Intrahepatic and systemic therapy with oxaliplatin combined with capecitabine in patients with hepatic metastases from breast cancer.

BACKGROUND: The aim was to evaluate activity and toxicity of hepatic arterial infusion of oxaliplatin in combination with capecitabine in patients with metastatic breast cancer with liver metastases and limited extrahepatic disease. PATIENTS AND METHODS: Sixteen consecutive patients received capecitabine 13 00mg/m(2) daily combined with oxaliplatin 85 mg/m(2) every two weeks. Seven patients alternated between intrahepatic and systemic oxaliplatin, and in 9 oxaliplatin was primarily given intrahepatic. Five patients had liver-only metastases and 11 had additionally bone metastases. The patients had received median two previous chemotherapeutic regimens for metastatic disease. RESULTS: The response rate was 50% and the stable disease (≥6 months) rate 44%. Median progression free and overall survival was 7.9 and 19.2 months, respectively. The toxicity was moderate with abdominal pain, neuropathy, and hand foot syndrome as the most common adverse events. CONCLUSION: The combination of capecitabine and intrahepatic/systemic therapy with oxaliplatin was active in pretreated patients with liver metastasis from breast cancer.

Liver resection and local ablation of breast cancer liver metastases--a systematic review.

AIM: To analyze surgical treatment of breast cancer liver metastases (BCLM) regarding selection criteria, outcome and prognostic parameters. METHODS: We searched Embase and Medline for all studies published 1999-2010. RESULTS: Resection was associated with a median survival (MOS) of 20-67 months and 5-year survival of 21-61%. Local ablation also had a favorable outcome; MOS was 30-60 months and 5-year survival 27-41%. Regarding selection, no specific limits regarding the number and size of BCLM can be given. Features of the primary breast cancer (BC) were not significant for the prognosis. Microscopically radical (R0) resection is a positive prognostic factor, while the effects of disease interval, hormone receptor status and response to preoperative chemotherapy were divergent. The presence of EHD had a negative effect on survival in some studies, but failed to have so in other studies. CONCLUSIONS: Surgical therapy may benefit a subset of patients with BCLM. Resection may be indicated, if an RO-resection can be done with a low risk of mortality. Liver resection in the presence of extrahepatic disease remains controversial, while patients with BCLM and bone metastases could possibly be managed differently than other EHD.

Traumatic abdominal hernia caused by cough, presenting with intestinal obstruction.

A case of traumatic abdominal hernia is reported in a patient with a history of chronic cough. After a bout of coughing 3 months prior to her presentation, the patient developed a large herniation on the left lateral side of the abdomen. The patient presented with intestinal obstruction due to the herniation. A CT scanning confirmed the hernia and showed a peritoneal defect with herniation of most of the intestine on the left lateral side of the abdomen. An emergency midline laparotomy was performed, and the defect was corrected.

Successful conservative management of a pyelo-duodenal fistula.

Uro-intestinal fistula is a rare entity and mostly managed by means of surgical intervention. We report a case of pyelo-duodenal fistula which was treated conservatively.

Mesenteric vein thrombosis due to factor V Leiden gene mutation.

BACKGROUND: Mesenteric venous thrombosis is a rare cause of acute abdominal pain that may be the result of coagulation abnormalities. METHODS: Four consecutive patients with mesenteric venous thrombosis underwent haematological evaluation. RESULTS: All four had activated protein C resistance resulting from a single mutation in the gene coding for coagulation factor V. Three had surgery; in one patient the diagnosis was made by ultrasonography. One of the patients who had surgery died but the other three survived and were treated with long-term anticoagulation. CONCLUSION: Activated protein C resistance may be an important pathogenetic factor in primary mesen-teric vein thrombosis.

Production of secretory leucocyte protease inhibitor (SLPI) in human pancreatic beta-cells.

