyl-leucyl-phenylalanine activation. O2- generation was measured by reduction of cytochrome c. Elastase was measured by cleavage of Ala-Ala-Pro-Val p-nitroanilide. CD11b expression was quantified by incubation with R-phycoerythrin-labeled monoclonal antibodies followed by flow cytometry. RESULTS: PAF and LTB4 primed PMNs maximally within 5 minutes for the production of O2-, elastase release, and simultaneous up-regulation of CD11b expression on the PMN surface. CONCLUSION: PAF and LTB4 prime human PMNs for the concordant release of elastase, generation of O2-, and CD11b up-regulation. Understanding the physiologic characteristics of PMN priming may offer new therapeutic targets to avoid the development of multiple organ failure after injury.

Beta-adrenergic stimulation down-regulates neutrophil priming for superoxide generation, but not elastase release.

Platelet-activating factor (PAF) concordantly primes neutrophils (PMNs) for superoxide generation and elastase release. beta-Adrenergic stimulation of PMNs enhances cAMP-dependent protein kinase A (PKA) activity and has been shown to inhibit PAF-mediated NADPH-oxidase activity. PMN superoxide generation is thought to play a predominate microbicidal role, whereas elastase is known to mediate untoward PMN-endothelial interactions. We hypothesized that beta-adrenergic neutrophil stimulation has disparate effects on PAF-mediated PMN superoxide generation versus elastase release. Human PMNs were isolated using a standard Ficoll/Hypaque gradient. PMNs were then primed with PAF (200 nM) and activated with fMLP (1 microM). Subsets of PMNs were pretreated for 5 min with a beta agonist (10(-4) M isoprotereno) or an adenylate cyclase agonist (10(-5) M forskolin). Superoxide generation was determined by superoxide dismutase inhibitive cytochrome c reduction. Elastase activity was measured by the cleavage of n-methoxylsuccinyl-A-A-P-V-p-nitroanilide. Pretreatment with isoproterenol and forskolin yielded superoxide generation of 3.2 +/- 0.6 and 3.1 +/- 1.2 nmole/2.5 x 10(5) PMN/min compared to 9.0 +/- 0.6 nmole/2.5 x 10(5) PMN/min for PAF/fMLP alone, whereas isoproterenol and forskolin did not significantly affect PAF-mediated neutrophil elastase release, 22.4 +/- 5.3 and 24.0 +/- 3.6%, respectively, compared to 39.4 +/- 9.1% for PAF/fMLP alone. Disparate PMN signal transduction for superoxide generation versus elastase release may explain the SICU clinical paradox, in which patients are both susceptible to infection and vulnerable to PMN-mediated multiple organ failure.

Reduced PAF-acetylhydrolase activity is associated with postinjury multiple organ failure.

Our basic laboratory work has identified the postischemic gut as a source of platelet-activating factor (PAF), which primes circulating neutrophils for the production of reactive oxygen metabolites (ROMs) leading to distant organ injury. Circulating PAF-acetylhydrolase (PAF-AH) hydrolyzes PAF to lyso-PAF. Recently, ROMs have been shown to rapidly and irreversibly inactivate human PAF-AH. Consequently, our study hypothesis was that reduced levels of PAF-AH in severely injured patients would be associated with the development of multiple organ failure (MOF). Over a 16 mo period, 26 patients at known risk for MOF (Injury Severity Score (ISS) > or = 25 or an ISS > 15 with > or = 6 U of blood transfused within the first 6 h) had blood sampled on postinjury days 0, 1, 2, 3, and 5. PAF-AH activity was assessed by measuring the percentage of 3H-labeled PAF hydrolyzed. MOF was defined by a standard score. The mean age of the 26 study patients was 34 +/- 2 yr; 19 (73%) were male. The injury mechanism was blunt in 18 (69%), and the mean ISS was 31 +/- 2. Eight patients (31%) developed MOF. In the MOF patients, plasma PAF-AH activity was significantly lower on the day of injury and remained depressed throughout the ensuing 5 days compared with the non-MOF patients. Reduced PAF-AH activity is associated with the development of postinjury MOF. With the recent molecular cloning of human plasma PAF-AH, repleting this circulating, anti-inflammatory enzyme may represent useful therapy for these high risk patients.

