Intraductal papillary-mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras,p53 and c-erbB-2 abnormalities in 26 patients

Intraductal papillary growth of mucin producting hypersecreting, columnar cells characterizes a group of rare pancreatic exocrine neoplasms which we propose to call intraductal papillary-mucinous tumors (IPMT). We analysed the histopathology of 26 IPMT in relation to gastro-enteropancreatic marker expression, genetic changes and biology. Four IPMT showing only mild dysplasia were considered to be adenomas. Nine tumours displayed moderate dysplasia and were regarded as borderline. Severe dysplasia-carcinoma in situ changes were found in 13 IPMT which were therefore classified as intraductal carcinomas. Six of these carcinomas were frankly invasive and two of these had lymph node metastases. The invasive component resembled mucinous noncystic carcinoma in all but one tumour which showed a ductal invasion pattern. Immunohistochemically, an intestinal marker type was found in most carcinomas, while gastric type differentiation prevailed among adenomas or borderline tumours. K-ras mutations (seven at codon 12 and one at codon 13) were found in 31% of IPMT (2 adenomas, 1 borderline, 5 carcinomas). Nuclear p53 overexpression was detected in 31% of IPMT (6 carcinomas and 2 borderline IPMT) and correlated with p53 mutations (one at exon 8 and the other at exon 5) in two carcinomas. p53 abnormalities were unrelated to K-ras mutation. c-erbB-2 overexpression was observed in 65% of IPMT, with various grades of dysplasia. Twenty-two of 24 patients are alive and well after a mean post-operative follow-up of 41 months. Only two patients, both with invasive cancer at the time of surgery, died of tumour disease. It is concluded that pancreatic IPMT encompass neoplasms which, in general, have a favorable prognosis, but are heterogeneous in regard to grade of dysplasia and marker expression. Adenoma, borderline tumour, intraductal carcinoma and invasive carcinoma can be differentiated. p53 changes but not K-ras mutation or c-erbB-2 overexpression are related to the grade of malignancy. Most IPMT differ in histological structure, marker expression and behaviour from ductal adenocarcinoma.     

Low‐Temperature Polymerization of Olefins in the Presence of Titanium Monoamidinate/MAO Catalyst

This paper reports the predominantly syndiotactic‐specific polymerization of propylene in the presence of titanium monoamidinate/methylaluminoxane (MAO) catalysts. The same catalysts, depending on the reaction conditions, also promote either predominantly 1,4‐cis or 1,4‐trans polymerization of 1,3‐butadiene and polymerization of styrene either to highly syndiotactic or to stereoirregular polymer. Some preliminary information about the features of propylene polyinsertion is also reported.

Expansion of the 20–24 ppm region of the ¹³C NMR spectrum of sample 2. The starred resonance at 21.75 ppm and the shoulders are not assigned.     

The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717)

Summary The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100–550 mg/m² in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40–200 M. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t_1/2=49±9 min, t_1/2=739±209 min). 27%±2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6%±0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid.Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m² CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m²) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r=0.69, P=0.02)These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies.This work was supported by grants from the Medical Research Council and Cancer Research Campaign, U. K.     

Attempted control of mucocutaneous leishmaniasis through treatment of diseased dogs

An attempt was made to control cutaneous leishmaniasis in the municipality of Santa Leopoldina, Espírito Santo State, Brazil, by treating infected dogs. Another area in the municipality of Afonso Cláudio, which is ecologically similar, served as the control area, and dogs were left untreated there. In an initial survey, 34/141 inhabitants of the first area had positive leishmanin tests and 8/26 dogs had cutaneous leishmaniasis, while in the second area 37/127 individuals had positive leishmanin tests and 7/44 dogs were infected. After treatment of the sick dogs in the first area the populations of both areas were periodically examined for new infections. More new human infections were observed in the control area, but the difference was not statistically significant.     

