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Biomedical subjects

J L Cameron

Publications and source records attributed to J L Cameron.

At least 145 records · Page 8Linked to original sources

Pancreaticoduodenectomy for selected pancreatic endocrine tumors.

Endocrine tumors are distributed throughout the pancreas and can usually be removed by local excision or distal pancreatectomy. Those tumors arising in the pancreatic head and uncinate process may be difficult to enucleate because of size, location or malignant extension. In the past, surgeons have been reluctant to perform a pancreaticoduodenectomy (Whipple procedure) for these lesions because of the high morbidity and mortality rates. In recent years, we and others have reported a marked reduction in the morbidity and mortality rates after the Whipple procedure and, since 1981, have used pancreaticoduodenectomy to resect pancreatic endocrine neoplasms successfully in 12 patients. Tumors were resected from six men and six women who ranged in age from 28 to 61 years (median of 49 years). Six of the tumors were benign and included three insulinomas, one glucagonoma, one gastrinoma and one nonfunctioning islet cell tumor. The six malignant tumors included two insulinomas, one VIPoma and three nonfunctioning islet cell tumors. In all instances, enucleation could not be performed safely or would have resulted in an inadequate excision. Pylorus preservation was used in seven of the patients, including the last six. The average operative time was 6.8 hours, and six of the patients did not require perioperative blood transfusions. There was no hospital mortality. Hospital morbidity included three self-limited pancreatic fistulas, one gastrocutaneous fistula, one hepatic abscess and one postoperative myocardial infarction. One patient with a malignant VIPoma died three years postoperatively of metastatic tumor. The remaining 11 patients are alive and well with a median follow-up period of three and one-half years (range of zero to 9.7 years). These data indicate that pancreaticoduodenectomy is an appropriate procedure for properly selected patients with pancreatic endocrine neoplasms and can be performed with acceptable morbidity and mortality rates.

Adenoma, Islet Cell↗

K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization.

We examined 82 surgically resected or biopsied, formalin-fixed, paraffin-embedded primary adenocarcinomas of the pancreas for the presence of activating point mutations in codon 12 of the K-ras oncogene. Mutations were detected using primer-mediated, mutant-enriched, polymerase chain reaction-restriction fragment length polymorphism analysis and characterized further by allele-specific oligonucleotide hybridization. This combination of mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis and allele-specific oligonucleotide hybridization results in a rapid and sensitive characterization of the mutations in codon 12 of K-ras. Sixty-eight (83%) of the 82 carcinomas examined harbored a point mutation. Of the 68 mutations, 33 (49%) were guanine to adenine transitions, 27 (39%) were guanine to thymine transversions, and eight (12%) were guanine to cytosine transversions. Mutations were found in carcinomas of the head (61 of 75, 81%) as well as in carcinomas of the body or tail (seven of seven, 100%) of the pancreas. The overall prevalence of K-ras point mutations in adenocarcinomas of the pancreas obtained from patients who smoked cigarettes at some point during their lives (88%; 86% in current smokers and 89% in ex-smokers) was greater than that seen in pancreatic adenocarcinomas from patients who never smoked cigarettes (68%, P = 0.046). The presence of K-ras point mutations did not correlate with tumor ploidy, tumor proliferating index, or patient survival. These results demonstrate that primer-mediated, mutant-enriched polymerase chain reaction-restriction fragment length polymorphism analysis combined with allele-specific oligonucleotide hybridization can be used to detect and characterize mutations in codon 12 of the K-ras oncogene in formalin-fixed, paraffin-embedded tissues, and the results confirm that activating point mutations in codon 12 of the K-ras oncogene occur frequently in adenocarcinomas of the pancreas.

Adenocarcinoma↗

The mechanism of conversion of xanthine dehydrogenase to xanthine oxidase in acute pancreatitis in the canine isolated pancreas preparation.

