[Multicenter phase II study of the Liver Metastases Study Group of weekly intra-arterial 24-hour high dose therapy with 5-FU and folinic acid (FA) in liver metastases of colorectal tumors]. / Multizentrische Phase II--Studie der Arbeitsgruppe Lebermetastasen zur wöchentlichen intraarteriellen 24 h Hochdosistherapie mit 5-FU und Folinsäure (FA) bei Lebermetastasen kolorektaler Tumoren.

This prospective multicenter trial was performed to determine the response rate, toxicity and applicability of continuous 24 h hepatic arterial infusion of high-dose 5-FU and folinic acid. An improved response rate (60.5% in non-pretreated patients) was however associated with many systemic side-effects (340/509), mainly nausea and diarrhea. Therefore this treatment should be applied only in selected patients in specialized centers.

[Intra-arterial (5-FU/FA and FUDR) versus systemic chemotherapy (5-FU/FA) of non-resectable colorectal liver metastases]. / Intraarterielle (5-FU/FA bzw. FUDR) versus systemische Chemotherapie (5-FU/FA) nicht-resektabler kolorektaler Lebermetastasen.

The relative efficacy of HAI FUDR, HAI 5-FU/FA, and i.v. 5-FU/FA chemotherapy for the treatment of unresectable colorectal liver metastases was compared in a prospective randomized clinical trial. The response rate after HAI treatment was significantly higher as compared to i.v. treatment with no statistical benefit regarding survival and time to progression. HAI FUDR treatment was inferior as compared to HAI or i.v. 5-FU/FA. i.v. 5-FU/FA-therapy is therefore the method of choice outside clinical trials.

[Therapy of esophageal carcinoma--surgical procedures]. / Therapie des Osophaguskarzinoms--operative Verfahren.

Transthoracic and transmediastinal resection without thoracotomy are the two possible surgical procedures for treatment of esophageal carcinoma. The transmediastinal procedure lends itself particularly for carcinomas in the distal part of the esophagus. The indication for operation is based on an exact preoperative tumor-staging. Primary surgery is only indicated, when R0-resection seems possible. Otherwise multimodal therapeutic concepts and palliating treatment should be preferred. The extent of lymphadenectomy, standard-lymphadenectomy, two-field- or three-field-lymphadenectomy are currently disputed. Extensive lymphadenectomy seems to yield significantly better prognosis in early esophageal carcinoma. The importance of multimodal therapeutic concepts is not yet sufficiently defined. Further studies are needed.

Characteristics and health service utilization patterns of ventilator-dependent patients cared for within a vertically integrated health system.

OBJECTIVE: To describe the characteristics and service utilization patterns of long-term ventilator-dependent patients. DESIGN: Using medical records, a cohort of ventilator-dependent patients was identified and followed. SETTING: A vertically integrated healthcare system in southwestern Pennsylvania. PATIENTS: Forty-nine adults requiring prolonged ventilatory assistance. MEASURES: Demographics, admission date, admission diagnosis, discharge diagnosis, reason for ventilator dependency, level of care to which the patient was admitted, dates of all transfer orders, dates of all transfers between levels of care, discharge destination and subsequent readmissions. RESULTS: The major reason for long-term ventilator dependency was progressive debilitating disease of either a pulmonary or nonpulmonary nature. The mean length of stay within the system was 72.6 days +/- 42.55 (median = 59 days, range = 24 to 267 days). Patients had an average of 3.3 transfers +/- 2.53 within the system (median = 3, range = 0 to 10). No delays in transfer to lower levels of care were found. Health utilization variables were largely unrelated to reason for ventilator dependency. Almost half of the patients (n = 24 or 49.0%) died in the system. Patients who died in the system were significantly older than patients for whom discharge home was possible. CONCLUSIONS: Additional studies are necessary to describe the prevalence, etiology, health status and functional status of ventilator patients at all levels of care; the impact of different system approaches on patient well-being and cost of care; and the process of medical decision making. Economic analyses of costs and outcomes for ventilator-dependent patients using a cost-utility approach are also needed.

alpha-Naphthyl butyrate carboxylesterase activity in human and rat nasal tissue.

