Multiple small "imaging" branch-duct type intraductal papillary mucinous neoplasms (IPMNs) in familial pancreatic cancer: indicator for concomitant high grade pancreatic intraepithelial neoplasia?

Most screening programs for familial pancreatic cancer are currently based on endoscopic ultrasonography and/or magnetic resonance imaging (MRI). Cystic lesions, especially those suspicious for small intraductal pancreatic mucinous neoplasms (IPMNs) of the branch ducts, can be visualized in up to 40 % of individuals at risk, but their pathological importance in the setting of FPC is yet not well established. Individuals at risk from a prospective screening program for familial pancreatic cancer with small "imaging" IPMNs of the branch-duct type (BD-IPMN) who underwent pancreatic resection were analysed regarding clinico-pathological data and the locations of pancreatic lesions. Five of 125 individuals at risk who underwent screening had multiple small (size 2-10 mm) unicystic lesions and/or multicystic single lesions in the pancreatic body and tail suspicious for BD-IPMNs upon MRI imaging and decided to undergo surgical resection after interdisciplinary counselling, although none fulfilled the consensus criteria for IPMN resection. Histological examination revealed BD-IPMNs with low or moderate dysplasia of the gastric type in combination with multifocal PanIN2 and PanIN3 lesions in 4 individuals. The remaining patient had only tiny ductectasias in the pancreatic tail with multifocal PanIN 2 lesions in the entire gland and one PanIN3 lesion in the pancreatic head. Intriguingly, the location of the most dysplastic histological lesions (PanIN3) did not correspond to the preoperatively detected lesions and were not visible in preoperative imaging. In the setting of FPC, the presence of multiple small "imaging" BD-IPMNs may indicate the presence of high-grade PanIN lesions elsewhere in the pancreas.

Harmonic scalpel versus conventional dissection technique in pylorus-preserving partial duodenopancreatectomy.

BACKGROUND/AIMS: Pancreatic head resection is performed with low mortality, but morbidity remains high. Extensive preparation, long operating times, intraoperative blood loss and the need for blood transfusions are risk factors for postoperative morbidity. The aim of our study was to evaluate the feasibility and safety of the ultrasonic dissection device in pylorus-preserving duodenopancreatectomy (PPPD). METHODS: Fifty consecutive patients who underwent PPPD with an ultrasonic dissection device (group 1) were compared with a match-controlled group of 50 consecutive patients who underwent PPPD with conventional dissection techniques (group 2). Duration of surgery, intraoperative blood loss, blood units, complications, mortality and duration of hospital stay were analyzed. RESULTS: There was no difference in age, gender or BMI between groups. In group 1, mean blood loss (446 ± 281.8 ml, p = 0.008) and number of blood units (0.32 ± 0.86, p = 0.001) were significantly lower than in group 2 (819 ± 915.4 ml; 1.36 ± 2.83 units). Duration of surgery was shorter in group 1 (345.6 vs. 373 min, p = 0.28). The rate of postoperative complications, mortality and hospital stay were not significantly different. CONCLUSIONS: Use of an ultrasonic dissection device in PPPD might significantly reduce intraoperative blood loss and the need for blood transfusions. These results should be verified in a prospective randomized controlled trial.

A simple and safe anastomosis for pancreatogastrostomy using one binding purse-string and two transfixing mattress sutures.

Pancreatic anastomotic leakage remains a persistent problem after pancreaticoduodenectomy (PD), especially in the presence of a soft, nonfibrotic pancreas. A modified technique for pancreatogastrostomy was devised, which combines one binding purse-string and two transfixing mattress sutures between the pancreatic stump and the posterior gastric wall. This technique was applied in 35 patients after PD for malignant and benign diseases of whom 10 (28.6%) had a soft pancreas. Median time for the anastomosis was 18 minutes. Operative mortality was zero, and morbidity was 34.3%. Three (8.6%) patients developed a pancreatic fistula (2 type A, 1 type B) as classified according to the International Study Group on pancreatic fistula. All fistulas resolved without further intervention. The described technique is a simple and safe reconstruction procedure after PD that warrants further evaluation.

A redox-based chemical delivery system that enhances estradiol distribution to the brain: disposition studies in the rat.

