Addition of matrix metalloproteinase inhibition to conventional cytotoxic therapy reduces tumor implantation and prolongs survival in a murine model of human pancreatic cancer.

Matrix metalloproteinases (MMPs) participate in basement membrane degradation, a critical step in invasion of cancer cells. We have previously shown that MMP inhibition of pancreatic cancers improves survival and decreases MMP production in vivo. The purpose of this study was to determine whether BB-94 was better than cytotoxic therapy and would increase the efficacy of cytotoxic therapy (gemcitabine) in a murine model of human pancreatic cancer. A human pancreatic adenocarcinoma cell line (HPAC) was injected into the pancreata of BALB/c nu/nu mice. The mice were randomized 7 days after cancer cell injection to receive vehicle control, BB-94, gemcitabine, or gemcitabine and BB-94 until death or sacrifice at 84 days. At necropsy, tumors were harvested, and the relative enzyme activities of MMP-2 and MMP-9 were determined by gelatin zymography. Active MMP-2 levels in serum were determined using an ELISA technique. Combination treatment with gemcitabine and BB-94 significantly reduced implantation rates and improved survival in mice with documented orthotopic tumors compared with either therapy alone or control. Tumor levels of active and latent MMP-2 were higher than those of MMP-9 in both treated and control mice. There was a significant reduction of tumor MMP-2 activity in mice treated with BB-94, gemcitabine, or gemcitabine and BB-94. Serum levels of active MMP-2 were reduced in all treated groups, with the greatest reduction occurring in mice treated with gemcitabine and BB-94. Combination therapy with gemcitabine and BB-94 reduces cancer implantation and improves survival compared to treatment with BB-94, gemcitabine, or vehicle control alone. MMP production was reduced in all treated groups, reflecting reduced tumor progression, which was particularly seen with combination therapy with gemcitabine and BB-94. This study supports combining MMP inhibition with cytotoxic therapy (gemcitabine) for patients with pancreatic cancer.

Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development.

Hypermethylation of the MLH1 promoter underlies most sporadic colorectal cancers with microsatellite instability (MSI). To investigate the role of hypermethylation in the normal colonic mucosa as a possible precursor lesion, we studied 700 bp upstream of MLH1 covering 51 CpG sites. We found partially methylated alleles in 15 of 34 (44%) patients <60 years of age and 20 of 24 (83%) patients > or =80 years of age (P = 0.0026). Fully methylated alleles were present in 18 of 33 (55%) patients with MSI+ tumors but in only 18 of 90 (20%) patients with MSI- tumors (P = 0.00019). By in situ analysis, methylation was patchy and located mainly in the cryptal regions close to the lumen. We conclude that the spread of methylation in the MLH1 promoter in the normal colonic mucosa is closely associated with age and the development of sporadic MSI+ colorectal cancers.

Bariatric surgery and multiple personality disorder: complexities and nuances of care.

BACKGROUND: Multiple personality disorder (MPD) can occur in patients with morbid obesity in need of bariatric surgery, though few reports noting this association exist in the literature. Herein we address MPD in morbid obesity, in the context of a patient presenting to us seeking surgical treatment of her morbid obesity. METHODS: A 31-year-old morbidly obese (BMI 49 kg/m2) Hispanic female presented in early 1994 requesting bariatric surgery. She had been a victim of violent sexual abuse as a young girl. Subsequently, she developed at least three personalities, including one male personality. RESULTS: Although she has lost nearly 45 kg after gastroplasty, her care has been complicated by her named multiple personalities. While MPD are infrequent and unfamiliar to most care providers, successful outcomes can be promoted with a proper approach. CONCLUSIONS: This patient's care illustrates that: (1) all personalities must agree to proposed operative intervention; (2) consent must be obtained from the 'true' patient; and (3) postoperative care and follow-up must address all personalities for an optimal outcome.

Outcome following bariatric surgery in super versus morbidly obese patients: does weight matter?

