Neil R. Thomford

Papillary cystic and solid tumors of the pancreas: A pancreatic embryonic tumor? Studies of three cases and cumulative review of the world's literature

BACKGROUND The papillary cystic and solid tumor of the pancreas is rare. It occurs predominantly in young women, and most present a benign behavior. The pathogenesis of this tumor has attracted a number of investigations but remains unclear. METHODS We present three patients with this tumor and a review of 289 others from the worlds literature, a total of 292 cases. On the basis of the analyses of the clinical and pathologic features from the reported cases, the pathogenesis of this unusual tumor has been further explored. RESULTS Ninety percent of the patients were female, with a mean age of 23.9 years. The tumors were usually quite large with a mean diameter of 10.3 cm. Ninety-two percent of these tumors were totally or partially cystic. Rupture of the capsule resulted in hemoperitoneum in eight cases, five of which were without any identifiable cause. Forty-three tumors (14.7%) have been recognized as malignant. The overall prognosis has been excellent and an aggressive approach to resection is indicated. CONCLUSIONS The results of immunohistochemical staining and electromicroscopy were rather diverse, but most, including the current cases, support the hypothesis that the tumor originates from pleuripotential embryonic stem cells. Thus the term pancreatic embryonic tumors seems preferable to papillary cystic and solid tumor of the pancreas to delineate the origin of the tumor and to reflect some of its biologic characteristics.

Pharmacokinetics and toxicity of isolated perfusion of lung with doxorubicin

The treatment of pulmonary metastases from soft tissue sarcomas with chemotherapy has an overall response rate of less than 30%, and the majority of these responses are short lived. It is postulated that increased drug delivery to the pulmonary metastases may improve the outcome of these patients. An isolated perfusion system would have the ability of delivering increased levels of drug to target tissue without the systemic toxic effect of the drug. The purpose of this study was to establish the pharmacokinetics of doxorubicin delivery, lung toxicity, and the ideal dose for clinical application in an in vivo isolated perfusion model. Our results suggest that normothermic isolated perfusion of the lung with doxorubicin using a dose level up to 6 micrograms/ml in the perfusate can be accomplished without histologic lung injury, systemic toxicity, or adverse clinical outcome. Perfusate concentration of greater than 7 micrograms/ml caused significant histologic injury and adverse clinical outcome without systemic toxicity. The technique may be utilized in selective settings to improve treatment in mesenchymal tumors metastatic to the lung.

Anatomic characteristics of the pancreatic arteries. Radiologic observations and their clinical significance

Major complications of operations that remove or transplant a portion of the pancreas appear related to the arterial blood supply. Hemorrhage is a result of inadequate control of the appropriate principal arteries, and ischemia and its consequences occur when the arterial blood supply to portions of preserved pancreas has been inadvertently interrupted. This radiographic study of the principal arteries of the pancreas demonstrates that these vessels may be visualized and their origin determined in the vast majority of cases. The application of data gained from preoperative arteriography can potentially decrease the incidence of major complications associated with removal or transplantation of portions of the pancreas.

Parenteral Monoacetoacetin and Liver Regeneration Interaction After Partial Hepatectomy in the Rat

Parenteral nutrients can be used to manipulate cell proliferation after partial hepatectomy. The relationship among macronutrients--glucose, monoacetoacetin, amino acids--and liver regeneration after partial hepatectomy was investigated. Male rats were anesthetized, received a 70% hepatectomy, and received a low-dose infusion of (1) glucose or (2) monoacetoacetin and a high-dose infusion of (3) glucose, (4) glycerol-glucose, or (5) monoacetoacetin-glucose beginning 6 hours after surgery. The five nonprotein nutrient combinations were infused with and without amino acids. Rats were killed 48 hours after partial hepatectomy, and the label and mitotic indices were determined. Each of the five treatments had a higher label index with amino acids present than with amino acids absent. Low-dose glucose and monoacetoacetin as well as high-dose glucose and glucose-glycerol had higher mitotic indices with amino acids than without amino acids. High-dose monoacetoacetin-glucose was associated with a greater mitotic index than was any other nonprotein substrate treatment, and this response was independent of amino acids being present or absent. In summary, (1) amino acids were needed for maximal cell proliferation rate; (2) the absence of amino acids and not the presence of glucose resulted in reduction of the label and mitotic indices for regenerating liver; (3) high-dose monoacetoacetin increased mitosis with or without amino acids; and (4) monoacetoacetin activity was dose dependent. The results indicate that the best nutrient for treatment of patients with liver injury is acetoacetate. The second best nutrient would be the combination of high-dose glucose and amino acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of ketosis and liver regeneration in the rat.

Monoacetoacetin, the monoglyceride of acetoacetate, was investigated as a nutritional support for the regenerating liver. Following partial hepatectomy, rats were either fed an oral diet ad libitum or administered by total parenteral feeding glucose alone, monoacetoacetin-glucose mixture, or lipid emulsion-glucose for the nonprotein calories. Five rats from each treatment were killed at 6-hr intervals beginning 12 hr after partial hepatectomy and ending at 72 hr. The number of cells synthesizing DNA and the number of cells in mitosis were compared. Rats fed orally or infused with glucose alone or with lipid emulsion had similar parameters throughout. Rats infused with monoacetoacetin had approximately double the number of cells in mitosis and DNA synthesis compared to the other treatments. This stimulation by monoacetoacetin persisted 72 hr. It was concluded from the data that acetoacetate was the agent responsible for increased DNA synthesis and mitosis, but the mechanism for the stimulation was not identified.

