John C. McDonald

Small-Bowel Tumors

BACKGROUND The rarity, delayed presentation, and diagnostic difficulty of small-bowel tumors prompted this study. STUDY DESIGN Charts were reviewed retrospectively for 85 patients with 89 small-bowel tumors (22 primary malignant, 23 primary benign, and 44 metastatic) over a 10-year period (1986-1996) at Louisiana State University Medical Center-Shreveport and two affiliated hospitals in Shreveport. RESULTS Of the primary malignant tumors, 10 carcinoids and 11 duodenal adenocarcinomas were identified. Most primary benign tumors were adenomatous or hyperplastic polyps, diagnosed by esophagogastroduodenoscopy. Metastatic tumors accounted for nearly 50% of all small-bowel tumors. Across all three tumor types, the most common presenting signs and symptoms were abdominal pain and nausea and vomiting. In addition, patients with benign tumors were more commonly presented with gastrointestinal hemorrhage, and those with metastatic tumors were more likely to present with obstruction. The mean interval from the onset of signs and symptoms to operation was 54 days for primary malignant tumors and 330 days for primary benign tumors. Esophagogastroduodenoscopy and computed tomography of the abdomen were occasionally helpful in diagnosis. Among the 22 primary malignant tumors, curative resections were performed in 11 patients (for 9 carcinoids and 2 adenocarcinomas) and palliative resections were performed in 10 patients (for 9 adenocarcinomas and 1 myxoliposarcoma). One patient had carcinomatosis from colon cancer and an incidentally discovered ileal carcinoid; this carcinoid was not included in this group of resections for primary malignant small-bowel tumors. All operations for 39 (of 44) patients with metastatic tumors were palliative. The remaining 5 (of 44) patients had metastatic duodenal cancer (confirmed by esophagogastroduodenoscopy or endoscopic retrograde cholangiopancreatography with biopsy) and did not undergo laparotomy. Surgical complications occurred more commonly with metastatic than with primary malignant tumors. Patients with primary malignant tumors had a 5-year survival rate of 36%. CONCLUSIONS These findings demonstrate that small-bowel tumors are difficult to diagnose because of delayed presentation, nonspecific signs and symptoms, and lack of accurate diagnostic studies. If the overall survival of patients with small-bowel tumors is to be improved, clinicians must have a high index of suspicion and be willing to perform exploratory celiotomy early.

P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion.

We have recently reported that hepatic ischemia/reperfusion (I/R) is associated with a biphasic increase in the expression of P-selectin in the liver microvasculature, with peak expression levels observed at 20 min and 5 h after reperfusion. This I/R-induced upregulation of P-selectin expression is accompanied by leukocyte-endothelial cell adhesion in terminal hepatic venules (THV). The objective of this study was to determine whether the early expression of P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in THV after liver I/R. Left hepatic lobe ischemia was induced for 30 min in anesthetized C57B1/6 and P-selectin knockout (KO) mice. The number of rolling, saltating, and adherent leukocytes in THV was measured at 0, 15, 30, 60, and 120 min after reperfusion using intravital video microscopy. Hepatic I/R elicited significant increases in the number of rolling, saltating, and adherent leukocytes, with peak values observed at 30 min after reperfusion. All of these responses were absent in P-selectin KO mice and in C57B1/6 mice treated with a blocking antibody to P-selectin. Our findings suggest that P-selectin is the primary determinant of leukocyte-endothelial cell adhesion observed in hepatic venules in the initial period after I/R. Hence, this adhesion molecule may represent a target for therapeutic intervention in liver transplantation and other conditions associated with hepatic I/R.

