Diagnosis and management of hepatocellular carcinoma: results of a consensus meeting of The Ottawa Hospital Cancer Centre.

Hepatocellular carcinoma (HCC) is an uncommon tumour, but its incidence is increasing in Canada and elsewhere. Currently, there are no Canadian recommendations for diagnosis and treatment of hcc, and possible options may have regional limitations. A consensus symposium was held in the Ottawa region to consider current diagnostic and management options for hcc. These recommendations were developed: Diagnosis-with adequate imaging, a biopsy is not required pre-surgery, but is required before the start of systemic therapy; lesions smaller than 1 cm should be followed and not biopsied; repeat biopsies should be core tissue biopsies; magnetic resonance imaging is preferred, but triphasic computed tomography imaging can be useful. Resection-recommended for localized HCC. Radiofrequency ablation-recommended for unresectable or non-transplantable HCC; should not be performed in the presence of ascites. Trans-arterial chemoembolization (TACE)-doxorubicin with lipiodol is the agent of choice; trans-catheter embolization is an alternative for patients if TACE is not tolerated or is contraindicated. Medical management-first-line sorafenib should be considered the standard of care. Transplantation-suitable patients meeting Milan criteria should be assessed for a graft regardless of other treatments offered. The authors feel that the recommendations from this consensus symposium may be of interest to other regions in Canada.

An informational approach to likelihood of malnutrition.

Unidentified protein-energy malnutrition (PEM) is associated with comorbidities and increased hospital length of stay. We developed a model for identifying severe metabolic stress and likelihood of malnutrition using test patterns of albumin (ALB), cholesterol (CHOL), and total protein (TP) in 545 chemistry profiles. Pattern classes were derived by converting decision values to a number code using cutoff values for nonmalnourished (0), moderate (1), and severe (2) of: ALB 35, 27 g/L; TP 63, 53 g/L; and CHOL 3.9, 2.8 mumol/L. Patterns defined by combinations of normal and abnormal laboratory results had decreased the likelihood of PEM from an all-2 to all-0 pattern. They were compressed to four final classes. ALB (F = 170), CHOL (F = 21), and TP (F = 5.6) predicted PEM class (r2 = 0.806, F = 214; P < E-6), but pattern class was the best predictor (r2 = 0.900, F = 1200, P < E-10). Kruskal-Wallis analysis of class by ranks was significant for pattern class (E-18), ALB (E-18), CHOL (E-14), and TP (2E-16). The means and SEM for tests in three PEM classes (mild, moderate, severe) were: ALB-35.7, 0.8; 30.9, 0.5; 24.2, 0.5 g/L; CHOL-3.93, 0.26; 3.98, 0.16; 3.03, 0.18 mumol/L, and TP-68.8, 1.7; 60.0, 1.0; 50.6, 1.1 g/L. We classified patients at risk of malnutrition using truth table comprehension. The pattern classes formed by the tests are a better classifier than the tests themselves.

Update on the use of metabolic probes to quantify liver function: caffeine versus lidocaine.

The search for continues for a safe, accurate and reliable method to quantify liver function similar in principle to renal creatinine clearance or pulmonary function spirometry tests. When evaluating patients in the more advanced stages of chronic liver disease, one's clinical judgement regarding the degree of liver dysfunction usually suffices, but in patients with early or only intermediate disease, and estimate based on routine blood tests and/or clinical severity scores is often unreliable. A more quantitative approach under investigation at present has been to monitor specific pharmacokinetic parameters of 'probe' drugs metabolized primarily by hepatic cytochrome P-450. These parameters include the plasma or salivary clearance rate of the parent compound and/or the formation rate of its metabolites. Following a review of basic hepatic pharmacology relevant to this topic, we shall explore the advantages and disadvantages of two 'metabolic probes' that have shown the most promise to date, caffeine and lidocaine.

Henoch-Schönlein purpura. A multisystem disease also seen in adults.

Henoch-Schönlein purpura is a common vasculitic syndrome of childhood that is also seen in adults. It is characterized by the deposition of immune complexes, mainly IgA and C3, in various organ systems. Diagnosis is based on the presence of nonthrombocytopenic purpura, arthritis or arthralgia, abdominal pain that may be complicated by intussusception, and glomerulonephritis. The disease is usually self-limited and lasts a few weeks but may recur. Recovery is complete in almost all patients, with the severity of renal involvement dictating any remaining sequelae. Corticosteroid therapy may provide acute symptomatic relief but apparently has no effect on the natural course of the disease.