The disposition of a chemical delivery system for estradiol (E2-CDS) which is based on a redox dihydropyridine-pyridinium salt conversion was investigated in rats. Tissue and plasma concentrations of E2-CDS and the oxidized metabolite (E2-Q+) were evaluated at times ranging from 1 to 14 days after intravenous administration of E2-CDS formulated as a modified cyclodextrin inclusion complex. While E2-CDS levels were below HPLC assay detection limits for all samples by 1 day postdosing, E2-Q+ was readily quantified. The calculated half-life of E2-Q+ was longest in brain tissue, significantly shorter in heart, lung, and kidney tissues, and shortest in plasma. There was a linear relationship between administered E2-CDS dose and oxidized metabolite measured in brain as well as in other tissues collected 24 hr after drug administration. Coadministration of high doses of a similarly oxidizable dihydropyridine, 1-methyl-1,4-dihydronicotinamide (NMN), in a dimethylsulfoxide (DMSO) vehicle decreased E2-Q+ measured in brain and other tissues without significantly affecting the relative patterns of distribution in these tissues. Brain tissue E2Q+ levels were not detected after dosing with the oxidized metabolite.

Effects of sodium salicylate on elimination kinetics of indomethacin and bile production in dogs.

We investigated the effects of sodium salicylate on the elimination kinetics of indomethacin in bile duct-cannulated beagles. Indomethacin and metabolites were quantified by HPLC in plasma, bile, and urine. Indomethacin was administered as iv bolus injection and iv infusion to yield a steady-state plasma concentration of approximately 1 microgram/ml. Following sodium salicylate, given either iv (25 mg/kg) or via duodenal fistula (50 mg/kg), the indomethacin plasma level dropped instantaneously by 60-70%. Concomitantly, total systemic clearance from the plasma and biliary clearance were increased significantly. In addition, a reduced plasma protein binding of indomethacin and a significant increase in the volume of distribution were observed. The amount of indomethacin, excreted as free and conjugated drug in bile, was significantly increased temporarily by sodium salicylate. The total amount eliminated in bile (approximately 70% of the dose), however, was not changed by sodium salicylate co-administration. The bile flow was significantly enhanced for at least 4 hr. Both phase 1 metabolism and renal excretion of indomethacin remained practically unaffected by sodium salicylate treatment.

A redox-based system that enhances delivery of estradiol to the brain: pharmacokinetic evaluation in the dog.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

Biliary elimination of non-steroidal anti-inflammatory drugs in patients.

In view of evidence in animals that enterohepatic recirculation of non-steroidal anti-inflammatory drugs contributes to small intestinal mucosal damage we have investigated the extent of biliary elimination of three nonsteroidals. Ibuprofen (n = 3), diclofenac (n = 2) and indomethacin (n = 3) were given to six patients with a percutaneous transhepatic cholangiodrainage placed in the bile duct system. One patient received all three drugs. The mean biliary elimination of ibuprofen was 0.82% of the given dose compared with 50.41% urinary excretion. When diclofenac or indomethacin was administered 4.62% and 6.40% of the dose were found in bile, whereas 34.73% and 32.22% (means) were recovered from urine, respectively. The mean percentage eliminated in bile as unchanged drug and active phase II metabolites was 0.15% for ibuprofen, 1.09% for diclofenac and 5.02% for indomethacin.

The biliary elimination and enterohepatic circulation of ibuprofen in rats.

The biliary and urinary excretion of ibuprofen and its metabolites were determined in rats after intravenous and peroral administration of 25 and 100 mg/kg of the drug. Within 24 hours 48% of the low i.v. dose and 59% of the high i.v. dose were eliminated via bile as ibuprofen and its metabolites. Following oral administration 40 to 41% of the dose were recovered in bile, whereas 16 to 32% of the dose were eliminated in urine, resulting in an overall drug recovery of 66 to 79% within 24 hours. Upon infusion of bile containing ibuprofen and its metabolites into the duodenum substantial enterohepatic cycling of the drug occurred in the rat.

Gastrointestinal ulcerations induced by anti-inflammatory drugs in rats. Physicochemical and biochemical factors involved.

Aspirin, diclofenac, diflunisal, ibuprofen and indomethacin were given orally or intravenously to fasted or fed rats. The resulting gastric and intestinal damage was assessed using standard methods. The same drugs were administered to rats with biliary fistulas, and the fraction of drug excreted in bile was quantified using HPLC methods. We found that gastric damage occurred only in the fasted animals and was found to be dose-dependent and related to the amount (r = 0.871) and solubility (r = 0.909) of the individual drug. As far as acute gastric toxicity is concerned, neither the potency of a drug as an inhibitor of cyclo-oxygenase nor the fraction of unchanged or conjugated agent excreted in bile appeared to be relevant. Secondly, ulcerations of the small intestine occurred in fed animals only. The degree of damage was related to the amount of unchanged or conjugated drug excreted in bile and cyclo-oxygenase inhibitory potency (r = 0.873). The administered dose (within the range investigated) and drug solubility appeared not to contribute to intestinal toxicity. It is concluded that, in the rat, acute gastric and intestinal toxicity of non-steroidal anti-inflammatory drugs are due to different mechanisms. Whereas gastric toxicity is strongly influenced by the amount of drug dissolved under the pH conditions in the stomach, intestinal toxicity appears to depend on biliary excretion and enterohepatic circulation of a drug as well as on its potency as an inhibitor of prostaglandin synthesis.