Jack A. Barney Resident Research Award winner. The inflammatory profile of interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 in postinjury multiple organ failure.

BACKGROUND: Interleukin-6 (IL-6), interleukin-8 (IL-8), and adhesion molecules have been implicated as mediators in neutrophil (PMN) and endothelial cell (EC) interactions leading to postinjury multiple organ failure (MOF). Our hypothesis was that circulating levels of IL-6, IL-8, and soluble intercellular adhesion molecule-1 (sICAM-1) would discriminate patients at risk for postinjury MOF. METHODS: Serial plasma levels of IL-6, IL-8, and sICAM-1 were measured in 27 high-risk trauma patients. RESULTS: The IL-6 and IL-8 levels were significantly elevated in MOF patients compared with non-MOF patients at 12 and 36 hours postinjury. The IL-6 level was also elevated at 84 and 132 hours, and IL-8 at 84 hours. The sICAM-1 level did not become elevated in MOF patients until 132 hours postinjury. CONCLUSION: Interleukin-6 and IL-8 are elevated early after trauma and discriminate patients who will develop MOF. Late elevation of sICAM-1 likely results from PMN cytotoxicity leading to EC injury or inflammation.

Tracheal gas insufflation is a useful adjunct in permissive hypercapnic management of acute respiratory distress syndrome.

BACKGROUND: Despite numerous advances in critical care, the mortality of postinjury acute respiratory distress syndrome (ARDS) remains high. Recently, permissive hypercapnia (PHC) has been shown to be a viable alternative to traditional ventilator management in patients with ARDS. However, lowering tidal volume, as employed in PHC, below 5 cc/kg impinges upon anatomic dead space and precipitates a significant rise in PaCO2 The purpose of this study was to determine if continuous tracheal gas insufflation (cTGI) is a useful adjunct to PHC by lowering PaCO2, thus allowing adequate reduction in minute ventilation to achieve alveolar protection. METHODS: Over a 5-year period, 68 trauma patients with ARDS were placed on permissive hypercapnia. Nine of these patients additionally received cTGI at 7 L/min. Arterial blood gas determinations and ventilatory parameters were examined immediately prior to the implementation of cTGI and after 6h. RESULTS: The cTGI produced significant improvement in pH (7.25 +/- 0.03 to 7.33 +/- 0.03), PaCO2 (72 +/- 5 to 59 +/- 5 torr), tidal volume (7.9 +/- 0.6 to 7.2 +/- 0.6 cc/kg), and minute ventilation (13 +/- 1 to 11 +/- 1 L/min; P < 0.05). CONCLUSIONS: Continuous TGI is a useful adjunct to permissive hypercapnia, allowing maintenance of an acceptable pH and PaCO2 while allowing further reduction in tidal volume and minute ventilation.

Soluble intercellular adhesion molecule-1 provokes polymorphonuclear leukocyte elastase release by CD18.

BACKGROUND: Elevated levels of soluble intercellular adhesion molecule-1 (sICAM-1) correlate with the development of postinjury multiple organ failure. Soluble ICAM-1 secretion is known to be induced in endothelial cells and monocytes by diverse inflammatory stimuli. We have found that incubation of quiescent polymorphonuclear leukocytes (PMNs) with sICAM-1 elicits elastase release and, more recently, that cross-linking CD18 receptors on PMNs also produces elastase release. Consequently, our study hypothesis was that sICAM-1 provokes PMN elastase release through its interaction with CD18. METHODS: To obtain sICAM-1, Chinese hamster ovarian cells transfected with human ICAM-1 were lysed and centrifuged at 150,000 g for 1 hour; the supernatant was passed over an ICAM-1 affinity column, eluted with 0.1 mmol/L glycine HCl, and concentrated with dialysis filter. Human PMNs (2.5 x 10(5)) were saturated with specific monoclonal antibodies for the beta 2 subunits (CD11a, CD11b, CD18) or nonspecific monoclonal antibodies for 30 minutes on ice before a 1-hour incubation with sICAM-1 (75 ng/ml) at 37 degrees C. Elastase activity was measured by the cleavage of n-methoxysuccinyl-A-A-P-V-p-nitroanilide. RESULTS: Neutrophil incubation with sICAM-1 resulted in 19.2% +/- 2.8% of total PMN elastase, compared with 2.4% +/- 0.5% in the controls. Blockade of CD18 abrogated sICAM-1 provoked elastase release with monoclonal antibodies to CD18 (TS1/18, 31H8) resulting in 4.3% +/- 1.0% and 5.5% +/- 1.4% elastase release, respectively. Blockade of CD11a, CD11b, and nonspecific antibody controls had no effect on sICAM-1 induced elastase release. CONCLUSIONS: In vitro, sICAM-1 provokes PMN elastase release through CD18. This may represent a mechanism by which elevated levels of circulating sICAM-1, released from local injury sites, provoke distal organ dysfunction.