Secretory leucocyte protease inhibitor (SLPI) is a potent inhibitor of granulocyte elastase and cathepsin G, and also an inhibitor of pancreatic enzymes like trypsin, chymotrypsin and pancreatic elastase. SLPI has also been shown to inhibit HIV-1 infections by blocking viral DNA synthesis. Since SLPI is an inhibitor of pancreatic proteases we wished to investigate whether SLPI was also actually produced in the pancreas. M-RNA from human pancreatic tissue showed evidence of SLPI production using the reverse transcriptase polymer chain reaction technique (RT-PCR). Using immunohistochemical methods SLPI was demonstrated in the beta-cells of the islets of Langerhans. The function could be local protease/antiprotease regulation or antiviral/antibacterial defence in the close vicinity of the cell surface, or even inside the beta-cell itself.

In vivo expression of neutrophil inhibitory factor via gene transfer prevents lipopolysaccharide-induced lung neutrophil infiltration and injury by a beta2 integrin-dependent mechanism.

The binding of beta2 (CD18) integrins on PMN cell membrane to intercellular adhesion molecule (ICAM) counter-receptors on the surface of vascular endothelial cells mediates PMN adhesion to endothelial cells. Neutrophil inhibitory factor (NIF), a 41-kD glycoprotein isolated from the canine hookworm (Ancylostoma caninum), is a beta2 integrin antagonist that inhibits PMN adhesion to endothelial cells. We transferred the NIF gene into CD1 mouse lungs by intravenous injection of cationic liposomes to study the effects of in vivo NIF expression on LPS-induced lung PMN sequestration and the development of lung injury. RT-PCR and Northern blot analysis indicated the lung-selective expression of the NIF transgene, and immunocytochemistry showed prominent NIF expression in pulmonary microvessel endothelial cells. NIF staining was also observed in intraluminal leukocytes present in pulmonary microvessels. This may be the result of NIF binding to leukocytes after its secretion from the transduced lung cells, since there was no evidence of NIF gene expression in circulating leukocytes. Pulmonary vascular NIF expression abrogated the lung tissue PMN uptake and airspace migration of PMN and prevented lung vascular injury (as measured by the lung tissue uptake of [125I]labeled albumin) after the intraperitoneal LPS challenge (200 microg/mouse). Expression of a control protein, chloramphenicol acetyltransferase (CAT), by the same strategy, had no effect on these responses. In vitro studies showed that NIF prevented mouse PMN adhesion consistent with the inhibition of lung uptake after LPS challenge in NIF transgene-expressing mice. We conclude that pulmonary vascular expression of NIF, a specific beta2 integrin- binding protein, is a potentially useful gene transfer strategy in modulating the infiltration of PMN across the alveolar-capillary epithelial barrier and in preventing lung vascular endothelial injury.

Gp60 activation mediates albumin transcytosis in endothelial cells by tyrosine kinase-dependent pathway.

We investigated the function of gp60, an endothelial cell membrane 60-kDa albumin-binding protein localized in caveolae, and the mechanism of its activation in regulating endothelial permeability of albumin. Gp60 organization on the bovine pulmonary microvessel endothelial cell (BPMVEC) surface was punctate as shown by immunofluorescence using an anti-gp60 antibody (Ab) conjugated with bisfunctional, N-hydroxysuccinimidyl fluorophore (Cy3). Addition of a secondary Ab to anti-gp60 Ab-treated BPMVEC induced cross-linking of gp60 as evident by increased size of fluorescent particles and cell surface gp60 clustering. Gp60 cross-linking also produced 2-3-fold increases in the endothelial cell uptake and the luminal to abluminal permeability of 125I-albumin as well as the fluid-phase tracer, horseradish peroxidase. The increased transendothelial permeability of macromolecules was the result of transcytosis as it was not associated with an increase in the paracellular pathway. Incubation of anti-gp60 Ab with BPMVEC at 37 degrees C caused internalization of gp60, and thereby reduced the uptake of the macromolecules. Activation of gp60 by either albumin (the gp60 ligand) or gp60 cross-linking induced the phosphorylation of both gp60 and caveolin-1 (the major structural caveolar protein) on tyrosine residues. Gp60 activation also phosphorylated the Src family tyrosine kinases pp60(c-Src) and Fyn. The activated pp60(c-Src) and Fyn co-immunoprecipitated with caveolin-1 in BPMVEC membrane. Protein tyrosine kinase (PTK) inhibitors, herbimycin A and genistein, prevented gp60-activated macromolecule uptake and transcytosis in a concentration-dependent manner, indicating the functional significance of the PTK pathway in activating albumin transcytosis. These findings indicate that activation of gp60 stimulates the Src PTK signaling pathway, and thus regulates the transcytosis of albumin across the endothelial cell monolayer.

