Treatment of resectable and locally advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer is the fifth leading cause of cancer death in the United States, with an overall 5-year survival rate of less than 5%. A minority of patients are candidates for surgical resection, but most treatment strategies focus on palliative care. METHODS: We discuss strategies in the diagnosis and treatment of resectable and locally advanced pancreatic cancer by reviewing available phase II and phase III trials, as well as large retrospective studies. RESULTS: Surgical resection for pancreatic cancer is done today with an operative mortality rate below 5% and a 5-year survival rate of approximately 25%. There is evidence that chemoradiation may improve survival and quality of life in both the adjuvant setting and for locally advanced disease. Operative, minimally invasive, and endoscopic techniques are successful in palliating pain and jaundice. CONCLUSIONS: The diagnosis and treatment of pancreatic cancer continue to improve although most patients will succumb to their disease. Novel methods of earlier detection and more effective systemic therapies are needed to significantly improve outcomes.

Surgical management of aberrant sentinel lymph node drainage in cutaneous melanoma.

BACKGROUND: Sentinel lymph node (SLN) mapping by lymphoscintigraphy has changed the surgical management of regional lymph node metastases for melanoma. SLNs lying outside of traditional nodal basins are now being identified. Our hypothesis is that when preoperative lymphoscintigraphy identifies aberrant SLNs, these nodes should be excised and, if histologically positive, lymphadenectomy of the aberrant nodal basin should be performed. METHODS: Patients with melanomas 1 mm or larger Breslow thickness and clinical stage N0M0 underwent lymphoscintigraphy and excision with SLN biopsy. Preoperative lymphoscintigraphy, intraoperative gamma probe, and intraoperative injection of isosulfan blue were performed to identify the SLN. Aberrant SLNs were defined as epitrochlear, supraclavicular, or popliteal nodes for extremity lesions and intramuscular nodes for truncal and head and neck lesions. RESULTS: Thirty-two patients were entered into the protocol. Seven (22%) were found to have aberrant nodes. Five of 19 patients with extremity melanoma had an aberrant SLN; 2 of 13 patients with truncal and head and neck melanoma had an aberrant SLN. CONCLUSIONS: This study demonstrates that (1) aberrant SLNs are encountered with similar frequency for extremity and truncal lesions, (2) biopsy should be performed on aberrant SLNs with intraoperative lymph node mapping with the gamma probe and blue dye, and (3) lymphadenectomy of the aberrant region should be considered if the aberrant SLN is positive.

Computed tomography in evaluation of patients with stage III melanoma.

BACKGROUND: Metastatic disease is detected infrequently by computed tomography (CT) in early stage melanoma. The diagnostic yield of routine CT for stage III melanoma is less established, despite extensive use in clinical practice. METHODS: Charts from 347 asymptomatic patients with stage III melanoma were reviewed. Findings suggestive of metastatic melanoma identified by head or body CT, chest radiography, bone scan, or liver function studies were confirmed histologically or by progression of disease. RESULTS: Individual CT scans identified 33/788 (4.2%) instances of metastatic melanoma, with 66/788 (8.4%) false positive studies. No metastases were identified among 104 head CT scans. Chest CT had the highest yield in patients with cervical adenopathy (7/35, 20%), and the lowest yield with groin adenopathy (1/50, 2%). Pelvic CT diagnosed metastases in 7/94 (7.4%) patients with groin adenopathy, but no patients with palpable axillary (n = 76) or cervical (n = 21) nodes. Metastatic melanoma was diagnosed in 11/136 (8.1%) patients having complete body CT imaging (chest, abdomen, and pelvis), including six patients (4.4%) identified by CT alone. CONCLUSIONS: Routine CT in patients with clinical stage III melanoma infrequently identifies metastatic disease. Head CT in the asymptomatic patient, chest CT in patients with groin adenopathy, and pelvic CT in the presence of axillary or cervical adenopathy are not indicated. Selective use of chest CT in patients with cervical adenopathy or pelvic CT in the presence of groin disease may be useful.

Proximal bile duct tumors.