ICAM-1 upregulation in distant tissues after hepatic ischemia/reperfusion: A clue to the mechanism of multiple organ failure

BACKGROUND/PURPOSE Endothelial cell adhesion molecules (ECAMs) are felt to play an important role in ischemia/reperfusion (I/R) injury by causing adhesion of leukocytes to endothelial cells. It is possible that ECAMs play a role in multiple organ system failure. ICAM-1 is one of the adhesion molecules that has been shown to be upregulated in response to cytokines. This upregulation leads to leukocyte endothelial cell interaction (adhesion) and to neutrophil infiltration of the affected tissue. The purpose of our study was to measure ICAM-1 expression in the liver and other organs after hepatic ischemia/reperfusion (I/R). METHODS A laparotomy was performed on 14 Sprague-Dawley rats; 45 minutes of occlusive ischemia to the left lateral lobe was followed by 5 hours of reperfusion. The rat was injected with I125-labeled ICAM-1 MAb and I131-labeled nonbinding MAb (to control for nonspecific accumulation of ICAM-1 MAb). Entire organs were harvested and accumulated activity was measured in each organ. ICAM-1 levels were expressed as percent injected dose per gram of tissue. Control animals underwent sham laparotomy. RESULTS ICAM-1 was upregulated in the ischemic lobe of the liver, nonischemic lobe of the liver, heart, kidney, intestine, and pancreas. Up-regulation in the lung was not significant. Both the lung and liver had high constitutive levels of ICAM-1. CONCLUSIONS These data show that (1) significant hepatic upregulation of ICAM-1 after hepatic ischemia/reperfusion and (2) significant ICAM-1 upregulation in other tissues (heart, kidney, and intestine) after hepatic ischemia/reperfusion. The ICAM-1 upregulation in distant organs is likely mediated by cytokines such as tumor necrosis factor (TNF). These data show that leukocyte endothelial cell interactions in distant organs may be mediated by hepatic ischemia/reperfusion. This is a possible explanation for how failure of one organ can lead to failure of others in multiple organ system failure.

Endoscopic diagnosis and management of biliary complications following orthotopic liver transplantation

Nonoperative management of biliary complications (BC) with endoscopic retrograde cholangiopancreatography (ERCP) is a natural sequel to the emergence of choledochocholedochostomy as the preferred biliary reconstruction for orthotopic liver transplantation (OLT). Overall, therapeutic ERCPs efficacy for posttransplant BC is difficult to assess because most published data are retrospective, anecdotal, or in abstract form, and there are no prospective, randomized studies. Thus, endoscopic management of posttransplant BC must be individualized. While T-tube-related late bile leaks and ductal calculi are amenable to endoscopic therapy, its efficacy for strictures is more difficult to define. Refined surgical technique has prevented many unifocal anastomotic lesions, while multifocal strictures (for which endoscopic therapeutic experience is minimal) are increasingly prevalent. Whether endoscopic sphincterotomy is appropriate for posttransplant sphincter of Oddi dysfunction is controversial, because the disorder may be transient and the risk significant. Multicenter, prospective studies are needed to determine more accurately the optimal role of endoscopic therapy after OLT.

Quantification of P-selectin expression after renal ischemia and reperfusion☆

Neutrophils are important in ischemia and reperfusion injury. Multiple factors may be responsible for the adhesion of granulocytes to endothelial cells. P-selectin is a carbohydrate-binding glycoprotein that is stored preformed in endothelial cells as Weibel-Palade bodies. This preformation implies a very early role of P-selectin in the leukocyte adhesion process. Previous studies of P-selectin have not quantified its expression. The purpose of this study is to quantitate the expression and time course of P-selectin in response to renal ischemia and reperfusion injury. P-selectin was measured in 34 C57BL-6 mice after 30 minutes of occlusive left renal ischemia followed by 20 minutes, 2, 5, 10, and 24 hours of reperfusion. This was also performed in control and sham laparotomy groups. P-selectin was quantified using a new double radiolabeled 125I/131I monoclonal antibody technique and reported as percent injected dose per gram of tissue. P-selectin expression peaked at 20 minutes, plateaued up to 5 hours, and fell at 10 hours. Additionally, genetically altered mice that do not express P-selectin showed no up regulation after 5 hours of reperfusion. Pathology results confirmed significant renal injury. Renal ischemia and reperfusion injury caused significant upregulation of P-selectin. Expression of P-selectin at the short reperfusion time of 20 minutes reinforces the premise that P-selectin is one of the earliest adhesion molecules expressed. This early peak is probably caused by the release of preformed P-selectin. The delineation of these mechanisms of injury may be important in understanding and preventing renal injury in transplantation, sepsis, and shock.