Therapeutically relevant differences in the pharmacokinetical and pharmaceutical behavior of ibuprofen lysinate as compared to ibuprofen acid.

The pharmacokinetic properties of ibuprofen p.o. given either as a lysine salt or as acid to eight young, healthy male volunteers was investigated. Ibuprofen lysinate, administered after overnight fasting, produced peak plasma concentrations significantly earlier and higher than ibuprofen acid. A similar difference was observed when the drugs were given following a standardized breakfast. Under these conditions the lat-time was significantly shorter for the lysine salt than for the acid. The pharmacokinetic differences are likely to result from the faster dissolution rate of ibuprofen lysinate. They indicate that the administration of ibuprofen as lysine salt before meals may be advantageous if rapid and reliable onset of pain relief is required.

High-performance liquid chromatographic determination of ibuprofen, its metabolites and enantiomers in biological fluids.

An isocratic high-performance liquid chromatographic method to determine racemic ibuprofen (assay I) and its major metabolites (assay II) in biological fluids (plasma, urine, bile) using a conventional reversed-phase column is described. A third assay using beta-cyclodextrin as stationary phase (Cyclobond I) for the separation of the ibuprofen enantiomers is also described. A wavelength of 220 nm was used to monitor the substances. The sensitivity of the method was 0.1 microgram/ml for all three assays. The method was demonstrated to be suitable for stereoselective pharmacokinetic studies of ibuprofen in humans and animals.

[The "normal" pneumatization of the temporal bone]. / Untersuchungen zur "normalen" Pneumatisation des Os temporale.

Radiographs of the mastoids and the petrous pyramids of ear-healthy adults were investigated to ascertain the normal appearance of the temporal bone pneumatisation. The radiographs included those of patients with skull trauma, provided that these subjects had had no signs or symptoms of middle ear disease or hearing loss before the trauma. The extent of pneumatisation of the mastoid and petrous pyramid ranged from small cell groups around the mastoid antrum to extensive cell formations in the squamous temporal bone, in the apex of the petrous pyramid and in the retrosinus area. The planimetric measurements did not correspond to a normal distribution. It was also striking that ears could be found among these healthy individuals with irregular, asymmetric or indistinct pneumatisation, probably as a residual of sub-clinical middle ear disorders during the development of the cell system. After eliminating these irregular findings the ears with exclusively regular, symmetric and clear cell pictures also did not follow a normal distribution. Rather, they resulted in a typical curve with a steep ascent rising from a functionally-necessary minimum of about 4 cm2 to mean values of 8-12 cm2, and then a wide distribution reaching a value of 26 cm2. All these can be taken as genetically-determined "normal variants". The irregular cell-formations were seen mainly in the smaller pneumatised mastoids, so that it can be concluded that exogenous influences have at some time disturbed the pneumatisation process.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained-release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: (i) There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. (ii) In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. (iii) Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clearcut advantages as well.

Recent insight into the mechanism of gastrointestinal tract ulceration.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their gastrotoxic and duodenotoxic effects. A few years ago the introduction of a sustained release form of indomethacin led to an apparently high incidence of jejunal and ileal perforations. Recently, Langman in England was able to demonstrate that the intake of some NSAIDs is related to an enhanced incidence of ileal and jejunal perforations in rats and dogs, even after parenteral or rectal administration. We have been able to show that: 1. There is a correlation between biliary excretion of NSAIDs or ester conjugates of these drugs and ileal perforations in rats. 2. In contrast to dogs there is no (ibuprofen) or little enterohepatic circulation (diclofenac and diflunisal) in man. This agrees with the low incidence of ileal and jejunal ulcers reported with these drugs in contrast to indomethacin or piroxicam. 3. Reduction of enterohepatic circulation of indomethacin in rats by dietary means reduces the degree of small intestinal erosions and ulcerations in parallel with the reduced biliary excretion of the drug. It may be safely assumed that the enterohepatic circulation of some NSAIDs, particularly indomethacin and piroxicam, may contribute to the reported incidence of ileal and jejunal damage caused by these drugs. These drugs may, on the other hand, have clear-cut advantages as well.

[Experiences with the microscopic mediastinoscopy (author's transl)]. / Erfahrungen mit der mikroskopischen Mediastinoskopie.

The mediastinoscopy is a routine method in cases with suspect changes of the mediastinum. The instruments for endolaryngeal microsurgery (KLEINSASSER) are usefully in this examinations. With this method no complications were observed in 50 patients.