Cholecystokinin-stimulated monocytes produce inflammatory cytokines and eicosanoids.

OBJECTIVES: Plasma cholecystokinin increases with enteral feeding. Cholecystokinin increases intracellular calcium in lymphocytes/monocytes and is a lymphocyte co-mitogen. We hypothesize that decreased cholecystokinin production with "bowel rest" and parenteral nutrition may be beneficial in inflammatory bowel disease by down-regulating gut immune/inflammatory mechanisms. The majority of cells observed in mucosa of inflammatory bowel disease are monocytes and neutrophils. Cholecystokinin effect was therefore measured on monocyte production of proinflammatory mediators (tumor necrosis factor alpha, interleukin-1 beta, interleukin-6) and neutrophil chemotaxins/activators (interleukin-8, granulocyte-macrophage colony stimulating factor, and leukotriene B4). METHODS: Peripheral blood monocytes (0.5 x 10(6)) from healthy donors in 1 mL of RPMI 1640 plus 5% fetal calf serum were cultured for 24 h in 5% CO2 at 37 degrees C with 5 micrograms/mL endotoxin, 1 x 10(-7) M cholecystokinin, or no agonist. Supernatants were analyzed by ELISA for cytokines and leukotriene B4. RESULTS: Endotoxin-stimulated monocytes produced 1130 pg/mL tumor necrosis factor versus 81 pg/mL for cholecystokinin, 612 pg/mL interleukin-1 versus 10 pg/mL, 694 pg/mL interleukin-6 versus 30 pg/mL, 4531 pg/mL of interleukin-8 versus 3848 pg/mL, 21 pg/mL granulocyte-macrophage colony stimulating factor versus 9 pg/mL, and 21 pg/mL leukotriene B4 versus 12 pg/mL. Controls produced no cytokines/eicosanoids (N = 8, p < 0.001). CONCLUSION: Cholecystokinin increase with enteral feeding may up-regulate gut immune response. Cholecystokinin suppression with parenteral alimentation may decrease inflammatory mediator production.

The gastrointestinal manifestations of Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune exocrinopathy that primarily affects the salivary glands but can also involve almost any other part of the gut. The most distressing manifestation of SS is xerostomia secondary to destruction of the salivary glands. The lack of saliva also leads to difficulty with chewing and initial swallowing and an increased frequency of dental caries. Another major problem is dysphagia due to the lack of saliva as well as esophageal dysmotility and/or esophageal webs. Chronic atrophic gastritis probably accounts for the epigastric pain, nausea, and other dyspeptic symptoms seen in SS. Sjögren's syndrome is also one of the most frequent extrahepatic diseases associated with primary biliary cirrhosis, suggesting that this entity may be a secondary form of SS. The degree to which SS affects the small and large bowel is unclear, whereas pancreatic involvement appears to lead to only subclinical exocrine insufficiency.

Pharmacokinetic and pharmacodynamic interactions during multiple-dose administration of nisoldipine and propranolol.

OBJECTIVES: The pharmacokinetic and pharmacodynamic interactions after 7 days of oral treatment with nisoldipine (10 mg twice daily) and propranolol (80 mg twice daily) were investigated in a partially randomized, placebo-controlled crossover study of 12 healthy volunteers. METHODS: At the end of each treatment period, pharmacokinetic parameters were measured, along with blood pressure, heart rate, cardiac function, systemic hemodynamics, plasma catecholamines, forearm blood flow, and apparent hepatic blood flow (estimated by the clearance of indocyanine green dye). RESULTS: After 7 days of treatment with nisoldipine and propranolol, neither drug altered the other's bioavailability or elimination parameters, and propranolol did not change the area under the plasma concentration-time curve of nisoldipine's metabolite, N-9425. Nisoldipine alone increased apparent hepatic blood flow and forearm blood flow compared with the other treatment groups but, with the addition of propranolol, both of these parameters were similar to those in the placebo group. Changes in the other hemodynamic parameters were consistent with the known effects of these drugs, and no differences in plasma catecholamine levels were detected. CONCLUSIONS: In contrast to the findings with single-dose treatment, administration of the combination of nisoldipine and propranolol for 7 days is not associated with any measurable kinetic interactions, although significant hemodynamic interactions do occur.