Carboxylesterase activity in the rat nasal mucosa plays an important role in the response of this tissue to certain toxic inhaled esters. We have examined this activity in extracts of both Fischer-344 rat and human nasal tissue using the substrate alpha-naphthyl butyrate, the same substrate as that used for histochemical analysis of this activity. We find substantially higher activity in rat nasal extracts than in human nasal extracts. The Michaelis constant (Km), however, is approximately the same for both activities and is significantly less than that reported for rat nasal carboxylesterase activity using dibasic esters as a substrate. p-Nitrophenyl butyrate is a competitive inhibitor of the rat alpha-naphthyl butyrate esterase, but surprisingly has no effect on the human activity. The assay reported here should prove a powerful tool in the development of a valid in vitro nasal toxicity assay system that uses cultured rat or human cells expressing carboxylesterase activity.

Duramycin enhances chloride secretion in airway epithelium.

The effect of duramycin, a polypeptide antibiotic, on Cl- transport in canine tracheal epithelium mounted in Ussing chambers was studied. Over a narrow concentration range, duramycin increased short-circuit current (Isc) and net Cl- secretion and had no effect on mannitol flux when added to the mucosal bathing solution. The maximum increase in Isc was observed at a duramycin concentration of 2 X 10(-6) M and was associated with an increase in both unidirectional Cl- fluxes. Higher duramycin concentrations produced a decrease in Isc. Submucosal addition of duramycin had no effect on Isc except at high concentrations. Pretreatment of tissues with mucosal amiloride (10(-4) M) to reduce basal Na+ transport had no effect on the subsequent response to duamycin. In other tissues pretreated with 10(-3) M dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP), duramycin produced a further increase in Isc and net Cl- secretion similar to its effect in nonpretreated tissues. In all instances the increase in Isc was entirely accounted for by an increase in net Cl- secretion. We conclude that duramycin increases Isc and Cl- secretion in airway epithelium. Although the mechanism of activation is not known, these data demonstrate that duramycin increases Cl- secretion by a pathway other than cAMP. An understanding of the mechanism of action of duramycin may further our understanding of Cl- secretion regulation in airway epithelium.

Altered chloride metabolism in cultured cystic fibrosis skin fibroblasts.

An abnormal regulation of chloride permeability has been described for epithelial cells from patients with cystic fibrosis (CF). To learn more about the biochemical basis of this inherited disease, we have studied chloride metabolism in cultured CF fibroblasts by comparing the efflux of 36Cl- from matched pairs of CF and normal fibroblasts. The rate constants describing 36Cl- efflux did not differ between the two cell types, but in each of the four pairs tested the amount of 36Cl- contained within CF cells was consistently reduced, by 25-30%, relative to normal cells. Comparisons of cell water content and 22Na+ efflux showed no differences between the two cell types, suggesting that overall intracellular chloride concentration is lower than normal in CF fibroblasts. Such data suggest that the CF gene defect is expressed in skin fibroblasts and that this defect may alter the regulation of intracellular Cl- concentration, perhaps through changes in Cl- permeability.

Human hypoxanthine-guanine phosphoribosyltransferase. Demonstration of structural variants in lymphoblastoid cells derived from patients with a deficiency of the enzyme.

We have explored the possibility of using cultured lymphoblasts from patients with a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a source of cells for the isolation and characterization of mutant forms of the enzyme. HPRT from lymphoblasts derived from six male patients of five unrelated HPRT-deficient families was highly purified and characterized with regard to: (a) level of immunoreactive protein, (b) absolute specific activity, (c) isoelectric point, (d) migration during nondenaturing polyacrylamide gel electrophoresis, and (e) apparent subunit molecular weight. There experiments were performed on small quantities of lymphoblasts using several micromethods involving protein blot analysis of crude extracts as well as isolation and characterization of enzyme labeled in culture with radioactive amino acids. The lymphoblast enzymes from four of the patients exhibited structural and functional abnormalities that were similar to the recently described abnormalities found with the highly purified erythrocyte enzymes from these same patients. In addition, a previously undescribed HPRT variant was isolated and characterized from lymphoblasts derived from two male siblings. This unique variant has been called HPRT Ann Arbor. We conclude that lymphoblastoid cell lines can be used as a source of cells for the detection, isolation, and characterization of structural variants of human HPRT.