Isolated perfusion of pancreas with mitomycin C

The current treatment of pancreatic cancer with resection and/or radiation is considered unsatisfactory because of a high incidence of failure and a moderate incidence of complications. A sizable number of these patients present with localized or regional disease. Regional high-dose chemotherapy, such as with isolated perfusion, may offer an alternative therapy with low treatment-related morbidity and mortality and better end results in this group of patients. In an effort to develop such a treatment modality, we evaluated the pharmacokinetics and toxicity of mitomycin C (MMC) during isolated perfusion of pancreas in a canine model. From this study, it appears that a dose of 0.25 mg MMC/kg body weight is most suitable for isolated perfusion of pancreas at 39 degrees C, maintaining flow rate and pressure within physiologic range. Isolated perfusion with a dose of 0.25 mg/kg body weight has very mild short- and long-term toxicities and markedly increases drug delivery to the pancreas, duodenum, and peripancreatic lymph nodes, making it the most suitable dose for possible clinical application.

The influence of ketosis on the metabolic response to skeletal trauma

Intravenous glucose and ketone body feeding were compared for their potential in altering urinary nitrogen losses by the traumatized rat. Eighteen male rats were traumatized by bilateral femoral fracture. The rats were fed totally by vein for 3 days prior and 3 days after injury and the infusion rate was held constant over the 6 days of infusion. Group GT rats were fed glucose as the source of nonprotein energy while group MT rats were fed a mixture of 72% monoacetoacetin (the monoglyceride of acetoacetate)-28% glucose for the nonprotein energy. Total urinary nitrogen excretion on a 24-hr basis was measured for each of the 6 days of intravenous feeding. On the third day post-trauma, each rat was evaluated for leucine kinetics using a continuous infusion of L-[1-14C]leucine and measurement of breath and plasma specific activities. Rats from group MT were hyperketonemic and normoglycemic and rats from group GT were normoketonemic and hyperglycemic. Urinary nitrogen losses, leucine oxidation, and leucine turnover were similar for the two groups. We conclude that ketone bodies are as good an intravenous source of energy as is glucose, and the ketone bodies do not cause hyperglycemia.

Evaluation of free fatty acid kinetics during TPN feeding of healthy rats

Free fatty acid (FFA) kinetics were evaluated in TPN-fed healthy rats using a single fatty acid tracer. Rats were divided into three groups according to the nonprotein energetic substrate infused: glucose (A), monoacetoacetin-glucose (B), and lipid emulsion-glucose (C). Fat kinetics were measured by continuous infusion of [1-14C]palmitate. Total FFA and individual FFA concentrations were measured and turnover and oxidation were determined for the total pool of FFA and for palmitate. Groups A and B were similar in all parameters. Group C had increased total and individual FFA concentrations. Group C appeared to have decreased total plasma FFA turnover and unchanged oxidation compared to groups A and B. Palmitate appeared to have a 400% increase in oxidation and a 50% increase in turnover for rats in Group C when compared to Groups A and B. It is concluded that a single tracer does not accurately reflect plasma FFA during TPN using lipid emulsion.

Feeding the rat intravenously with ketone bodies following colon anastomosis

Ketone bodies are an important metabolic fuel for the gastrointestinal system and as a consequence may promote colonic healing. Ketone bodies and glucose were compared in a dose dependent manner as nonprotein fuels for support of resected colon. Rats had their descending colons resected and received all nutrients by vein for 5 days postoperation. Colonic healing was evaluated from the air pressure required to break the wound. All rats received constant nutrients except for non-protein energy which was fed at 10.5, 21, 31.5, and 42 kcal/day using either glucose or monoacetoacetin as substrate. Colonic bursting pressure was measured on day 5 after surgery. When energy intake was 21 kcal/day or greater, the bursting pressure was two-thirds of nonwounded tissue and was independent of energy quantity and source. At 10.5 kcal/day, bursting pressure for glucose-fed animals was similar to that for animals with no added nonprotein energy while, in contrast, bursting pressure for animals fed monoacetoacetin was similar to that for animals fed 42 kcal/day. It was concluded that bursting pressure was influenced by dietary intake only if the energy intake was sufficiently low, and then ketone bodies were better than glucose for support of colonic healing.

Pharmacokinetics and tissue uptake of mitomycin C in isolated perfusion of pancreas

Isolated perfusion of organs or anatomic sites with chemotherapeutic agents offers a pharmacokinetic advantage of increasing drug bioavailability to target tissues which may result in a greater magnitude of biologic effect (pharmacologic or toxic) without systemic toxicity. Using a previously developed animal model, isolated perfusion (IP) of the canine pancreas-duodenum with incremental doses of mitomycin C (MMC) had shown a dose of 0.25 mg/kg body weight to be the maximum tolerable dose. The current study was designed to compare the pharmacologic advantage of drug delivery by IP by directly measuring tissue drug levels of radiolabeled MMC and comparing them with tissue levels attained by selective intraarterial (IA) and intravenous (IV) routes using identical doses of drug (n = 4 each). IP of pancreas-duodenum was performed for 45 min with a perfusate-to-systemic drug leak rate of less than 5%. IP was accomplished by using extracorporeal pump oxygenator at 39 degrees C and flow initiated at 110-120 ml/min, with a mean pressure of 90 mm Hg. Vascular inflow and outflow was isolated to the cannulated superior pancreaticoduodenal artery and vein. In the IA group drug was infused over 45 min through same artery as IP. IV group underwent identical dosing through the jugular vein. Direct measurement of drug in harvested pancreas and duodenum for each individual was done by tissue solubilization and scintillation assay. A 6-fold greater tissue level of drug in IP over IA and a 15-fold increase in IP over IV methods of delivery were found (P less than 0.01).