Toxicity and effects of adjuvant therapy in colon cancer: results of the german prospective, controlled randomized multicenter trial fogt-1

In this adjuvant three-arm multicenter trial, we studied whether modulating the standard 5-fluorouracil (S-FU) treatment with either folinic acid (FA) or interferon-alpha-2_a (IFN-α) was superior to the recommended standard of adjuvant treatment in RO resected colon cancer, 5-FU plus levamisole (LEV) for 12 months, in terms of toxicity and outcome. From July 1992 to October 1999, a total of 813 patients with resected colon cancer in stage II (T4N0M0; n = 63) or stage III (TxNl-3M0; n = 750) were randomized into three treatment groups and stratified according to N stage and participating centers (64 hospitals). The patients received a postoperative loading dose of S-FU (450 mg/m² on days 1 to 5 [arms A and C]) or S-FU (450 mg/m²) plus FA (Rescuvolin, Medac, Hamburg, Germany, 200 mg/m² on days 1 to 5 [arm BJ). After completion of the first chemotherapy cycle, LEV was administered orally at a dosage of 1.50 mg per day on days 1 to 3, once every 2 weeks. After a 4-week chemotherapy-free interval, the treatment was continued weekly for 52 weeks. Treatment in one arm A ("standard") (n = 279) consisted of 5-FU intravenously (450 mg/m² on day 1, once a week) plus LEV 5-FU plus LEV was modulated in arm B (n = 283) with FA (200 mg/m² on day 1, once a week) and in arm C (n = 251) with IFN-α at 6 million units three times a week repeated weekly. Treatment dosages were adjusted if toxic events above WHO grade 2 occurred. Patients were closely followed to determine recurrence and survival; the latter was calculated according to Kaplan-Meier analysis. Toxic events above WHO grade 2, mainly leukopenia, diarrhea, and nausea, occurred in 113 (14%) of 649 patients who had completed treatment in arms A (8.4%), B (13.5%), and C (31.7%). Discontinuance rates were as follows: 28% for all patients, 29% in arm A, 21% in arm B, and 34% in arm C. Overall relapse rates were 27% for all patients, 30% in arm A, 24% in arm B, and 28% in arm C. Relapses were local (8%) distant (78%), or combined (12%). Fouryear overall survival rates in arms A, B, and C were 66.1%, 77.5%, and 66.2%, respectively. The 4-year survival rate in arm B was significantly higher compared to arm A (P <0.02, log-rank test) with arm A being equal to arm C. Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV for 12 months). IFN-α modulation of 5-FU (plus LEV) adds to the toxicity with no therapeutic benefit.     

Pancreatic injury in severe trauma: early diagnosis and therapy improve the outcome

BACKGROUND: Pancreatic injury is a dangerous complication in multiple injury, and experience with its diagnosis and treatment is usually limited. METHOD: Retrospective analysis of 3,840 patients admitted after multiple trauma from January 1, 1982, until May 31, 2000. RESULTS: A laparotomy was performed in 121 cases (3.15%) due to suspected intra-abdominal lesion. 32% of the patients (39/121) had a pancreatic lesion; 23% (9/39) had a rupture of the major pancreatic duct. Primary laparotomy was performed in 72% of the patients (28/39). Superficial lesions were treated by explorative laparotomy alone (n = 7), debridement and external drainage (n = 20), or necrosectomy and lavage (n = 3). Complex pancreatic lesions were treated by pancreatojejunostomies (n = 5), pancreatic left resections (n = 2), or exploration alone (n = 2). 8 of 39 patients died (20%), 4 intraoperatively. Of the surviving 35 patients, a pancreas-associated complication developed in 8 patients (23%): pancreatic abscesses (n = 4), traumatic pancreatitis (n = 3), pancreatic fistulas (n = 2), and pseudocysts (n = 2). CONCLUSIONS: Pancreatic injury is an infrequent but dangerous complication in severe trauma. Superficial lesions not affecting the major pancreatic duct can be managed by debridement and external drainage. If the major pancreatic duct is ruptured, organ-preserving, complex reconstructive procedures are necessary. When diagnosed timely and treated according to severity and overall situation, pancreatic injuries have an acceptable morbidity, but usually a high mortality.     