Regulation of amino acid transport system L in Chinese hamster ovary cells.

The regulation of the activity of transport System L for neutral amino acids has been investigated in Chinese hamster ovary cells. Incubation of the temperature-sensitive leucyl-tRNA synthetase mutant CHO-tsH1 at marginally permissive temperatures results in leucine-limited growth and increased transport of branched chain and aromatic amino acids. This temperature-dependent transport enhancement is restricted to transport System L and results in increased Vmax values of uptake of System L substrates with unchanged Km values of uptake. Several lines of evidence suggest that trans-stimulation by intracellular amino acids cannot account for the increased System L activity in CHO-tsH1. Other temperature-sensitive aminoacyl-tRNA synthetase mutants of the Chinese hamster ovary line show increased transport of the amino acid corresponding to the synthetase defect after incubation at elevated temperatures. Increased transport by System L occurs in CHO-S, the parental line of CHO-tsH1, after growth in limiting levels of leucine. The System L enhancement can be prevented by cycloheximide but not, at early times, by actinomycin D. We conclude that the activity of transport System L in Chinese hamster ovary cells is regulated by a mechanism which appears to act at the level of translation.

[Modified cardiomyotomy using Rapant's method - guaranteed prevention of esophageal reflux in the operative therapy of achalasia?]. / Die modifizierte Kardiomyotomie nach Rapant - eine sichere Refluxprophylaxe in der operativen Therapie der Achalasie?

13 patients of 23 who had been treated for achalasia by a modified esophagomyotomy were reexamined by objective assessment of esophageal function with special regard to the problems mentioned above. Pull-through-manometry displayed a decrease of resting tonicity from 37 to 8 mm Hg. In the reflux-provocation-test all patients had a normal test result. In endoscopy normal histological findings raised 70% preoperatively to 83% postoperatively. The esophageal diameter was reduced in 11 of 13 patients. No patient had symptoms to suggest the presence of reflux and relapse.

Gastro-oesophageal reflux: an aetiological factor for bleeding in oesophageal varices?

The precipitating factor in bleeding oesophageal varices is unknown. To investigate this problem 10 patients who had bled from oesophageal varices were examined by manometry, pH monitoring and gastroscopy to determine whether gastro-oesophageal reflux occurred. No evidence for reflux was found. These results, together with previously published reports, cast doubt on peptic oesophagitis or reflux as an aetiological factor in the initiation of oesophageal variceal bleeding.

[Stress-ulcer prevention with pirenzepine-a controlled study]. / Stressulkus-Prophylaxe mit Pirenzepin-eine kontrollierte Studie.

In polytraumatised or septic patients without adequate medical prophylaxis the incidence-rate of postoperative complications is very high. The incidence-rate of acute mucosal stress lesions is to be expected 100 per cent. The parenteral application of pirenzepine shows in comparison to placebo a clear protective effect measured as incidence-rate of stress lesion (p greater than 0,05) and occurrence of bleeding (p greater than 0,01).

[Jaundice-dependent hepatic failure and stress ulcer - an animal experiment]. / Verschlussbikterus und Stressulcus--eine tierexperimentelle Untersuchung.

Experimental studies confirm the clinical results of a correlation between jaundice-dependent hepatic failure and an incidence of stress ulcers: stress ulcers appeared much more frequently in stress-exposed rats with ligation of the choledochus and in animals with operative restitution of the bile flow after ligation of the choledochus than they appeared in controls.