The elimination of secretory leukocyte protease inhibitor (SLPI) from the gastrointestinal tract in man.

Secretory leukocyte protease inhibitor (SLPI) is the dominant protease inhibitor in the mucus secretions of the genital and respiratory tract and it was recently also detected in intestinal mucosa. Furthermore an earlier study showed high concentrations of SLPI in peritoneal fluid from patients with perforations of the large and small intestines. As SLPI is acid-stable, this raised the question of to what extent swallowed SLPI may contribute. The present study investigated the turnover of swallowed SLPI in the gastrointestinal tract. Native 125I-labelled SLPI was instilled in the duodenum of three healthy volunteers and radioactivity in plasma, faeces and urine was measured. Within 72 h 81.4% of the injected radioactivity was excreted in urine and 3.6% in faeces as radioactive low molecular weight proteins (< 1 kDa). Recombinant human SLPI (rh-SLPI) was incubated with porcine pepsin or human gastric or duodenal juice. This resulted in rapid degradation of SLPI to smaller molecules. In conclusion, SLPI is rapidly degraded in the stomach and duodenum. There were no measurable amounts of SLPI in the faeces. We have shown that during normal conditions, swallowed SLPI was rapidly degraded in the stomach and duodenum, and therefore it probably can not be of any importance for inflammatory diseases in the intestines.

Localization of immunoreactive secretory leukocyte protease inhibitor (SLPI) in intestinal mucosa.

Secretory leukocyte protease inhibitor (SLPI) is the dominant protease inhibitor in the mucus secretions of the repiratory and genital tracts, and local production seems likely, as immunoreactive SLPI has been found in the corresponding mucosa. To our knowledge, SLPI has not been previously demonstrated in intestinal epithelia or secretions. In an earlier study, however, we found surprisingly high levels of SLPI in peritonitis exudate from patients with gastrointestinal perforations. This study extends these observations by demonstrating the presence of immunoreactive SLPI in intestinal mucosa. In the small intestine, SLPI was present in Paneth cells and in scattered mucosa cells of goblet-type. In normal mucosa of the large bowel, SLPI was also found in scattered cells of goblet-type in the epithelium. In addition, immunoreactive SLPI was frequently found in colonic adenomas. The findings in this study raise several interesting questions on the possible role of SLPI in the gut epithelial defense against inflammatory assaults.

Studies of the release and turnover of a human neutrophil lipocalin.

A 24-kDa protein was purified from human neutrophil extracts and shown to be the newly discovered neutrophil gelatinase-associated lipocalin (NGAL), based on structural and immunochemical data. A specific enzyme-linked immunosorbent assay (ELISA) was developed for the determination of NGAL in human plasma and tissue fluids. Normal human plasma contains 72 micrograms l-1 of NGAL (range 40-109 micrograms l-1) in two main forms, monomer and dimer. 35S-methionine metabolic studies of human neutrophils showed that granulocyte macrophagecolony-stimulating factor (GMCSF) stimulated significant synthesis and secretion of NGAL in a dose- and time-dependent fashion. NGAL was rapidly released as monomer and dimer on incubation of heparinized whole blood with opsonized yeast, reaching a plateau corresponding to about 35% of total cell content after 30 min. Following intravenous injection of 125-iodine labelled NGAL there was a more rapid initial clearance of the monomeric than of the dimeric form; t1/2 10 min vs. 20 min. During the second phase the two forms cleared at similar rates. Severe acute peritonitis was accompanied by a 10-fold increase in NGAL plasma levels and the NGAL level in peritoneal exudates, which reached about 40 mg l-1. There was a good linear correlation between the concentrations of NGAL, leucocyte elastase and NP4 (neutrophil proteinase 4 = P3).