Four models of acute pancreatitis have been previously developed that use the ex vivo perfused isolated canine pancreas preparation. The four models include the intraarterial infusion of oleic acid (FFA) that mimics hyperlipemic pancreatitis, partial obstruction of the pancreatic duct with secretin stimulation (POSS) that mimics gallstone pancreatitis, a 2-hour period of ischemia before perfusion (ISCH 2) that mimics shock pancreatitis, and the infusion of cerulein at supramaximal stimulatory doses (CER), which lacks an obvious clinical counterpart. In the FFA, POSS, and ISCH 2 pancreatitis, but not in the CER pancreatitis, toxic oxygen metabolites, generated by the enzyme xanthine oxidase (XO), have been shown to be important mediators in the early pathogenesis. Ordinarily XO primarily occurs as xanthine dehydrogenase (XD) but can be converted to XO, which is the form that generates toxic oxygen metabolites. This conversion of XD to XO may take place either reversibly by way of sulfhydryl group oxidation or irreversibly by means of proteolytic cleavage of XD. This study was undertaken to investigate the mechanism of conversion of XD to XO in the FFA-, POSS-, and ISCH 2-induced pancreatitis models. CER pancreatitis was studied for comparison. After 4 hours of perfusion, pancreatitis was manifest by edema, weight gain, and hyperamylasemia in all four models. Dithiothreitol, a sulfhydryl group protector, ameliorated the weight gain in the FFA (40 +/- 14 gm to 18 +/- 13 gm; p < 0.05), POSS (28 +/- 10 gm to 9 +/- 3 gm; p < 0.05), and ISCH 2 pancreatitis (30 +/- 13 gm to 15 +/- 3 gm; p < 0.05), and ameliorated the hyperamylasemia in the POSS pancreatitis (12,062 +/- 4304 units/dl to 5877 +/- 2659 units/dl; p < 0.05). The CER pancreatitis was not ameliorated with dithiothreitol. A serine protease inhibitor of low molecular weight, phenylmethylsulfonyl fluoride, ameliorated only the CER pancreatitis (weight gain from 28 +/- 10 gm to 17 +/- 10 gm, p < 0.05; amylase activity from 38,116 +/- 6491 units/dl to 23,372 +/- 11,654 units/dl, p < 0.05), and not the FFA, POSS, or ISCH 2 pancreatitis. We conclude that in the three models of pancreatitis (FFA, POSS, and ISCH 2) that are mediated by toxic oxygen metabolites, XD is converted to XO reversibly by way of sulfhydryl group oxidation rather than irreversibly by way of proteolysis. In the CER pancreatitis, where XO does not play a role in the pathogenesis, proteolytic enzymes may be important mediators in the injury.

Acute Disease↗

Biliary tract anomalies associated with intestinal malrotation in the adult.

Intestinal malrotation is a rare disorder typically beginning in childhood. In the adult it is an uncommon diagnosis, and it usually begins with bowel obstruction. It is a congenital anomaly only once reported to be associated with other gastrointestinal abnormalities in an adult. We reviewed all patients with intestinal malrotation at the Johns Hopkins Hospital during the past 7 years to determine the incidence of associated biliary tract anomalies. Eight adult patients were found to have complete malrotation of the gut. Four patients (50%) had an associated abnormality of the biliary tree. Two of four patients had a clinical presentation consistent with biliary tract disease rather than intestinal malrotation. Two patients underwent exploration; the gallbladder was found to arise from the left lobe of the liver. Two patients underwent exploration; in these patients the porta hepatic structures were anterior to the duodenum (complete anteroposterior portal hepatic malrotation). None of the biliary abnormalities were suspected before surgery. Malrotation was diagnosed before operation in only two of the eight patients. We conclude that intestinal malrotation is rare in the adult, and it can be associated with biliary tract anomalies or disease. In an adult with suspected intestinal malrotation and biliary tract disease, the surgeon should be aware of possible variable or abnormal extrahepatic choledochal anatomy.

Abnormalities, Multiple↗

Internal pancreatic fistula.

Internal pancreatic fistulae are well-recognized complications of inflammatory pancreatic disease. From 1963 to 1990, 50 patients with either pancreatic ascites (34), pancreatic ascites and pleural effusion (7), or pancreatic pleural effusion (9) were treated. Initial therapy was conservative, consisting of gastrointestinal rest, serosal apposition with paracentesis or thoracentesis, with or without the administration of anti-secretagogues. This therapy was successful in 21 of 42 patients, but 5 deaths occurred. Operative therapy was performed in 24 patients. There was one surgical failure and two deaths early in the experience. Ten of our final 16 patients underwent liver biopsy, and all 10 were found to have cirrhosis. All patients, even those with documented cirrhosis, should have routine amylase and albumin determinations on ascitic or pleural fluid. Internal pancreatic fistulae should be treated initially nonoperatively; if this is ineffective, operative therapy has an acceptably low morbidity and mortality.