Soluble HLA in human body fluids

There is a growing body of information about the soluble forms of HLA in serum but there are only a few reports discussing sHLA in other body fluids. We quantitated sHLA-I and sHLA-II concentrations in sweat, saliva and tear samples from five normal individuals with known HLA-phenotypes. We also studied sweat samples from an additional 12 normal nonphenotyped subjects, as well as in CSF of 20 subjects with different illnesses, using solid phase enzyme linked immunoassay. Sweat, saliva and tears from normal subjects were found to contain very low or nondetectable amounts of sHLA-I. In contrast, sHLA-II molecules were found in each of these body fluids, although, with considerable variation between individuals. The presence of sHLA-II in saliva was further confirmed by Western-blotting. It was observed that sHLA-II having molecular mass of 43,900 and 18,100 daltons was comparable with that found in serum from normal individuals. In addition, no association of sHLA-II levels with allospecificities in either body fluid or in serum was apparent. The results of CSF sHLA concentrations in different diseases were as follows: (1) High CSF SHLA-I levels were measured during viral encephylitis (n = 3), while none of these patients contained sHLA-II in CSF; (2) The levels of sHLA-II, but not sHLA-I were elevated in CSF of patients during seizure (n = 6) and of patients with neonatal hepatitis (1 of 2) or with connective tissue disease accompanied with viral infection (n = 2); (3) No CSF sHLA-I or sHLA-II could be detected at polyneuropathy (n = 2), or in patients with syphilis (n = 3), or leukemia (n = 2) with evidence of neurologic involvement of central nervous system. Taken together, it may be concluded that the presence of sHLA in several body fluids is physiologically normal. It appears that sHLA-II is the predominant class of HLA molecules present in different body fluids. We propose that the system responsible for sHLA-II production in various body fluids must involve different mechanisms than those responsible for sHLA-I synthesis in serum.

Pancreatic Transplantation and Subsequent Graft Surveillance by Pancreatic Portal–Enteric Anastomosis and Temporary Venting Jejunostomy

ObjectiveTo evaluate portal–enteric (PE) pancreas and kidney transplantation with venting jejunostomy (VJ) for its efficacy, safety, and reproducibility. Summary Background DataSimultaneous pancreas and kidney transplantation for patients with long-standing insulin-dependent diabetes mellitus that progresses to renal failure has revolutionized their treatment and quality of life. A current clinical focus is to refine the technical aspects of this procedure. Simultaneous pancreas and kidney transplantation with PE anastomosis with VJ appears to offer several advantages over bladder drainage. VJ allows initial decompression of the enteric anastomosis, monitoring of pancreatic function by ostomy amylase, and simple access for endoscopic evaluation and biopsy of the allograft. MethodsSimultaneous pancreas and kidney transplantation with VJ was performed in 21 patients from December 1996 to October 2000 at Willis Knighton/LSU Regional Transplant Center. All patients had long-standing insulin-dependent diabetes mellitus and subsequent renal failure. They were evaluated at the time of surgery by a multidisciplinary transplant team and monitored for numerous factors, including length of hospital stay, immunosuppressive regimen, and ischemia times. All patients had intermittent visual and biochemical evaluation of pancreatic secretions monitored by means of the VJ. ResultsOf the 21 patients, 10 were women and 11 were men. Four patients were black and 17 were white. The mean age at transplantation was 38 years; average human leukocyte antigen (HLA) match was one; and average cold ischemia time was 12 hours. The median hospital stay was 16 days. Four episodes of postoperative bleeding requiring exploration occurred in four patients. Postoperative wound infections developed in four patients. There were 12 episodes of rejection in nine patients. All patients with suspected acute pancreatic rejection underwent endoscopy by means of the VJ and duodenal biopsy for evaluation. Two patients lost pancreatic function subsequent to kidney failure, one secondary to noncompliance and the other as a result of hemolytic-uremic syndrome. Patient, kidney, and pancreatic survival rates were 100%, 90%, and 90%, respectively. The mean follow-up period was 25 (range 2–48) months. ConclusionThe authors believe that PE pancreatic drainage with VJ is a more physiologic method to perform pancreatic transplantation than bladder drainage. PE drainage allows rapid diagnosis of acute rejection and anastomotic leak and provides a simple way to monitor ostomy amylase and transplant duodenal bleeding. This technique is safe and has minimal associated complications.