Levels of leukocyte proteases in plasma and peritoneal exudate in severe, acute pancreatitis.

Levels of leukocyte elastase and neutrophil protease 4 (NP4(3)) in plasma and peritoneal exudate were studied in 25 patients with severe, acute pancreatitis. Pancreatitis was diagnosed from the clinical picture and an increased serum amylase level. The diagnosis was verified by computerized tomography, ultrasound, and findings at operation or autopsy. Peritoneal exudate on admission contained high concentrations of leukocyte elastase (6100 +/- 2000 micrograms/l) and NP4(3) (2310 +/- 900 micrograms/l). High initial levels were found also in plasma, which contained 659 +/- 110 micrograms/l of leukocyte elastase and 254 +/- 33 micrograms/l of NP4(3). The levels in plasma were still increased 3 weeks after the acute attack, also in the absence of complications, indicating that the resolution of acute pancreatitis is a protracted process. Plasma levels of both leukocyte proteases were persistently increased in patients with pancreatic abscess, in contrast to the gradual decrease seen in patients with a pseudocyst or uncomplicated recovery. The levels were increased already before the abscess was diagnosed clinically, which indicates that determinations of leukocyte elastase and NP4(3) may be helpful in detecting this complication. A pathophysiologic role for leukocyte proteases in the development of severe, acute pancreatitis should be considered.

Protease-antiprotease levels and whole-blood chemiluminescence in acute peritonitis.

Whole-blood chemiluminescence and levels of leukocyte proteases and plasma protease inhibitors were studied in 43 patients with acute, generalized peritonitis. An almost three-fold increase in whole-blood chemiluminescence was found in acute peritonitis, which may indicate activation or "priming" of the leukocytes by blood-borne factors. High levels of leukocyte elastase and neutrophil proteinase 4(3) were found in plasma and peritoneal exudate. Patients with sepsis had higher plasma levels of both proteases than other patients. Large variations in the plasma levels among patients decreased their sensitivity as markers of infectious complications during the postoperative period. The plasma levels of the protease inhibitors followed three different patterns of reaction. The acute phase proteins alpha 1-proteinase inhibitor and C1-inactivator, increased during the first week of disease, to normalise later in its course. alpha 2-macroglobulin, antithrombin III and alpha 2-antiplasmin were all decreased from onset and normalised later in the course, while secretory leukocyte protease inhibitor showed a slow decrease throughout the course of disease. In peritonitis exudate, the levels of the main protease inhibitors, alpha 1-Proteinase Inhibitor and alpha 2-Macroglobulin, were decreased, probably due to complexation and subsequent elimination, as a part of the defense against liberated leukocyte proteases. The immunoreactive and especially functional levels of the protease inhibitors alpha 2-Antiplasmin, Antithrombin III and C1-Inactivator were also decreased in the exudate, indicating an increased turn-over of these proteins through activation of the cascade systems and/or break-down by leukocyte proteases. In contrast to the other inhibitors, secretory leukocyte protease inhibitor showed higher levels in exudate than in plasma, and unexpectedly high exudate/plasma-quotients were seen in cases with colonic perforations. Degradation of complement factor 3 (C3) and decreased "opsonic capacity" were found in exudate. The "opsonic capacity" could be correlated to the levels of leukocyte proteases in the exudate, which indicates that degradation of complement factor 3 may have been at least partly due to the action of leukocyte proteases. Further depletion of complement factors in exudates of long-standing peritonitis or abscesses may create a vicious circle of deficient opsonisation and clearance of bacteria, as earlier reported for chronic pleural exudates.