BACKGROUND: Numerous investigators have attempted to identify prognostic indicators for successful outcome following bariatric surgery. The purpose of this study was to determine whether degree of obesity affects outcome in super obese [>225% ideal body weight (IBW)] versus morbidly obese patients (160-225% IBW) undergoing gastric restrictive/bypass procedures. METHODS: Since 1984, 157 patients underwent either gastric bypass or vertical banded gastroplasty. Super obese (78) and morbidly obese (79) patients were followed prospectively, documenting outcome and complications. RESULTS: Super obese patients reached maximum weight loss 3 years following bariatric surgery, exhibiting a decrease in body mass index (BMI) from 61 to 39 kg/m2 and an average loss of 42% excess body weight (EBW). Morbidly obese patients had a decrease in BMI from 44 to 31 kg/m2 and carried 39% EBW at 1 year. After their respective nadirs, each group began to regain the lost weight with the super obese exhibiting a current BMI of 45 kg/m2 (61% EBW) versus 34 kg/m2 (52% EBW) in the morbidly obese at 72 months cumulative follow-up. Currently, loss of 50% or more of EBW occurred in 53% of super obese patients versus 72% of morbidly obese (P < 0.01). Twenty-six percent of super obese patients returned to within 50% of ideal body weight (IBW) while 71% of morbidly obese were able to reach this goal (P < 0.01). Co-morbidities and complications related to surgery were similar in each group. CONCLUSIONS: Super obese patients have a greater absolute weight loss after bariatric surgery than do morbidly obese patients. Using commonly utilized measures of success based on weight, morbidly obese patients tend to have better outcomes following bariatric surgery.

Fluorodeoxyglucose positron emission tomography as an adjunct to carcinoembryonic antigen in the management of patients with presumed recurrent colorectal cancer and nondiagnostic radiologic workup.

BACKGROUND: The purpose of this study was to determine the role of fluorodeoxyglucose positron emission tomography (PET) in localizing disease in patients with colorectal cancer with radiologically occult symptomatology or increases in carcinoembryonic antigen (CEA) level. METHODS: Two hundred seventy-seven patients with colorectal cancer underwent PET scanning between November 1998 and September 2000 prompted by (1) increasing CEA level and nondiagnostic imaging or (2) symptoms with normal CEA level and nondiagnostic imaging. PET results were correlated with operative findings/histology, clinical follow-up data, and CEA level to determine PET's accuracy in determining the source of symptoms or CEA. RESULTS: Fifteen patients had increasing CEA levels, and 14 had abnormal PET. Two of these 14 were denied exploration because PET suggested widely metastatic disease. Nine patients underwent exploration with curative intent. In 1 patient, recurrence was not pathologically confirmed (false-positive rate, 8%). Two had disease beyond that predicted by PET, and 6 underwent complete resection and normalized their CEA levels. Four symptomatic patients with normal CEA levels and negative x-rays had abnormal PET; at exploration, 3 had no evidence of recurrence. CONCLUSIONS: PET imaging can often accurately localize the source of radiologically occult increases in CEA level and select that subset of patients eligible for therapeutic laparotomy. Symptomatic, PET-positive patients with normal CEA levels frequently undergo nontherapeutic laparotomy, and PET findings should be interpreted with caution in these patients.

Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer.

BACKGROUND: The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers. METHODS: We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model. RESULTS: Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P < .01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01). CONCLUSIONS: Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.

Transjugular intrahepatic portosystemic shunt versus H-graft portacaval shunt in the management of bleeding varices: a cost-benefit analysis.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is popular in treating portal hypertension because of its perceived efficacy and cost benefits, although it has never been compared with surgical shunting in a cost-benefit analysis. This study was undertaken to determine the cost benefit of TIPS versus small-diameter prosthetic H-graft portacaval shunt (HGPCS). METHODS: Cost of care was determined in 80 patients prospectively randomized to receive TIPS or HGPCS as definitive treatment for bleeding varices, beginning with shunt placement and including subsequent admissions for complications or follow-up related to shunting. RESULTS: Patients were similar in age, gender, severity of illness/liver dysfunction, and urgency of shunting. After TIPS or HGPCS, variceal rehemorrhage (8 versus O, respectively; p = 0.03), shunt occlusion (13 versus 4; p = 0.03), shunt revision (16 versus 4; p < 0.005), and shunt failure (18 versus 10; p = 0.10) were compared; all were more common after TIPS. Through the index admission, TIPS cost $48,188 +/- $43,355 whereas HGPCS cost $61,552 +/- $47,615. With follow-up, TIPS cost $69,276 +/- $52,712 and HGPCS cost $66,034 +/- $49,118. CONCLUSIONS: Early cost of TIPS was less than, though not different from, cost of HGPCS. With follow-up, costs after TIPS mounted. The initially lower cost of TIPS is offset by higher rates of subsequent occlusion and rehemorrhage.