Adolescent↗

Spectrum of cystic tumors of the pancreas.

The pathologic and clinical classification, as well as the behavior, of cystic tumors of the pancreas has been the subject of controversy. We retrospectively reviewed 50 patients with a diagnosis of cystic tumor of the pancreas observed at The Johns Hopkins Hospital from 1984 to 1991. These tumors were classified into three broad groups: I, cystadenoma; II, cystadenocarcinoma; and III, adenocarcinoma with mucin production or an associated cyst. The three groups did not differ with respect to age or sex. The most common clinical presentation was abdominal pain. Symptoms and signs among the three groups were similar except that patients with cystadenomas were less likely (p less than 0.05) to be jaundiced and more likely (p less than 0.05) to be asymptomatic. Radiologic findings on computerized tomography, cholangiography, and arteriography also overlapped, making precise preoperative determination of tumor type difficult. Operative classification was also often not possible. The resectability rate (Group I, 91%; Group II, 67%; Group III, 53%) and 5-year survival rate (Group I, 90%; Group II, 72%; Group III, 14%) correlated with careful pathologic determination. Cystic tumors of the pancreas represent a spectrum of disease ranging from benign cystadenoma to adenocarcinoma masquerading as cystadenocarcinoma. We recommend resection whenever possible, even when preoperative evaluation suggests benign disease.

Actuarial Analysis↗

Acute effects of a nucleoside analog dideoxyinosine (DDI) on the pancreas.

Dideoxyinosine (DDI, Videx) is a recently developed nucleoside analog with activity against the human immunodeficiency virus. A significant number of patients with AIDS or AIDS-related complex treated with DDI have developed acute pancreatitis. This study was performed to investigate the acute effects of DDI on the pancreas utilizing an isolated ex vivo perfused canine pancreas preparation. Control preparations remained normal throughout a 4-hr perfusion period. The addition of 12.5 mg of DDI to the perfusate (ca. 100 mumol/liter) did not induce any changes in the preparation. The addition of 62.5 mg of DDI to the perfusate (ca. 500 mumol/liter) did not induce changes in the gross appearance, weight gain, or amylase activity. However, the arterial pressure and the oxygen consumption of the preparation decreased significantly after the administration of DDI. The amount of zymogen in the acinar cells also decreased, as evaluated by electron microscopy. Protein secretion increased temporarily, probably as a result of acinar cell emptying (increased secretion without new synthesis). Water and bicarbonate secretion were also increased during the fourth perfusion hour.

Animals↗

Carcinoma of the body and tail of the pancreas.

Recently, several institutions have reported improved results in the treatment of patients with carcinoma of the head of the pancreas. In an attempt to determine whether similar trends could be demonstrated for patients with carcinoma of the body and tail of the pancreas, the records of all 113 patients with an adenocarcinoma of the body or tail of the pancreas treated at The Johns Hopkins Hospital between 1972 and 1989 were reviewed. The patients were divided into two groups: those diagnosed between 1972 and 1982 (41 patients) and those between 1983 and 1989 (72 patients). No significant differences in tumor stage were observed between the two groups. The proportion of patients who underwent surgery decreased from 68% to 47% (p = 0.02). The number of patients who had bypass operations (15% versus 17%) or pancreatic resection (5% versus 10%) was similar in the two groups, but the proportion of patients who underwent exploratory laparotomy with biopsy only decreased from 49% to 21% (p = 0.002). The postoperative 30-day mortality (7% versus 3%), postoperative morbidity (18% versus 21%), median survival (4 months versus 3 months), and the 1-year survival (8% versus 9%) did not differ significantly between the two groups. One patient survived for 6 years after resection, and another patient is still alive 3 years after resection. Thus, unlike adenocarcinoma of the head of the pancreas, it appears that treatment results for patients with adenocarcinoma of the body or tail of the pancreas have not improved in recent years, the only change being a decreased need for exploratory laparotomy with biopsy only.