Release of neutrophil proteinase 4(3) and leukocyte elastase during phagocytosis and their interaction with proteinase inhibitors.

Neutrophil proteinase 4 (NP4) is a major neutral proteinase of the human polymorphonuclear (PMN) leukocyte, which is present in amounts similar to leukocyte elastase. NP4(3) is a potent, non-specific proteinase, which may degrade structural and soluble proteins in the tissues and body fluids, and it has been implicated as an important pathogenetic factor in lung emphysema. We have studied the release of elastase and NP4(3) in an in vitro model of phagocytosis. alpha 1-proteinase inhibitor (alpha 1-PI) is the major plasma inhibitor of both leukocyte elastase and NP4(3), but alpha 1-PI bound leukocyte elastase more readily than NP4(3). The basic conditions were designed so that some proteolytic activity was present in the medium. Addition of increasing amounts of Secretory leukocyte protease inhibitor (SLPI) to the incubation mixtures resulted in binding of leukocyte elastase to this inhibitor and extinction of free proteolytic activity against both natural and synthetic substrates. The progressive binding of leukocyte elastase to SLPI instead of alpha 1-PI was paralleled by an increasing binding of NP4(3) to alpha 1-PI. SLPI is a potent inhibitor of leukocyte elastase and cathepsin G, and although it lacks inhibitory effect on NP4(3), it may obviously indirectly aid in the binding and inhibition of NP4(3) to alpha 1-PI, by taking care of at least part of the leukocyte elastase. As a specific NP4(3)-inhibitor is not readily available for therapeutic use, this effect may prove useful under in vivo conditions and enhance the protective effect of administered recombinant human SLPI.

Stimulation of human polymorphonuclear leukocytes by recombinant human interleukin-1 beta.

Leukocyte activation is a property of systemic infection. Animal experiments indicate interleukin-1 (IL-1) as a possible modulator, while contradictory results have been reported from in-vitro stimulation of isolated leukocytes. The purpose of the present study was to investigate the activation of isolated polymorphonuclear (PMN) leukocytes in vitro by preparations of recombinant human IL-1 beta and IL-1 receptor antagonist, which in earlier studies could elicit and abrogate, respectively, a sepsis-like syndrome in rabbits. They have also been shown to influence acute phase protein synthesis in mice and rats, and release of leukocyte cathepsin G in vivo. It was found that recombinant human IL-1 beta elicited a dose-dependent luminol-enhanced chemiluminescence response in isolated human PMN leukocytes in the dose range 8.8 x 10(-11)-8.8 x 10(-8) M. The effect could be blocked by prior treatment with the IL-1 receptor antagonist, indicating a direct effect on the specific IL-1 receptor. Preincubation by IL-1 beta enhanced the effect of a secondary challenge with phorbol 12-myristate 13-acetate or formyl-Met-Leu-Phe by 30-40%. The priming effect of rhIL-1 beta could also be blocked by the specific receptor antagonist. In this study, incubation of PMN leukocytes with rhIL-1 beta failed to induce degranulation of both azurophil (neutrophil proteinase 4/proteinase 3) and specific (lactoferrin) granules. rhIL-1 beta has been shown to induce degranulation in vivo, which is thus indicated as an indirect effect. We conclude that IL-1 beta is a direct and specific, but probably weak stimulator of the PMN leukocyte.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatico-duodenectomy: 13-years' experience.

