BACKGROUND Pheochromocytomas are rare catecholamine–producing tumors derived in at least 30% of cases from mutations in 9 tumor-susceptibility genes identified to date. Testing of multiple genes at considerable expense is often undertaken before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine and methoxytyramine, the O-methylated metabolites of catecholamines, might help distinguish different hereditary forms of the tumor. METHODS Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome and 59 with mutations of succinate dehydrogenase (SDH) type B or D genes. RESULTS In contrast to patients with VHL and SDH mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDH mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL and SDH mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases. CONCLUSIONS The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily utilized tool to guide cost-effective genotyping of underlying disease-causing mutations.

Key words: omega-3 fatty acid; fish oil; soybean oil; immunonutrition; inflammation; acute-phase response; parenteral nutritionEpidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancers. 1 Further laboratory experiments showed reduced risk of colon carcinogenesis after omega-3 PUFA supplementation. In a phase II clinical trial of patients with colonic polyps, dietary FO supplements inhibited cell proliferation. Mechanisms accounting for the antitumour effects in animal models are reduced levels of PGE 2 and inducible NO synthase as well as increased lipid peroxidation or translation inhibition and subsequent cell-cycle arrest. 2 In patients with advanced cancer, weight loss is a major cause of morbidity and mortality. While it is possible to increase energy and protein intake on the enteral or parenteral route, this appears to have little impact on patients' progressive weight loss. 3 Clinical studies in the last few years have provided evidence for beneficial effects of FO administration in cancer cachexia 4 and during radioand chemotherapy. 5 Omega-3 EPA is capable of downregulating the production and action of a number of mediators of cachexia, e.g., IL-1, IL-6, TNF-␣ and proteolysis-inducing factor. 6,7 However, SO (omega-6) emulsions appear to impede tumoricidal activity compared to EPA. 8 Beyond the beneficial effects of long-term intake of omega-3 PUFA in cancer patients, we likewise observed rapid-onset effects in previous experimental studies. Compared to SO emulsion, we found decreased inflammatory pulmonary vascular response in isolated rabbit lungs after omega-3 PUFA infusion. 9 Lung edema formation was blunted because proinflammatory 4-series leukotrienes were shifted to less inflammatory 5-series leukotrienes and, consequently, pulmonary vascular resistance and permeability were reduced. 9 These rapid effects of omega-3 PUFA were confirmed in patients with acute respiratory distress syndrome, showing improved pulmonary function within a few days on an omega-3 fatty acid-enriched diet. 10 The background of these beneficial effects was reduced release of proinflammatory AA derivatives. 11 Following major abdominal nonliver surgery, increases in ALAT were observed and correlated with ultrastructural damage of the liver. 12 In the postoperative course after major abdominal surgery, intact liver function is crucial not only for energy balance (glucose and lactate metabolism) but also for providing several humoral factors, which induce, support and ultimately terminate regenerative mechanisms. This APR of the liver sets off immediately after the (surgical) trauma and upregulates coagulation factors and proteinase inhibitors for wound healing and complement components and opsonins (e.g., CRP) for early bactericidal activity at the site of trauma. 13

The presence of both 1alpha-hydroxylase activity and 25-hydroxylase activity is a biochemical prerequisite for the enzymatic generation of 1alpha,25(OH)2D3 from vitamin D3 in keratinocytes. In contrast to 1alpha-hydroxylase, however, activity of a 25-hydroxylase in keratinocytes has not previously been demonstrated. In this study, using RT-PCR we detected vitamin D3 25-hydroxylase mRNA in human keratinocytes. The expression of vitamin D3 25-hydroxylase mRNA in keratinocytes was identical to that of CYP27 expressed in mitochondria of human hepatoma HepG2 cells. CYP27 mRNA in keratinocytes is not constitutively expressed but is inducible both by vitamin D3 (780 nM) and by UVB radiation (300 nm, 30 mJ/cm2).

The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44-49 vs. 30-35 yr, respectively).

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