Preoperative staging of periampullar cancer with US, CT, EUS and CA 19-9.

BACKGROUND/AIMS: Several diagnostic methods are available for preoperative staging of periampullary cancers. It happens that on the basis of preoperative findings the patient is prepared for radical surgery, but during the operation the lesion turns out to be unresectable. METHODOLOGY: We studied 43 patients operated on for periampullary cancer. Preoperatively, all patients were evaluated by ultrasonography, computed tomography, endoscopic ultrasonography and the level of carbohydrate antigen 19-9 was assessed. Statistical parameters were calculated and compared. RESULTS: Endoscopic ultrasonography has specificity of 70.8% and positive predictive value regarding tumor resectability 55.8%. Computed tomography has a specificity of 45.8% and carbohydrate antigen 19-9 of 66.7%. Positive predictive value for computed tomography and carbohydrate antigen 19-9 is 40.6% and 52.6%, respectively. Ultrasonography is the least accurate method with specificity of 12.5% and positive predictive value 29.7%. A combined use of different diagnostic methods has higher positive predictive value, highest (65.1%) being found for the combination of endoscopic ultrasonography and carbohydrate antigen 19-9. Statistical tests showed statistically significant differences between diagnostic methods. CONCLUSIONS: Among the diagnostic methods studied, endoscopic ultrasonography showed the highest accuracy in predicting tumor resectability. The use of either endoscopic ultrasonography and carbohydrate antigen 19-9 or computed tomography and carbohydrate antigen 19-9 is accurate enough for assessing tumor resectability.

Can we evaluate the pressure of perihepatic packing? Results of a study on dogs.

The pressure of perihepatic packing can cause organ perfusion disturbances. The problem is to determine the pressure applied during the operative procedure. The objective of this animal study was to assess the perihepatic packing pressure and its effect on the pressure in the inferior vena cava (IVC). In order to assess the pressure in the IVC a catheter was introduced through the femoral vein. A rearranged tourniquet for blood pressure measurement was placed on the dog liver and with various perihepatic pressures the resulting pressures in the IVC were assessed. It was established, that by applying pressure of 30 mm Hg to the liver, the pressure in the IVC did not exceed 10 cm of water. Two clinical cases are reported where the method was shown to be crucial for the management. The first one is related to haemodynamic instability after successful perihepatic packing for grade V injury. In the second case, an otherwise stable patient had significantly elevated pressure in the IVC, which crucially influenced the treatment. The introduction of a catheter into the IVC to monitor the pressure in patients with liver injuries is useful.

Mechanism of action of HI-6 on soman inhibition of acetylcholinesterase in preparations of rat and human skeletal muscle; comparison to SAD-128 and PAM-2.

HI-6 is presently considered the most potent oxime antidote against soman poisoning in mice, rats, dogs and monkeys. However, it is still an open question whether efficiency of HI-6, observed in experimental animals, can be extrapolated to soman intoxicated humans. In this paper efficiency of HI-6 and possible mechanisms of action were compared in rat and human fresh muscle preparations. In rat muscle, about 50% of control AChE activity could be recovered by both therapeutic (5 min after soman) and prophylactic (5 min before soman) application of HI-6. On the other hand, in human muscle therapeutic treatment restored only 5%, while prophylactic application of HI-6 again resulted in about 50% recovery of control AChE activity. As revealed by comparison of the prophylactic effects of HI-6 and the non-oxime bispyridinium compound SAD-128, competitive inhibition of AChE plays a minor role as a protective mechanism. Immediate reactivation of rapidly aging human AChE must therefore be instituted for successful protective treatment by HI-6. Retardation of aging, a direct effect of SAD-128, was roughly estimated to improve reactivation by HI-6 for about 10% of control AChE activity of the human muscle. PAM-2 proved completely inefficient as a therapeutic and as a prophylactic agent on both rat and human muscle preparations.

Inhibition of murine thymidylate synthase and human dihydrofolate reductase by 5,8-dideaza analogues of folic acid and aminopterin.

A series of 5,8-dideaza analogues of folic acid, isofolic acid, aminopterin, and isoaminopterin were evaluated for inhibition of thymidylate synthase, TS, from mouse L1210 leukemia cells with 10-propargyl-5,8-dideazafolic acid, CB3717, 4a, as the reference inhibitor. These compounds were also tested as inhibitors of human dihydrofolate reductase, DHFR, obtained from WIL2 cells. None of the analogues studied were as potent as 4a toward TS; however, 9-methyl-5,8-dideazaisoaminopterin, 6d, was only 2.5-fold less effective. Compound 4a was prepared by direct alkylation of the di-tert-butyl ester of 5,8-dideazafolic acid followed by hydrolysis of the resulting diethyl ester, which resulted from concomitant transesterification. It was found to be identical with a sample of 4a prepared by earlier methodology by using a variety of spectroscopic techniques. Its isomer, 9-propargyl-5,8-dideazaisofolic acid, 4b, which was synthesized by an analogous approach, was found to be dramatically less inhibitory toward TS than 4a. Each of the 2,4-diamino derivatives, including those possessing an allyl or propargyl group at N9, was an excellent inhibitor of DHFR, having a level of potency similar to that of methotrexate, MTX. However, many of these 5,8-dideazaaminopterin analogues were far more inhibitory toward TS than MTX.

Synthesis of 5-chloro-5,8-dideaza analogues of folic acid and aminopterin targeted for colon adenocarcinoma.

Several classical quinazoline analogues of folic acid bearing chloro or methyl substituents at position 5 were evaluated as inhibitors of the growth of four human gastrointestinal adenocarcinoma cell lines in vitro. The preparation of two of these, 5-chloro-5,8-dideazaisofolic acid, 1e, and 5-chloro-5,8-dideazaisoaminopterin, 2a, is reported for the first time. In addition, a new synthetic route to 5-chloro-5,8-dideazaaminopterin, 2b, is described. For compounds having a 2,4-diamino configuration, the presence of chlorine at position 5 afforded superior growth inhibitory potency. However, compound 1e was substantially less effective than its 5-methyl counterpart.