Pancreatic ascites as a powerful inducer of inflammatory cytokines. The role of known vs unknown factors.

OBJECTIVES: To determine if pancreatic ascites will induce interleukin 1 beta (IL-1 beta) or tumor necrosis factor alpha (TNF-alpha) production outside the pancreas and examine the possible components responsible. DESIGN: Severe pancreatitis was induced in rats (n = 30) by pancreatic duct infusion with 4% glycodeoxycholic acid; pancreatic ascites was collected 18 hours later. In vitro studies used quiescent murine splenic or pulmonary macrophages (10(5)/mL) which were exposed to media alone (control), trypsin, chymotrypsin, cathepsin-B, 20% ascites (vol/vol), 50% ascites, or endotoxin (lipopolysaccharide, 10 micrograms/mL, positive control) for 4 hours. Subsequently, pancreatic ascites was cultured for bacteria and assayed for endotoxin and cytokines (interleukin 1, interleukin 6, interleukin 8, TNF-alpha, or interferon gamma). The experiments were then repeated using 20% and 50% ascites that was sterile and cytokine-free (SCF ascites). In vivo studies used 100% (n = 8) or 50% (n = 12) SCF ascites or normal rat serum (control, n = 12) for a 10-second pulmonary lavage (100 microL) in adult mice, with lungs collected at 6 hours for cytokine gene analysis. SETTING: Surgical basic science research laboratory. MAIN OUTCOME MEASURES: Interleukin 1 beta and TNF-alpha gene induction was assessed by quantitative competitive reverse-transcription polymerase chain reaction and cytokine protein production was determined by enzyme-linked immunosorbent assay. RESULTS: Macrophages responded to untested and SCF ascites in a dose-dependent fashion, with a multifold increase in both IL-1 beta and TNF-alpha messenger RNA (mRNA) and protein, which was often more potent than lipopolysaccharide. Expression of IL-1 beta and TNF-alpha mRNA could not be induced by trypsin, chymotrypsin, or cathepsin-B. All animals undergoing lavage with 100% SCF ascites died within 2 hours, while those undergoing lavage with 50% SCF ascites showed a multifold increase in pulmonary IL-1 beta and TNF-alpha mRNA. CONCLUSIONS: Pancreatic ascites contains factors that are capable of inducing IL-1 beta and TNF-alpha production in vitro and in vivo. This effect cannot be reproduced by activated digestive enzymes and is propagated despite the absence of known inducers of cytokines such as bacteria, endotoxin, or other inflammatory cytokines.

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.

Small-diameter prosthetic H-graft portacaval shunt: definitive therapy for variceal bleeding.

Partial portal decompression has become a popular option in the treatment of complicated portal hypertension. This study was undertaken to report long-term follow-up after partial portal decompression obtained utilizing 8 mm prosthetic H-graft portacaval shunts. A total of 110 consecutive patients underwent H-graft portacaval shunting through a protocol that detailed care and studies from 1988 to 1996. Prospective follow-up recorded efficacy of partial portal decompression, shunt patency, morbidity of shunting, and survival. Seventy males and 40 females, whose average age was 54 +/-12.7 years (standard deviation), underwent shunting. Cirrhosis was due to alcohol abuse in 64%. Fourteen percent were in Child's class A, 55% in Child's class B, and 31% in Child's class C. Shunts were undertaken as emergencies in 20%, urgently in 13%, and electively in 67%. Shunting decreased portal pressure in all patients (30 +/-5.3 Hg to 19.9 -/+5.5 mm Hg; P <0.001). Early and late thrombosis was 6.4% and 3.6%, respectively. Late rebleeding occurred in 5.4%. Perioperative (30-day) mortality was 11.8%, and was highest for patients in Child's class C. Three-year survival was 53%. Five-year survival was 41%. Partial portal decompression is achieved with H-graft portacaval shunting. Rebleeding, shunt occlusion, and encephalopathy are uncommon. In this series of unselected older patients with alcoholic cirrhosis, 5-year survival after H-graft portacaval shunting was greater than 40% with minimal intervention.