SOLUBLE HLA-I IN RHEUMATIC DISEASES

OBJECTIVE To study serum levels of Class I soluble HLA (sHLA-I) in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), polymyositis or dermatomyositis (PM/DM) or scleroderma and to assess the possible influence of ethnic factors on concentration in each disease group. METHODS Solid-phase enzyme linked immunoassay was used to measure sHLA-I in the serum of 385 patients with varied ethnic backgrounds (American-Caucasians, African-Americans, Georgian-Caucasians) with rheumatic diseases. Studies on patients were compared to similar measurements of 189 healthy individuals. RESULTS Mean sHLA-I levels were significantly higher in patients with SLE than those observed in healthy individuals or other rheumatic diseases. Highest concentrations were present in Georgian-Caucasian patients with SLE. American-Caucasian patients with RA or scleroderma had higher sHLA-I levels than normal Caucasian individuals. The majority of patients with PM/DM in all ethnic subgroups were low secretors of sHLA-I. CONCLUSION Mechanisms underlying the secretion of sHLA-I appear to differ among the rheumatic diseases studied and various ethnic groups. These genetic differences in sHLA-I secretion could be associated with ethnic and pathophysiologic differences among these rheumatic diseases.

Kinetics of P-selectin expression in regional vascular beds after resuscitation of hemorrhagic shock: a clue to the mechanism of multiple system organ failure.

Leukocyte-endothelial cell interactions play an important role in mediating organ dysfunctions observed after hemorrhagic shock. P-selectin is the first endothelial cell adhesion molecule to be upregulated after an ischemic insult. The objective of this study was to define kinetics of P-selectin expression in different regional vascular beds of mice exposed to hemorrhagic shock. In-vivo P-selectin expressions were determined using dual radiolabeled monoclonal antibody technique in lungs, heart, liver, kidneys, intestinal mesentery, stomach, small bowel, and colon 0.5, 1, 2, 5, 10, and 24 h after resuscitation of 40 mmHg hemorrhagic shock. In another group, P-selectin expression was determined in same organs 5 h after resuscitation of 30 mmHg hemorrhagic shock. Hemorrhagic shock of 40 mmHg caused significant upregulation of P-selectin in lungs and liver at 30 min after resuscitation (P < 0.001). There was a second and more pronounced upregulation of P-selectin in lungs and liver at 5 h after resuscitation (P < 0.001). In heart, intestinal mesentery, stomach, small bowel, and colon, P-selectin was not upregulated until 5 h after resuscitation from 40 mmHg hemorrhagic shock (P < 0.001). While hemorrhagic shock of 40 mmHg did not cause P-selectin upregulation in kidneys, hemorrhage to 30 mmHg did elicit a significant increase at 5 h after resuscitation (P < 0.001). We conclude that P-selectin is upregulated after resuscitation of hemorrhagic shock in lungs, liver, heart, stomach, and intestines. P-selectin upregulation in kidneys only takes place after more severe hemorrhagic shock.

Recent Advances in the Management of Gallstones

Demands for less invasive, more cost-effective therapy have revolutionized the management of gallstones over the past 10 years. There are no reliable methods of permanently reversing the pathophysiologic defects that cause gallstones. Open cholecystectomy (OC), the gold standard for managing symptomatic cholelithiasis, has been largely replaced by laparoscopic cholecystectomy (LC), which has the advantages of a minimal hospital stay and quicker return to work. Other adjunctive therapies, limited in applicability to selected patients, include oral bile acid therapy (BAT), dissolutional agents, and extracorporeal shock wave lithotripsy. Choledocholithiasis (CDL), formerly managed exclusively with surgical common duct exploration, is increasingly treated with therapeutic biliary endoscopy. Methods of laparoscopic common bile duct exploration are being developed. Optimal algorithms for applying these techniques to patients undergoing LC are evolving. In a sense, the solution to all, or certainly most, gallstones now can be seen through a scope.