This paper reports a retrospective study of 51 consecutive pancreatico-duodenectomies from a Swedish university hospital concerning postoperative morbidity, number of reoperations and mortality. Resection of the distal common bile duct, duodenum, and head of the pancreas with hemigastrectomy and cholecystectomy was done in 48 patients and modified pancreaticoduodenectomy with preservation of the pylorus was done in three patients. Three patients (6%) died within 30 days. Nine patients required reoperation, three more than once. The most common major complications were anastomotic breakdown (n = 7), severe hemorrhage (n = 3) and abscess formation (n = 3). We conclude that a low postoperative morbidity and mortality can be achieved outside large, specialist centres, but the operation should be done by experienced surgeons. The results may justify carrying out the operation when the chances of cure are small, but it has yet to be evaluated as a palliative procedure.

Release of immunoreactive human neutrophil proteinase 4, normally and in peritonitis.

A specific enzyme-linked immunoassay (ELISA) has been developed for the determination of neutrophil proteinase 4 (NP4) in human plasma/serum and tissue fluids. Comparison of the sequence for the first 20 N-terminal amino acids of NP4, neutrophil elastase and cathepsin G shows that NP4 is distinct from the other two proteases. However, all three show considerable homology. Neither elastase nor cathepsin G show any immunoreactivity when tested in the present ELISA. Normal human plasma contains about 38 micrograms/l of NP4, identified as alpha 1-proteinase inhibitor complexes. This represents about 50% of the total amount of NP4 released in plasma. The remaining 50% is bound by alpha 2-macroglobulin. Blood coagulation leads to a rapid release of NP4 from the leukocytes. Peritonitis is accompanied by a pronounced release of NP4, as shown by a three-to 10-fold increase of NP4 plasma levels and by the NP4 level in peritoneal exudates, which reaches about 40 mg/l in severe cases.

Interleukin-1 receptor antagonist reduces mortality from endotoxin shock.

About five out of 1,000 patients admitted to hospital develop bacterial sepsis leading to shock, the mortality rate for which is high despite antibiotic therapy. The infection results in hypotension and poor tissue perfusion, and eventually leads to the failure of several organ systems. Bacterial endotoxin is thought to be the direct cause of shock in Gram-negative sepsis, because it can cause shock in animals, and antibodies against endotoxin prevent Gram-negative shock in animals and in humans. But, the symptoms of septic shock are the result of the actions of host cytokines induced by the endotoxin. The cytokine interleukin-1 has been implicated as an important mediator of septic shock because it can induce tachycardia and hypotension and act synergistically with tumour necrosis factor to cause tissue damage and death. We now report that a specific interleukin-1 receptor antagonist reduces the lethality of endotoxin-induced shock in rabbits, indicating that interleukin-1 does indeed play an important part in endotoxin shock.

The elimination of secretory leukocyte protease inhibitor (SLPI) after intravenous injection in dog and man.

After an intravenous injection of 35Sulphur-labelled secretory leukocyte protease inhibitor (SLPI) in four dogs, there was a rapid initial clearance (half-life 10 min) of radioactivity and immunoreactive SLPI from plasma. Later, the immunoreactive SLPI cleared more rapidly (T1/2 = 60 min) than the radioactivity, indicating the gradual appearance of radioactive degradation products. Intact recombinant human SLPI as well as radioactive fragments appeared in the urine. The urinary excretion of radioactivity during the first 3 h was less than 10% of the injected dose. After killing at 3 h, the kidneys contained more radioactivity per gram tissue than the other parenchymatous organs. Following an intravenous injection of 125Iodine-labelled native SLPI in three human volunteers, a rapid initial clearance of both protein-bound and total plasma radioactivity (half-life 10 min) was seen. Later, the protein-bound radioactivity cleared slower (half-life 120 min) than the total radioactivity, indicating a progressive degradation of SLPI with release of radioactive fragments to plasma. After 54 h 80-96% of the radioactivity had been excreted in the urine, mainly as free 125Iodine. No intact SLPI was found in the urine. A renal metabolism of SLPI is assumed, which is supported also by the finding of elevated serum levels of SLPI in uraemic patients. The possible therapeutic use of SLPI is briefly discussed.