Management of medically refractory ascites.

BACKGROUND: Medically refractory ascites is a clinical entity for which there exists few effective therapeutic options. Available treatment modalities include diuresis and sodium restriction, peritoneovenous shunt, liver transplant, transjugular intrahepatic portosystemic shunts and surgical shunts, and large-volume paracentesis. Herein we review the current therapeutic options for medically refractory ascites focusing on indications, benefits, and drawbacks of each specific therapy. DATA SOURCES: Data and recommendations are based on the authors' cumulative experience with complicated cirrhotic and cancer patients and on past and current literature addressing intractable ascites. CONCLUSIONS: The absence of a single, effective therapy in the management of refractory ascites speaks to the complex nature of this complication. Although most patients will respond to medical management, thoughtful application of available therapeutic options in patients who fail, as described herein, not only makes decisions regarding their care easier but also provides the best palliation in a vexing clinical scenario.

Predictors of positive axillary lymph nodes after sentinel lymph node biopsy in breast cancer.

OBJECTIVE: The purpose of this study was to determine the factors that predict the presence of metastasis in nonsentinel lymph nodes (SLN) when the SLN is positive. METHODS: A prospective database was analyzed and included patients who underwent SLN biopsy for invasive breast cancer from July 1997 to August 2000 (n = 442). One hundred (22.6%) patients had one or more positive SLNs, and were analyzed to determine factors that predicted additional positive axillary nodes. RESULTS: Of the 100 patients with a positive SLN, 40 patients (40%) had additional metastasis in non-SLNs. The only significant variables that predicted non-SLN metastasis were tumor lymphovascular invasion (P = 0.004), extranodal extension (P < 0.001), and increasing size of the metastasis within the SLN (P = 0.011). In analyzing just those patients who had lymphovascular invasion, extranodal extension, and a SLN metastasis > 2mm, 92% were found to have additional positive nodes. CONCLUSIONS: In patients with invasive breast cancer and a positive sentinel lymph node, lymphovascular invasion, extranodal extension, and increasing size of the metastasis all significantly increase the frequency of additional positive nodes.

Selective analysis of the sentinel node in breast cancer.

BACKGROUND: This study was designed to determine the minimum number of sentinel nodes necessary to accurately stage patients with breast cancer. METHODS: Between August 1997 and February 2001, 509 consecutive patients were enrolled in a prospective sentinel node database. Nodes were characterized as either blue or hot (>2 times background), or both, and ranked based on the order harvested. Predictive value of the sentinel node based on these characteristics was evaluated to determine the minimum number necessary to stage the basin. RESULTS: In all, 990 sentinel nodes were harvested from 465 basins. Pathologic stage in 126 of 128 positive basins was predicted by the first or second node harvested. The remaining 2 patients were positive by immunohistochemistry only. The hottest node predicted the status in 114 of 128 basins. CONCLUSIONS: Although all nodes should be examined, these data suggest that limiting frozen section analysis to the first two sentinel nodes identified will not compromise the accuracy of staging and may provide a vehicle for resource savings.

Small-diameter H-graft portacaval shunt reduces portal flow yet maintains effective hepatic blood flow.

