ABSTRACT
AIM: To evaluate the influence of distinguishing between well and poorly differentiated nonfunctioning neuroendocrine pancreatic carcinomas (PC). METHOD: Six well differentiated and 11 poorly differentiated nonfunctioning neuroendocrine PC were retrospectively analyzed for differences and compared with 340 ductal PC. RESULTS: 1. There was no difference in pT categories between well differentiated and, poorly differentiated nonfunctioning neuroendocrine PC and ductal PC. 2. The rate of the pN1 category was lower in well differentiated lesions (20%) than in poorly differentiated lesions (66%) and in the ductal PC group (75%). 3. The outcome of patients with R0 resections was significantly better for well differentiated neuroendocrine PC with all patients alive than for poorly differentiated ones and for ductal PC (5-year survival rate 0% and 18%, respectively). 4. The outcome following R1/R2 resections for poorly differentiated neuroendocrine PC tended to be similar than for ductal PC (1-year survival rate 20% vs. 33%). 5. There was no difference in mean survival time (9 months) between poorly differentiated lesions and ductal PC after palliative procedures. CONCLUSIONS: The better outcome of surgical treatment of nonfunctioning neuroendocrine PC vs. that of ductal PC was confined to well differentiated neuroendocrine lesions. For poorly differentiated lesions the outcome was as poor as for ductal PC. These results underscore the importance to distinguish between well and poorly differentiated nonfunctioning neuroendocrine PC.
Subject(s)
Carcinoma, Neuroendocrine/pathology , Carcinoma, Neuroendocrine/surgery , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/surgery , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Adult , Aged , Biopsy, Needle , Carcinoma, Neuroendocrine/mortality , Carcinoma, Pancreatic Ductal/mortality , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Staging , Pancreatectomy/methods , Pancreatic Neoplasms/mortality , Probability , Prognosis , Retrospective Studies , Risk Assessment , Survival Analysis , Time FactorsABSTRACT
The aim of this study was to evaluate in vivo whether nitric oxide (NO) is able to diffuse from blood into tissues and vice versa from tissues into blood. We used an in vivo model of intestinal ischemia (superior mesenteric artery occlusion) selectively increasing NO levels in intestinal tissue and an infusion of L-arginine selectively increasing NO levels in blood. In this model we followed formation of nitrosyl complexes of hemoglobin (Hb-NO) in blood and nitrosyl-diethyldithiocarbamate-iron complexes (DETC--Fe--NO) in ischemic intestine and normoxic tissues by means of electron paramagnetic resonance spectroscopy. NO trapping by DETC--Fe in the tissues resulted in a reduction of Hb--NO levels in blood accompanied by the formation of water-insoluble DETC--Fe-NO complexes in ischemic intestine and normoxic tissues both during ischemia and during reperfusion. Administration of L-arginine increased NO levels in blood but neither in ischemic intestine nor in normoxic tissue. Our data suggest that NO released in blood from endothelial cells does not diffuse into tissue. In contrast, NO formed in tissue diffuses into blood. The latter indicates that NO formed in tissues may exert its biological activities systematically.
Subject(s)
Ditiocarb/analogs & derivatives , Nitric Oxide Synthase/biosynthesis , Nitric Oxide/metabolism , Animals , Arginine/administration & dosage , Disease Models, Animal , Ditiocarb/chemistry , Ditiocarb/metabolism , Electron Spin Resonance Spectroscopy , Erythrocytes/metabolism , Ferrous Compounds/blood , Ferrous Compounds/chemistry , Ferrous Compounds/metabolism , Hemoglobins/metabolism , Infusions, Intravenous , Intestinal Diseases/blood , Intestinal Diseases/etiology , Intestinal Diseases/metabolism , Intestinal Mucosa/metabolism , Ischemia/blood , Ischemia/etiology , Ischemia/metabolism , Male , Nitric Oxide/blood , Nitric Oxide/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase Type III , Rats , Rats, Sprague-DawleyABSTRACT
Intestinal ischemia/reperfusion may lead to local and distant organ damage involving nitric oxide (NO). NO rapidly reacts with heme/non-heme-iron-yielding nitrosyl complexes, which can be determined directly by electron paramagnetic resonance spectroscopy. The aim of the present study was to characterize nitrosylation reactions induced by transient intestinal ischemia in blood and tissues. We used electron paramagnetic resonance spectroscopy and reverse transcription polymerase chain reaction analyses to estimate nitrosyl complex levels and inducible NO synthase mRNA expression in rats subjected to superior mesenteric artery occlusion for 60 min followed by the reperfusion. Nitrosyl hemoglobin concentrations in circulating blood were significantly increased during ischemia and reperfusion. Nitrosyl hemoglobin complexes were detected in ischemic intestine, but not in normoxic lung and liver or reperfused intestine. Administration of N-G-monomethyl-L-arginine, a non-specific NO synthase inhibitor, did not affect the formation of circulating nitrosyl complexes. Moreover, inducible NO synthase mRNA was not found in intestinal tissues at 30 min of reperfusion. Our data suggest an organ-specific NO formation indicated by the increased nitrosylation reaction in ischemic intestinal tissue, but not in the distant normoxic organs, in spite of high circulating nitrosyl hemoglobin levels. NO involved in nitrosylation under intestinal ischemia/reperfusion is probably formed by NO synthase-independent mechanism(s).
Subject(s)
Intestinal Mucosa/metabolism , Ischemia/metabolism , Nitric Oxide/metabolism , Reperfusion Injury/metabolism , Animals , Intestines/blood supply , Intestines/physiopathology , Male , Nitric Oxide Synthase/metabolism , Nitric Oxide Synthase Type II , Organ Specificity , Rats , Rats, Sprague-DawleyABSTRACT
Nitric monoxide (NO) exerts a great variety of physiological functions. L-Arginine supplies amino groups which are transformed to NO in various NO-synthase-active isoenzyme complexes. NO-synthesis is stimulated under various conditions increasing the tissue of stable NO-metabolites. The major oxidation product found is nitrite. Elevated nitrite levels were reported to exist in a variety of diseases including HIV, reperfusion injury and hypovolemic shock. Denitrifying bacteria such as Paracoccus denitrificans have a membrane bound set of cytochromes (cyt cd1, cyt bc) which were shown to be involved in nitrite reduction activities. Mammalian mitochondria have similar cytochromes which form part of the respiratory chain. Like in bacteria quinols are used as reductants of these types of cytochromes. The observation of one-e- divergence from this redox-couple to external dioxygen made us to study whether this site of the respiratory chain may also recycle nitrite back to its bioactive form NO. Thus, the aim of the present study was therefore to confirm the existence of a reductive pathway which reestablishes the existence of the bioregulator NO from its main metabolite NO2-. Our results show that respiring mitochondria readily reduce added nitrite to NO which was made visible by nitrosylation of deoxyhemoglobin. The adduct gives characteristic triplet-ESR-signals. Using inhibitors of the respiratory chain for chemical sequestration of respiratory segments we were able to identify the site where nitrite is reduced. The results confirm the ubiquinone/cyt be1 couple as the reductant site where nitrite is recycled. The high affinity of NO to the heme-iron of cytochrome oxidase will result in an impairment of mitochondrial energy-production. "Nitrite tolerance" of angina pectoris patients using NO-donors may be explained in that way.