One-year experience with a new expanded polytetrafluoroethylene vascular graft for hemodialysis

Hemodialysis access achieved through a prosthetic vascular graft has become more popular, especially in diabetic and older patients and those who have had several unsuccessful surgical accesses. From January to December 1996, we implanted a newly available expanded polytetrafluoroethylene (ePTFE) graft (DIASTAT Vascular Access Graft) that allows early cannulation in 18 patients (11 men and 7 women; mean age +/- SD, 63.7 +/- 11 years). Thirteen of these patients had at least one failed vascular access. All grafts were cannulated for dialysis within 7 days of implantation, with flow rates > or = 300 ml/min. The time to hemostasis after the first cannulation ranged from 2 to 4 min. The primary patency rate at one year was 56%. Four grafts developed thrombosis requiring surgical intervention; three were salvaged and one was removed. The one-year assisted or cumulative patency rate was 72%. One patient had persistent bleeding requiring graft revision immediately after surgery. The bleeding stopped and its origin was not determined. There were no graft infections or hematomas. Because of the early cannulation possible with the DIASTAT graft, as well as the lesser time to hemostasis than that generally achieved with standard ePTFE grafts, this prosthesis is a good alternative to autogenous access construction.     

In vitro schedule-dependency of myelotoxicity and cytotoxicity of Ecteinascidin 743 (ET-743)

Background: Ecteinascidin (ET-743) is a marine derived compound with an interesting preclinical profile currently completing phase I clinical trials. The present study was undertaken to compare the toxicity of different schedules of ET-743 against human hemopoietic progenitors and tumour cell lines.Materials and methods: Human hemopoietic progenitors and solid tumour cell lines were incubated with ET-743 for one hour, 24 hours and one hour daily for five consecutive days to define by comparison an in vitro therapeutic index. Additional experiments were set up to assess whether incubation for 24 hours or five days could change either the sensitivity of cells or the activity of ET-743.Results: Prolonged or repeated exposures were more toxic than a single one hour exposure (P < 0.001), but due to the higher sensitivity to prolonged exposure of several tumor cell lines, prolonged treatment yielded a more favorable in vitro therapeutic index. After incubation for 24 hours, ET-743 showed a significantly (P < 0.01) lower inhibiting capacity. Incubation before treatment rendered progenitors more resistant, but incubation after treatment increased their sensitivity, so that overall the toxicity of ET-743 on hemopoietic cells appears to be close to AUC dependency.Conclusions: Despite the possible effect of some experimental artefacts, prolonged exposure could represent the best schedule of administration of ET-743.     

Pharmacokinetics of VP16-213 given by different administration methods

Summary Plasma pharmacokinetics of VP16-213 were investigated after a 30–60 min infusion in 14 adult patients and six children. In adults the elimination half-life (T_1/2 ), plasma clearance (Cl_p) and volume of distribution (Vd) were respectively 7.05±0.67 h, 26.8±2.4 ml/min/m², and 15.7±1.8 l/m²; in children 3.37±0.5 h, 39.34±6.6 ml/min/m², and 9.97±3.7 l/m². After repeated daily doses no accumulation of VP16-213 was found in plasma. The unchanged drug found in the 24 h urine after administration amounted to 20–30% of the dose.In eight choriocarcinoma patients plasma levels of VP16-213 were measured after oral capsules and drinkable ampoules. The bioavailability compared to the i.v. route was variable, mean values being 57% for capsules and 91% for ampoules. In one further patient, with abnormal d-Xylose absorption results, VP16-213 was not detectable in plasma after the oral ampoule dose.Steady state levels investigated in three patients after 72 h continuous VP16-213 infusion (100 mg/m²/24 h) were around 2–5 g/ml. Levels of VP16-213 were undetectable in CSF after i.v. or oral administration.     

Corrigendum

M. Maneo should read A. Maneo. The author's correct affiliationis III Clinica Ostetrico Ginecologica, Università diMilano, Milan, Italy.