Modern radiologic diagnostic approaches that identify patients with high bile duct cancer can predict resectability and provide information for biliary-enteric bypass in the case of irresectability. Twenty percent to 40% of patients are resectable by local excision with or without hepatic resection, and this represents the only opportunity for cure. Operative mortality is now acceptable and resection is associated with a median survival of approximately 35 months. Numerous palliative operative and nonoperative approaches are available, including biliary-enteric bypass, transtumoral stenting, and percutaneous endoprostheses. The role of both intraluminal and external beam radiotherapy also is discussed.

The effect of pancreatic denervation and atropine on the cholecystokinin-induced pancreatic exocrine response.

To study the influence of extrapancreatic neural and cholinergic activity on the pancreatic response to cholecystokinin (CCK), six dogs underwent creation of Herrera pancreatic fistulas, placement of Thomas gastric cannulas, and distal pancreatectomies (innervated; INN). Six additional dogs were prepared similarly, with the addition of total extrinsic pancreatic denervation (denervated; DEN). The pancreatic protein and bicarbonate response to graded 12.5 to 200 ng/kg/h CCK doses was determined for INN and DEN animals both alone and with 10 micrograms/kg/h atropine infusion. The influence of extra-pancreatic neural and cholinergic activity on secretin's potentiation of the CCK-induced pancreatic response was then determined by repeating the studies with a 125 ng/kg/h secretin infusion. The latter results were compared to those predicted by summating the responses seen during separate 12.5-200 ng/kg/h CCK dose-response and 125 ng/kg/h secretin studies. Unstimulated protein output was diminished by atropine in INN animals (78 +/- 21 vs. 39 +/- 9 mg/15 min; p < 0.05) but not in DEN animals. Unstimulated bicarbonate outputs, integrated bicarbonate and protein outputs, and bicarbonate and protein dose-response curves were unaffected by denervation or atropine. Potentiation of CCK-induced bicarbonate output by secretin was also unaffected by atropine and denervation. We conclude that cholinergic elements are involved in unstimulated, but not CCK-induced, enzyme secretion. Further, potentiation of CCK-induced bicarbonate output by secretin does not depend on extrinsic neural or cholinergic elements.

Palliation of irresectable hilar cholangiocarcinoma with biliary drainage and radiotherapy.

Twelve patients with irresectable or recurrent hilar cholangiocarcinoma were treated with internal biliary drainage followed by intraluminal (iridium-192) and external-beam radiotherapy. Biliary drainage was accomplished by means of a combined surgical and interventional radiological approach. Initial biliary decompression was performed surgically by tumour resection, intrahepatic biliary enteric bypass or distal biliary-enteric anastomosis with a temporary stent. Maintenance of internal biliary drainage and application of intraluminal radiotherapy were accomplished radiologically with the use of percutaneous dilatation and metallic expandable biliary endoprostheses. Median survival was 14.5 months; all 12 patients survived for at least 6 months. Early complications during radiotherapy were minor and included two patients with cholangitis and one with transient haemobilia. Jaundice was relieved in ten of 12 patients, while episodes of cholangitis were seen during long-term follow-up in 11 (median 1.5 episodes per patient). Internal biliary drainage, in conjunction with radiotherapy, appears to be safe and effective palliation of irresectable or recurrent hilar cholangiocarcinoma. Patients can maintain a reasonable quality of life with an acceptable incidence of cholangitis, without the hindrance of external drainage devices.

Somatostatin inhibits cholecystokinin-induced pancreatic protein secretion via cholinergic pathways.

Although somatostatin is a potent inhibitor of pancreatic exocrine secretion in vivo, its mechanism of action remains unclear. The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion was studied in conscious dogs. Chronic pancreatic fistulae were created in six mongrel dogs, and a second group of six dogs also underwent complete pancreatic denervation. The pancreatic responses to graded doses of cholecystokinin (12.5-200 ng/kg/h) and bethanechol (57-916 micrograms/kg/h), both alone and during background infusion of somatostatin-14 (800 pm/kg/h), were determined in all dogs. The cholecystokinin dose-response with a somatostatin-14 background was then repeated with the addition of atropine (10 micrograms/kg/h). In both groups of animals, cholecystokinin elicited a dose-dependent increase in pancreatic protein secretion that was inhibited significantly by somatostatin-14. Regardless of the status of extrapancreatic nerves, atropine further inhibited cholecystokinin-induced protein secretion beyond that evoked by somatostatin-14. In both innervated and denervated animals, cholinergic stimulation with bethanechol elicited a dose-dependent increase in pancreatic protein secretion that was unaffected by somatostatin-14. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Somatostatin-14 appears to inhibit cholecystokinin-induced pancreatic secretion by an intrapancreatic cholinergic mechanism.