Small-diameter H-graft portacaval shunts (HGPCSs) effectively treat bleeding varices due to cirrhosis, although the effects of such shunts on hepatic blood flow are not well established. Proponents of HGPCS believe that portal flow diverted through the shunt is regained through increased hepatic arterial inflow while others argue that this flow is never recovered; resulting in compromised nutrient flow. In this study, we sought to determine the effects of HGPCS on effective hepatic and portal blood flow. Patients undergoing HGPCS had portal pressures and flow (via color-flow Doppler ultrasound) measured intraoperatively before and after placement of HGPCS. Effective hepatic blood flow was determined utilizing low-dose galactose clearance 1 day preoperatively and 5 days postoperatively. Over a 7-year period, 64 patients (42 male and 22 female), average age 54 +/- 13.6 years (SD), were studied. Cirrhosis was due to alcohol in 37 patients, hepatitis in 9, alcohol and hepatitis in 5, and assorted other causes in 13. Child's class was A in 11 patients, B in 35, and C in 18. Both portal flow and pressures decreased significantly postoperatively (15 +/- 14.2 to 10 +/- 15.1 mL/min [P < 0.05] and 29 +/- 13.0 to 18 + 6.2 mm/Hg [P < 0.05]), whereas effective hepatic blood flow decreased insignificantly (1441 +/- 1719 to 1332 +/- 863 mL/min). Small-diameter HGPCS significantly reduce portal pressures and portal blood flow while maintaining effective hepatic flow. These findings suggest that hepatic arterialization occurs as early as 5 days after shunting and thus support the application of HGPCS.

Peritoneovenous shunts in patients with intractable ascites: palliation at what price?

Intractable ascites carries great morbidity by affecting appetite, mobility, and quality of life. Peritoneovenous shunts (PVSs) are utilized to abate intractable ascites, although long-term efficacy is unestablished. Thirty male and 18 female cirrhotics, 55 +/- 12 (standard deviation) years of age, failed multiple large-volume paracenteses and diuretic therapy before undergoing PVS. Data were collected until death or the present time. Nine patients (19%) are alive and palliated, four with working shunts [average follow-up (ave. f/u), 30 months] and five without shunts (ave. f/u, 19 months). Thirty-two (67%) patients died: 18 palliated with functional shunts (survival time, 4.4 +/- 5.7 months), 8 unpalliated with dysfunctional shunts (ave. f/u, 3.9 +/- 4.5 months), 4 unpalliated with shunts removed (ave. f/u 5.5 +/- 4.7 months), and 2 with unknown shunt function at death. Function was lost to occlusion in 26 patients, infection in 9, and ligation for disseminated intravascular coagulation in 3. Thirteen patients underwent 18 shunt replacements. At death/present time, 22 (46%) patients were palliated with functioning shunts. Seven patients were lost to follow-up. PVSs provide palliation for intractable ascites short term, but commonly occlude within 1 year. Despite palliation, complications with PVSs are high, and survival is limited.

Lymphatic mapping for breast cancer: experience at The Ohio State University.

BACKGROUND: Though not yet the standard of care, lymphatic mapping is becoming more widely utilized by surgeons who care for women with breast cancer. The purpose of this study is to report the early experience of lymphatic mapping at a large NCI designated cancer center. METHODS: Beginning in 1997, selected newly diagnosed breast cancer patients at our institution have undergone lymphatic mapping. Blue dye and radiolabelled colloid were used as mapping agents. Patients were entered into a prospective database which recorded demographics, mapping characteristics and pathologic correlation. RESULTS: In total, 352 patients were entered into the study, and 312 (89%) had an identifiable sentinel lymph node at the time of definitive surgery. Eight surgeons contributed to the database, four of whom performed more than 30 lymphatic mapping procedures. 149 patients underwent complete axillary lymphadenectomy either as part of a validation study (68) or because of metastasis disease to the sentinel node (81). The false negative rate was 4%. The surgeon's experience with the procedure was the only independent predictor of the ability to localize a sentinel node. CONCLUSIONS: Sentinel lymphadenectomy at our institution is an accurate means of predicting the status of the draining nodal basin. Experience with the technique correlates with successful localization, but patient selection and an institutional commitment to the procedure are also critical for success.

Matrix metalloproteinase (MMP) inhibition selectively decreases type II MMP activity in a murine model of pancreatic cancer.