Actuarial Analysis↗

Patterns of ileal recurrence in Crohn's disease. A prospective randomized study.

To gain information on the pathogenesis of ileal recurrence, 86 patients with Crohn's disease undergoing their first ileocolic resection were randomized to receive either an end-to-end (n = 47) or side-to-end (n = 39) anastomosis. The demographic and clinical characteristics of both groups were similar. There were no statistically significant differences between the two groups in postoperative complications or in the subsequent development of symptomatic or documented recurrences. Among the 43 patients with follow-up in the end-to-end anastomosis group, there were 10 documented ileal recurrences (23%), and all involved distal ileum in the characteristic preanastomotic location. Among the 35 patients with follow-up in the side-to-end anastomosis group, there were 11 documented recurrences (31%, not significant). The ileal recurrence pattern could be determined accurately in five of these 11 patients and involved the ileum adjacent to the colon, but spared the distal ileum in the blind pouch. This study suggests that the fecal stream and reflux of colonic contents are important factors in determining the pattern of ileal recurrence after ileocolectomy for Crohn's disease.

Adult↗

Biliary tract complications following laparoscopic cholecystectomy: imaging and intervention.

Radiologic studies and interventional procedures were performed in a series of 13 patients with biliary complications following laparoscopic cholecystectomy, and the results were evaluated. Two categories of ductal complication--minor and major--were found. Minor complications (n = 6) included bile leaks and bilomas; these were managed with percutaneous techniques or simple surgical repair. Major complications (n = 8), consisting primarily of common hepatic duct injuries or strictures, were markedly resistant to percutaneous therapy, requiring major surgical repair (hepaticojejunostomy). Percutaneous treatment of recurrent strictures after primary repair was undertaken in three patients. Diagnostically, radionuclide imaging appeared most helpful in screening for biliary complications of laparoscopic cholecystectomy, supplemented by endoscopic retrograde cholangiopancreatography and/or percutaneous transhepatic cholangiography for definitive diagnosis.

Adult↗

Suppression of luteinizing hormone secretion during food restriction in male rhesus monkeys (Macaca mulatta): failure of naloxone to restore normal pulsatility.

Short periods of fasting have been shown to cause a significant slowing of pulsatile LH secretion in men and male rhesus monkeys, which appears to result from a slowing of GnRH drive to the reproductive axis. To determine whether an increased activity of endogenous opioid peptides causes this slowing of pulsatile LH secretion, the ability of naloxone administration to reverse the fasting-induced suppression of LH secretion was tested. For this study, 6 adult male rhesus monkeys, with indwelling femoral and jugular venous catheters, were maintained on tether/swivel systems. Naloxone was administered to monkeys as a continuous infusion (0.25 mg/kg/h, with an initial loading dose of approximately 1.0 mg) for 8 h (16.00 to 24.00 h) on a day of normal feeding and again on a day of fasting. The LH response to naloxone was determined by collecting blood samples every 15 min from 12.00 to 24.00 h. LH pulse frequency on a day of normal feeding was 4.0 +/- 0.52 pulses/8 h, and naloxone administration on a day of feeding increased LH pulse frequency to 6.8 +/- 0.86 pulses/8 h. On a day of fasting, LH pulse frequency was 1.67 +/- 0.67 pulses/8 h, and naloxone administration on a day of fasting slightly, but not significantly, increased LH pulse frequency to 2.5 +/- 0.51 pulses/8 h. Similar studies were performed with a higher dose of naloxone (0.625 mg/kg/h, with an initial loading dose of approximately 2.0 mg) and again naloxone administration did not reverse the effects of fasting on pulsatile LH secretion. These results suggest that the slowing of pulsatile LH release that occurs with short periods of food restriction does not result from increased secretion of endogenous opioid peptides.

Animals↗

Pulses of oxytocin in the cerebrospinal fluid of rhesus monkeys.