Adrenergic pathways do not mediate peptide YY-induced inhibition of pancreatic exocrine secretion.

The influence of extrapancreatic nerves and intrapancreatic adrenergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/h) and cholecystokinin (CCK; 50 ng/kg/h) was administered over 2 h. An infusion of PYY (400 pmol/kg/h) was then given randomly, during either the first or second experimental hour. The experiments were then replicated after establishing adrenergic blockade with continuous background infusions of either phentolamine (0.2 mg/kg/h), propranolol (0.5 mg/kg bolus) or a combination of phentolamine and propranolol. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. Adrenergic blockade failed to eliminate the inhibitory effects of PYY. We conclude that extrapancreatic neural pathways, including adrenergic mechanisms, do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an indirect nonadrenergic mechanism.

Inhibition of pancreatic exocrine secretion by galanin.

The influence of extrapancreatic nerves on the inhibition of meal- and secretogogue-induced pancreatic secretion by galanin was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs and a second group of five dogs also underwent complete pancreatic denervation. After recovery, galanin dose response (150-1,200 pmol/kg/h) revealed that 600 pmol/kg/h was the lowest dose of galanin to significantly inhibit pancreatic exocrine secretion. Pancreatic responses to a mixed meal, cholecystokinin (CCK) dose response (12.5-200 ng/kg/h), and secretin dose response (16-500 ng/kg/h) were determined. The experiments were then replicated with a continuous background infusion of galanin (600 pmol/kg/h). Galanin inhibited meal-, CCK-, and secretin-induced bicarbonate outputs in both the innervated and denervated pancreas. Galanin also inhibited meal- and CCK-induced protein responses in both groups. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of galanin.

Extrapancreatic cholinergic nerves mediate cholecystokinin-stimulated pancreatic polypeptide release.

Although vagal cholinergic stimulation is the predominant regulatory mechanism governing the release of pancreatic polypeptide (PP), recent studies suggest that cholecystokinin (CCK) is also an important mediator. The present study examined the role of cholinergic neural pathways in the PP response to exogenous CCK-8 using a selectively denervated canine pancreas model. Chronic denervated pancreatic preparations were created in five dogs, while five dogs underwent sham laparotomy as controls. On study days, the fasted animals were infused intravenous CCK-8 (40 or 400 pmole/kg/hr) for 60 min both with and without atropine (20 micrograms/kg/hr). Plasma was collected at 20-min intervals and PP levels were determined by radioimmunoassay. CCK-8 elicited a dose-dependent increase in circulating PP in dogs with a neurally intact pancreas. Atropine and pancreatic denervation eliminated the PP response to CCK-8 at 40 pmole/kg/hr (P < 0.01) and inhibited the PP response to CCK-8 at 400 pmole/kg/hr (P < 0.05). The high dose of CCK-8 still elicited a small PP response in the denervated dogs (P < 0.05), which was subsequently abolished by the addition of atropine. These findings suggest that extrapancreatic cholinergic nerves are essential components of CCK-stimulated PP release, and that intrapancreatic cholinergic activity may play a limited role.

Potentiation of canine pancreatic bicarbonate output by oleic acid is not neurally dependent.