BACKGROUND: Basement membrane degradation is a critical component of tumor invasion and metastasis that is facilitated by the family of enzymes known as matrix metalloproteinases (MMPs). MMP-2 and MMP-9 are two subtypes that have specifically been identified in tumors of gastrointestinal origin. We have previously shown that broad inhibition of these enzymes with the MMP inhibitor BB-94 improves survival in a murine model of pancreatic cancer. The purpose of this study was to determine MMP-2 and MMP-9 activity in orthotopic tumors from mice treated with and without BB-94. METHODS: Ten million cells of a moderately differentiated pancreatic cancer cell line (HPAC) were implanted orthotopically into Balb/c nu/nu mice. The mice were treated with BB-94 or vehicle control for 70 days or until death. At necropsy, tumors were harvested, total protein was extracted, and MMPs were purified from 400 microgram of crude protein extract by gelatin-Sepharose affinity chromatography. Relative enzyme levels and activity of MMP-2 and MMP-9 were determined by Western blot and gelatin zymography. RESULTS: Tumors from treated animals were significantly smaller than those from nontreated animals. MMP-2 was present in greater amounts in both treated and nontreated animals than MMP-9. Active MMP-2 was present in both groups but significantly decreased in animals treated with BB-94. Active MMP-9 was absent in both groups, whereas levels of latent MMP-9 appeared lower than those of MMP-2 in all samples. CONCLUSIONS: Activated MMP-2 and not MMP-9 in HPAC cells grown in nude mice suggests that this MMP subtype is more critical in the phenotypic behavior of such tumors. Furthermore, attenuated levels of active MMP-2 in animals treated with the enzyme inhibitor BB-94 suggest that previously observed improvements in survival correlate with the level of MMP-2 activity.

Immediate and long-term portal hemodynamic consequences of small-diameter H-graft portacaval shunt.

BACKGROUND: Effective hepatic blood flow is thought to play a critical role in outcome following portal decompressive procedures. We have shown previously that hepatic arterialization occurs soon after shunting, preserving nutrient flow, but the remote effects of shunting are unknown. The purpose of this study was to determine the effect of small-diameter prosthetic H-graft portacaval shunt (HGPCS) on effective hepatic blood flow (EHF) and portal pressures 1 year from shunt placement. METHODS: Patients undergoing 8-mm HGPCS had effective hepatic blood flow determined using low-dose galactose clearance preoperatively, postoperatively, and at 1 year postshunt. Portal blood flow, pressures, and portal vein/inferior vena cava pressure gradients were determined intraoperatively before and after shunt placement and at 1 year. RESULTS: Twenty patients undergoing shunting had flows measured. All patients had significant reductions in portal vein/inferior vena cava pressure gradients while effective hepatic flow was maintained immediately postoperatively. At 1 year following shunting, effective hepatic blood flow was significantly lower than both pre- and postoperative rates of flow while portal pressures and gradients were significantly increased. Albumin, cholesterol, and PT were improved at 1 year while total bilirubin was slightly worse. Nineteen of 20 patients are still alive with average follow-up of 26 +/- 10.3 months. Four patients were encephalopathic preop, 5 postop, and none chronically. CONCLUSIONS: Recollateralization of varices and progression of cirrhosis may account for the observed reductions in EHF at 1 year. Regardless of the cause, diminution of EHF at 1 year is well compensated as demonstrated by minimal encephalopathy and ascites, improved hepatic function reflected in blood chemistry profiles, and good survival.

Candida antigen titre dilution and death after injury.

BACKGROUND: Candida infections affect outcome after injury. Candida antigen titres were used to detect these infections early. This study was undertaken to correlate Candida antigen titre dilution with conventional injury scoring and outcome after severe injury. METHODS: Candida antigen titres were determined by agglutination when clinically apparent source(s) of Candida were noted, when Candida was grown in culture of body fluids, or when unexplained clinical deterioration occurred. The findings were compared with the Injury Severity Score (ISS). RESULTS: Seventy-five seriously injured adults (median ISS 25 (range 18-50)) developed raised Candida antigen titres. Multivariate analysis showed that age and Candida antigen titre correlated significantly with mortality, but not with each other. Culture evidence of Candida, or lack thereof, did not correlate with Candida antigen titre or mortality. Sixteen of 75 patients died, 14 from bacterial sepsis and none from Candida infection. CONCLUSION: In seriously injured adults, the mortality rate is related to raised Candida antigen titres. The association between Candida antigen titre and mortality, although real, remains unexplained.