Cerebrospinal fluid (CSF) samples were collected at frequent intervals (every 10-15 min) to determine if oxytocin pulses were present in the CSF of monkeys. Temporary indwelling subarachnoid catheters, with the tip of the catheter at the T12-L1 subarachnoid space, were placed in 4 nonlactating and 3 lactating (4 months post partum) female monkeys. Monkeys were maintained on jacket/tether/swivel systems in a constant photoperiod (07.00-19.00 h). CSF was continuously withdrawn at a rate of 1.2 ml/h by peristaltic pump, and CSF was collected in 15-min fractions (from 3 lactating monkeys and 1 nonlactating monkey) or in 10-min fractions (from the other 3 nonlactating monkeys) using a fraction collector. CSF oxytocin was measured by radioimmunoassay. Pulses of oxytocin were analyzed using the computerized Pulsar pulse detection algorithm. A pulsatile pattern of oxytocin concentrations was found in the CSF of lactating and nonlactating monkeys. The ultradian pulses of oxytocin were superimposed upon the diurnal rhythm of oxytocin in CSF. We conclude that frequent sampling of CSF provides a way to monitor moment-to-moment changes in central nervous system concentrations of oxytocin in primates.

Animals↗

Effect of naloxone administration upon the diurnal concentrations of oxytocin in the cerebrospinal fluid of rhesus and cynomolgus monkeys.

A diurnal pattern in oxytocin concentrations is present in cerebrospinal fluid (CSF) removed from the spinal subarachnoid space of monkeys, with elevated levels occurring in the early light hours. In order to investigate the possible role of endogenous opioid peptides in the generation of this oxytocin rhythm, we administered naloxone (0.4 mg/kg/h x 48 h) to rhesus and cynomolgus monkeys and examined the effects on the diurnal pattern of oxytocin in CSF collected from the lumbar subarachnoid spinal space. Monkeys maintained on jacket/tether/swivel systems and in a 12 h light: 12 h dark cycle (lights on 07.00-19.00 h) were implanted with temporary spinal subarachnoid catheters. CSF was continuously collected from the lumbar subarachnoid space and assayed for oxytocin. Oxytocin concentrations in CSF showed a diurnal variation with peak and nadir concentrations during light and dark hours, respectively. The lumbar CSF concentrations of oxytocin were not significantly different during naloxone vs. saline infusion. Plasma oxytocin concentrations, measured in the same animals, displayed no diurnal variation and were not significantly different during naloxone vs. saline infusion. We conclude that naloxone administration for 48 h does not perturb the diurnal variation in oxytocin concentrations in the CSF of monkeys. Mu opioid receptors are unlikely to be involved in modulating the diurnal rhythm of oxytocin in the CSF of monkeys.

Animals↗

Effects of cysteamine administration on somatostatin biosynthesis and levels in rat hypothalamus.

A single injection of cysteamine (CSH; 2-aminoethanethiol; 300 mg/kg, sc) into male rats produced a rapid decline in immunoreactive somatostatin (IR-SRIF) levels in the hypothalamus (to 20% of preinjection values within 12 h) which persisted for several days. The levels of both somatostatin-14 (SRIF-14) and somatostatin-28 (SRIF-28) were reduced. In contrast, the levels of somatostatin-28(1-12) were unaffected. Most (80-90%) of the lost SRIF molecules (both SRIF-14 and SRIF-28) could be recovered from CSH-injected rats by subjecting hypothalamic samples to denaturing, reducing, and reoxidizing conditions. These results suggest that CSH does not deplete the hypothalamus of SRIF molecules, but, instead, alters their chemical structures, rendering them undetectable using a SRIF-14-directed RIA. CSH injection also caused a rapid and complete suppression (within 1 h) of [35S]cysteine incorporation into SRIF-14 and SRIF-28. This reduction, however, was short-lived; normal incorporation rates returned within 10 h of drug administration. CSH did not influence [35S] cysteine incorporation into acid-precipitable protein or [35S]cysteine specific activity in the hypothalamus. In addition, [35S]SRIF molecules were not recovered from hypothalami of CSH-treated rats by subjecting samples to denaturing, reducing, and then reoxidizing conditions. These findings indicate that CSH injection causes a true, but short-lived (1- to 10-h), suppression of hypothalamic SRIF-14 and SRIF-28 formation. Finally, biosynthesis studies of longer duration revealed no prolonged effects of CSH. The drug produced no changes 4, 24, or 72 h postinjection in hypothalamic levels of the prepro-SRIF mRNA. Moreover, two injections of CSH, separated by 3 days, which continuously suppressed IR-SRIF levels for almost 1 week, caused only a transient suppression of [35S]SRIF-14 and [35S]SRIF-28 synthesis after each injection. These results indicate that the SRIF biosynthetic pathway is not activated by the prolonged CSH-induced depletion of IR-SRIF stores.