To study neural involvement in potentiation of acid-induced pancreatic bicarbonate output, six dogs underwent extrapancreatic denervation and pancreatic fistula creation. Pancreatic responses to secretin (16 and 32 ng/kg/h) and cholecystokinin (50 ng/kg/h) were then assessed. The duodenum was then perfused with three sets of perfusates. The first set contained hydrochloric acid with either D- or L-phenylalanine. The second set contained bovine serum albumin and hydrochloric acid with or without oleic acid; the albumin and acid were varied so that each 50 ml contained 1, 2, or 4 meq titratable acid (pH 2.0-4.5). The third set was identical to the second except for initial pH of 3.5. Pancreatic responses predicted upon addition of cholecystokinin to secretin, L-phenylalanine to hydrochloric acid, or oleic acid to bovine serum albumin were compared with observed responses. At both doses, secretin-induced bicarbonate output was increased by cholecystokinin (16 ng/kg/h: 0.88 +/- 0.29 meq/15 min; 32 ng/kg/h: 1.01 +/- 0.23 meq/15 min). The latter significantly exceeded predicted output (16 ng/kg/h: 0.38 +/- 0.10 meq/15 min; 32 ng/kg/h: 0.58 +/- 0.15 meq/15 min), verifying potentiation. L-phenylalanine failed to potentiate bicarbonate output evoked by acidified D-phenylalanine. In contrast, addition of oleic acid to pH 2.0 or 3.5 bovine serum albumin potentiated bicarbonate output. These data suggest that enteropancreatic reflexes mediate potentiation of acid-induced pancreatic bicarbonate output by amino acids, but not by fatty acids.

Effect of pancreatic denervation and atropine on the pancreatic response to secretin.

To study the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the pancreatic response to secretin, six dogs underwent extrapancreatic denervation and creation of pancreatic fistulae. A second group of six dogs had pancreatic fistulae created without pancreatic denervation. The pancreatic exocrine response to graded doses of secretin (16-500 ng/kg/h) was determined, both alone and during a background infusion of cholecystokinin-octapeptide (CCK8, 50 ng/kg/h). All studies were replicated during administration of atropine (10 micrograms/kg/h). Secretin-induced bicarbonate output was significantly inhibited by atropine in both the innervated and denervated groups. Combined secretin and CCK8 elicited a dose-dependent increase in bicarbonate output and a sustained increase in protein output in both groups, regardless of atropine. In addition, potentiation of secretin-induced bicarbonate output by CCK8 was observed despite both extrinsic pancreatic denervation and administration of atropine. We conclude that endogenous intrapancreatic cholinergic activity influences the pancreatic response to secretin. Potentiation of secretin-induced bicarbonate output by CCK, however, is not dependent on neural mediation.

Somatostatin inhibits secretin-induced canine pancreatic response via a cholinergic mechanism.

BACKGROUND: Somatostatin inhibits pancreatic exocrine secretion in intact animals but not in vitro, suggesting an indirect effect. The present study examined the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion in conscious dogs. METHODS: Seven dogs underwent extrapancreatic denervation and creation of pancreatic fistulae, while a second group of 6 dogs had pancreatic fistulae created without denervation. The pancreatic responses to graded doses of secretin (16-500 ng.kg-1.h-1), both alone and during background infusions of somatostatin-14 (400 and 800 pmol/L.kg-1.hr-1), were determined in all dogs. The secretin dose response was then repeated with a continuous infusion of bethanechol (90 micrograms.kg-1.h-1) both with and without somatostatin-14 (800 pmol/L.kg-1.h-1). RESULTS: Secretin-induced bicarbonate and protein outputs were significantly inhibited by somatostatin-14 in both the innervated and denervated animals. The inhibitory effects of somatostatin-14 were partially reversed by bethanechol in the innervated animals and completely reversed in the denervated animals. Bethanechol alone potentiated secretin-induced bicarbonate output from both the innervated and denervated pancreas. CONCLUSIONS: The data suggest that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Rather, somatostatin-14 appears to inhibit secretin-induced pancreatic response by an intrapancreatic cholinergic mechanism.

Peptide YY inhibits pancreatic secretion via cholinergic pathways.

The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/hr) and cholecystokinin (50 ng/kg/hr) was administered over 2 hr. An infusion of PYY (400 pm/kg/hr) was then given randomly, during either the first or second experimental hour. The experiments were then replicated with a continuous background infusion of (90 micrograms/kg/hr) bethanechol, a cholinergic agonist. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. In the denervated animals, bethanechol eliminated the inhibitory effects of PYY. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an intrapancreatic cholinergic mechanism.