Laparotomy and proximal gastric vagotomy in Zollinger-Ellison syndrome: results of a 16-year prospective study.

OBJECTIVE: Pharmacological control of gastric acid hypersecretion in the Zollinger-Ellison syndrome has steadily improved, but medical treatment does not address the underlying tumor. The objective of this study was to evaluate the long-term effectiveness of a surgical approach to both tumor and acid hypersecretion in 22 patients with the Zollinger-Ellison syndrome. METHODS: Patients underwent laparotomy to resect tumors, combined with vagotomy to reduce acid secretion, followed by postoperative antisecretory therapy, if necessary. RESULTS: No surgical mortality or serious morbidity occurred. Tumor was found at laparotomy in nine patients (41%) and during long-term follow-up in an additional two patients (9%). Ten-year survival is 81%, with a long-term cure rate of at least 14%. Most patients (86%) have had long-term inhibition of acid secretion. Eight patients have discontinued regular use of acid-inhibiting medications. Patients requiring medication need less of it, and they have an improved acid inhibitory response to medication for up to 16 yr after surgery. CONCLUSION: Cure of the Zollinger-Ellison syndrome is possible in a minority of patients. Acid secretion can be safely reduced in almost all patients with laparotomy/vagotomy, usually allowing discontinuation, or reduced dose, of acid-inhibiting drugs. Long-term survival and quality of life are generally excellent.

Soluble ICAM-1 (sICAM-1) provokes PMN elastase release.

Elevated levels of soluble intercellular adhesion molecule-1 have been shown predictive of post-injury multiple organ failure. We hypothesized that sICAM-1 augments distant organ injury via its affect on the PMN and; thus, have examined neutrophil elastase and superoxide production in response to sICAM-1. To obtain soluble ICAM-1, Chinese Hamster Ovarian (CHO) cells were transfected with human ICAM-1 (cDNA vector CD1.8), lysed and centrifuged at 150,000g for 1 hr; supernatant was passed over an ICAM-1 affinity gradient, eluted with 0.1 mM glycine x HCl, and concentrated using an Amicon Spin-X filter. PMNs were incubated for 1 hr with sICAM-1 at 37 degrees C. Quiescent and PMA-activated PMNs served as negative and positive controls respectively. Elastase activity was measured by the cleavage of methoxy-succinyl-alalyl-alalyl-prolyl-valyl-p-nitroanilide. Superoxide production was determined by superoxide dismutase inhibitive ferricytochrome C reduction over a 5-60 min incubation. PMN incubation with sICAM-1 provoked marked increase in elastase release 10.43 +/- 2.90 (10(-6) U/hr) compared to control 1.64 +/- 0.57, and was equivalent to PMA-activated PMN elastase release 11.60 +/- 1.50 (10(-6) U/hr). In contrast, sICAM-1 alone did not promote spontaneous PMN superoxide production beyond buffer treated PMNs (0.25 +/- 0.09 nmole/2.5 x 10(5) PMN/min). In sum, sICAM-1 stimulates PMN elastase release in vitro. Clinically, this may represent a mechanism by which sICAM-1 participates in the genesis of post-injury multiple organ failure.