Animals↗

Dopaminergic stimulation of oxytocin concentrations in the plasma of male and female monkeys by apomorphine and a D2 receptor agonist.

Administration of the dopamine receptor agonist apomorphine causes a dose-dependent increase in plasma oxytocin concentrations and dose-specific behavioral changes in rodents. To investigate whether dopamine receptor agonists will elicit similar neuroendocrine and behavioral effects in primates, we administered graded doses of apomorphine and the respective dopamine D1 and D2 receptor agonists, CY 208-243 and LY 163502, to monkeys and monitored plasma concentrations of oxytocin and behavior. Five female rhesus, two male rhesus, and two male cynomolgus monkeys had chronic indwelling venous catheters implanted and were maintained on standard jacket/tether/swivel systems to allow remote blood sample collection. During experiments, blood samples were collected 10 and 5 min before drug injection and at 2- to 120-min intervals after each injection. Apomorphine (50-400 micrograms/kg) and LY 163502 (10-100 micrograms/kg) elicited dose-dependent stimulations of oxytocin secretion. CY 208-243 (100-400 micrograms/kg) did not significantly affect oxytocin secretion. Low doses of apomorphine (50-100 micrograms/kg) and LY 163502 (10-25 micrograms/kg) elicited yawning, and high doses of apomorphine (200-400 micrograms/kg) and LY 163502 (50-100 micrograms/kg) elicited stereotypic behaviors. No behavioral effects of CY 208-243 (100-400 micrograms/kg) were observed. The magnitude of the oxytocin secretory responses varied among animals, but was similar in male and female monkeys. In summary, apomorphine and LY 163502 both elicited dose-related stimulation of oxytocin secretion coupled with dose-specific behavioral changes in male and female monkeys, while no effects of CY 208-243 on these parameters were observed. We conclude that dopamine receptor agonists, and in particular D2 agonists, may be useful tools for studies exploring the physiological and behavioral actions of oxytocin in primates.

Animals↗

Gastric and duodenal obstruction in patients with cholangiocarcinoma in the porta hepatis: increased prevalence after radiation therapy.

OBJECTIVE: Our objective was to study the imaging findings in patients who had gastric and duodenal obstruction as a long-term complication of cholangiocarcinoma and to determine if the obstruction was associated with radiation therapy. MATERIALS AND METHODS: Between 1973 and 1989, 96 patients had either curative resection or palliative stenting for cholangiocarcinoma involving the hepatic duct bifurcation. Sixty-three (66%) also received adjuvant radiation therapy ranging from 4960 to 7220 rad (cGy). Gastric outlet or duodenal obstruction or both developed subsequently in seven of the 63 patients treated with radiation therapy. Radiographic studies, including upper gastrointestinal series and CT, and medical and surgical records for these seven patients were retrospectively reviewed. RESULTS: Upper gastrointestinal series in the seven patients with obstruction showed narrowing of the lumen, deformity and enlargement of gastric and duodenal mucosal folds, and delayed gastric emptying. CT performed in five of the seven patients showed thickening of the wall of the gastric antrum and small bowel and retained food and fluid within the stomach. All seven patients required gastrojejunostomy; at surgery, dense adhesions and fibrosis were found, and it was not evident whether the obstruction was due to the tumor or to radiation fibrosis. However, because this complication was seen only after radiotherapy, it was presumed to be radiation fibrosis. CONCLUSION: Our experience suggests that radiation therapy increases the risk of postoperative gastric and duodenal obstruction in patients undergoing surgery for cholangiocarcinoma.

Adenoma, Bile Duct↗