Serum transferrin as a prognostic indicator of spontaneous closure and mortality in gastrointestinal cutaneous fistulas.

OBJECTIVE: This study determined whether there are any laboratory or other features that will enable prediction of spontaneous closure in patients with gastrointestinal cutaneous fistulas. SUMMARY BACKGROUND DATA: Although the anatomic criteria for spontaneous closure of gastrointestinal cutaneous fistulas have been presented by several authors, less than 50% of such fistulas tend to close, even in the most recent series. METHODS: A group of patients with gastrointestinal cutaneous fistulas with anatomical features favorable to study were investigated with respect to a series of parameters including the usual demographic parameters, plus fistula output, number of blood transfusions, presence of sepsis, as well as metabolic parameters including serum transferrin, retinol-binding protein, thyroxin-binding prealbumin, and serum albumin. RESULTS: Of 79 patients with 116 fistulas, 16 (20.3%) died. Causes of death were uncontrolled sepsis in eight patients and cancer in five patients. Postoperative fistulas constituted 80% of the group. The presence of local sepsis, systemic sepsis, remote sepsis (such as pneumonia or line sepsis), the number of fistulas, fistula output, and the number of blood transfusions were not predictive of spontaneous closure, whereas serum transferrin was predictive of spontaneous closure. Serum transferrin, retinol-binding protein, and thyroxin-binding prealbumin were predictive of mortality. CONCLUSIONS: Serum transferrin does not appear to be an entirely independent variable, but seems to identify those patients with significant remote sepsis, systemic sepsis, and neoplasia in whom these processes are clinically significant. The results, if confirmed, and provided that nutritional needs are met, suggest that short-turnover proteins, particularly serum transferrin, might be useful in predicting which patients with gastrointestinal cutaneous fistulas should undergo surgery despite anatomic criteria favorable for spontaneous closure.

Neuropeptide Y secretion from a malignant extraadrenal retroperitoneal paraganglioma.

A patient with a malignant extraadrenal retroperitoneal paraganglioma had elevated levels of immunoreactive neuropeptide Y (NPY) in the peripheral blood (5988 pg/ml; normal, 123 +/- 30 pg/ml [mean +/- standard error of the mean]). A 6-month course of chemotherapy allowed surgical removal of the previously unresectable primary tumor. Postoperatively, the plasma NPY level initially fell to 1089 pg/ml; continued chemotherapy caused an additional decrease to 440 pg/ml. Four months after surgery, the plasma NPY level increased to 940 mg/ml, coincident with hepatic metastases. This case is the first report of a NPY-secreting clinically nonfunctional malignant extraadrenal paraganglioma. Determination of circulating NPY levels may be useful in the diagnosis and follow-up of patients with neuroendocrine tumors.

Effects of intraluminal peptide YY on pancreatic function.

Peptide YY (PYY) is released postprandially into both the circulation and the distal intestinal lumen. While circulating PYY inhibits pancreatic secretion and insulin release, the effects of intraluminal PYY on pancreatic function are unknown. The aim of the present study was to evaluate the effect of exogenous, intraileal luminal PYY on pancreatic exocrine function and fasting glucose levels. Chronic pancreatic and ileal fistulae (50 cm from the ileocecal valve) were created in nine mongrel dogs. The animals were given intravenous infusions of secretin (125 ng/kg/h) and cholecystokinin octapeptide (CCK-8, 50 ng/kg/h) for four hours. At the beginning of the second hour, either normal saline or PYY, at low [physiologic (2 ng/min)] or high [supraphysiologic (50 ng/min)] levels, was infused antegrade into the ileal fistula for two hours. Pancreatic juice was collected for PYY and glucose levels. Ileal luminal PYY infusions had no effect on pancreatic bicarbonate or protein output. Fasting serum PYY and glucose concentrations were unaffected by either dose of intraluminal PYY. We conclude that ileal luminal PYY does not influence pancreatic exocrine function or fasting glucose levels.