Financial implications of malnutrition.

PEM or the possibility of developing PEM occurs in 30% to 50% of hospitalized patients, the frequency determined by the criteria used in its assessment and the case mix of patients in the hospital population. This condition exists independently of other medical conditions and results from preadmission or postadmission failure to meet nutrient requirements with associated loss of body weight and function, as well as impaired immunity. PEM also frequently arises in patients with a chronic condition and decreased functional reserve when a superimposed acute metabolic stress leads to accelerated nutrient depletion. Whether preexisting or not, PEM increases morbidity and mortality along with LOS and may be associated with complications such as pneumonia, sepsis, operative site infection, delayed wound healing, or decubitus ulcers. The cost of these complications and an extended LOS is a significant financial burden and a controllable medical liability for hospitals. Other costs include identifying patients at risk of PEM, providing nutrition support, not to mention treating any of its complications (mechanical, metabolic, and so forth). A proper analysis of the financial implications of late or untreated PEM versus nutrition support must therefore take into account not only the costs of complications or extended LOS due to the delay or failure to provide nutrition support but also the costs associated with this intervention itself. In this review, we described a model for examining the financial implications of malnutrition and nutritional therapy.

Effect of nutrition status and other factors on length of hospital stay after major gastrointestinal surgery.

Various factors may prolong postoperative recovery and the length of stay (LOS) in the hospital. In a retrospective study of 245 adult patients who had no oral intake for 5 days after major gastrointestinal surgery, we used a correlation matrix to describe the population and determine the effects of the following factors on LOS: malnutrition, complication status, stress level, type of surgery, pathology, period of inadequate nutrient intake, and use of nutritional support. LOS was markedly prolonged in malnourished patients compared with those who were not (23.5 +/- 16.5 vs. 16.5 +/- 10.7 days, means +/- SD, p < 0.001). Patients were then grouped into those who had nutritional support and those who had not, and a nutrition classification was derived by examining the uncertainty (entropy) in the data matrix that allowed separation of the population into distinct groups. Nutrition and complication status and days without oral nutrient intake were discriminative. Analysis of variance and multivariate studies were also used to determine whether the presence of malnutrition, complications, both together, or neither could predict LOS and to determine the confounding effect of nutritional support on LOS. A significantly extended LOS persisted for patients with malnutrition or complications and was most prolonged for those with both, but patients who received nutritional support had a greater LOS than those who did not. In addition to the effects of nutritional support, malnutrition, and complication status, LOS correlated with the duration of the postoperative period without oral nutrient intake. We therefore recommend systematic and early nutritional intervention for selected gastrointestinal surgical patients.

Renal prostaglandin E2 and other vasoactive modulators in refractory hepatic ascites: response to peritoneovenous shunting.

To assess the role of renal prostaglandin E2 in the pathogenesis of refractory ascites, in relation to renal sodium handling and circulating levels of vasoconstrictive substances, we studied 12 cirrhotic patients with refractory ascites before and after peritoneovenous shunting. Baseline values for urinary prostaglandin E2 excretion, sodium excretion, and creatinine clearance, as well as serum aldosterone, plasma renin activity, and plasma free norepinephrine, were obtained preoperatively with patients on a sodium- and fluid-restricted diet. Diuretics were also withheld. Similar parameters were measured immediately postoperatively during four consecutive 2-h intervals, then again at 2 wk and 3 mo. In patients with refractory ascites, mean baseline urinary prostaglandin E2 excretion was significantly elevated (2.5 +/- 0.8 pmol/min), compared with that in both normal controls and cirrhotics without ascites (1.3 +/- 0.3 pmol/min). A significant natriuresis occurred immediately postoperatively and persisted at 2 wk and 3 mo. Concomitantly, the elevated levels of preoperative vasoconstrictor substances gradually normalized by 2 wk. Urinary prostaglandin E2 excretion, however, rose transiently in the immediate postoperative period and then fell gradually to within the normal range by 3 mo. Enhanced renal prostaglandin E2 synthesis, therefore, does not play a role in the sustained improvement in sodium homeostasis after peritoneovenous shunting in patients with refractory ascites.