Cholecystokinin influences pancreatic trophism following total gastrectomy in rats

In rats, total gastrectomy (TG) has been shown to induce pancreatic hyperplasia and increased tissue concentrations of pancreatic trypsin and amylase, whereas lipase concentration was decreased. We performed total gastrectomy with the additional insertion of a duodenal tube in 17 rats. A central venous catheter was placed after 3 wk. The control groups consisted of sham-operated rats with a gastrotomy plus duodenal tube and a group of rats with only a duodenal tube. The rats received meal stimulation with a 6 mL liquid diet (3 mL oil, 2 mL amino acid solution, and 1 mL glucose) via duodenal tube upon recuperation. Blood samples were taken before as well as 5, 15, 30, and 60 minutes after the meal and analyzed for insulin, pancreatic glucagon, gastrin, and CCK by specific RIA techniques. Glucose tolerance was found to be impaired after total gastrectomy. Though insulin release was delayed compared to the controls, the integrated postprandial output was unchanged.     

Results of anorectal manometry for the determination of age- and sex-dependent pressure differences

Manometric findings in 88 anorectal healthy probands are reported. Basal (PAC) and maximal squeeze (PAC max) pressures in the anal canal as well as rectal pressure at rest (PAR) and the pressure increase in the anal canal after dilatation of the ampulla recti (delta PAC) were registered with a 2 balloon catheter and statistically analysed in the 52 male and 36 female probands, divided in three age groups (group I under 40 years, group II 40-60 years and group III over 60 years). PAC showed for all three groups a statistically significant difference for men and women as well as a statistically significant decrease with age in both sex groups. PAC max, PAR and PAC decreased statistically significantly with age in both sex groups whereas in the three age groups, men and women showed nearly equal values. These age- and sex correlated differences in the anorectal pressure profile must be considered in the evaluation of the continence function.     

Neoadjuvant, adjuvant, and palliative treatment of pancreatic cancer

Pancreatic cancer remains a highly malignant disease. Curative treatment is only possible for patients diagnosed at a very early stage. Therefore, the vast majority of pancreatic cancer patients receive palliative treatment. Surgical palliation is offered to patients who are found not to have a resectable tumor. The treatment of obstructive jaundice is managed by stenting of the common bile duct or by a surgical bypass. The best possible surgical procedure should be based on the factors that influence hospital mortality, length of survival, and quality of life. In patients with a life expectancy of longer than 3 months, surgical bypass is recommended, with hepaticojejunostomy the treatment of choice. In the same surgical procedure, the relief of duodenal obstruction with a gastroenteric bypass should be achieved. Chemotherapy, radiotherapy, or a combination of both is employed as a neoadjuvant measure, as an adjuvant treatment, or, in most patients, as palliation. As palliative chemotherapy alone, 5-fluorouracil (5-FU) plus folinic acid is still the treatment of choice; however, newer drugs, such as gemcitabine, seem to have similar or marginally better results. Palliative radiochemotherapy with external-beam radiation plus 5-FU and folinic acid seems to lead to better local control of tumor progression but not to better survival, for which distant metastases are the limiting factor.     

Duodenumerhaltende totale Pankreaskopfresektion

Cystic neoplasms of the pancreas are being detected and surgically treated increasingly more frequently. Intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) are primary benign lesions; however, the 5-year risk for malignant transformation has been estimated to be 63 % and 15 %, respectively. Surgical extirpation of a benign cystic tumor of the pancreas is a cancer preventive measure. The duodenum-preserving total pancreatic head resection technique (DPPHRt) is being used more frequently for cystic neoplasms of the pancreatic head. The complete resection of the pancreatic head can be applied as a duodenum-preserving technique or with segmental resection of the peripapillary duodenum. Borderline lesions, carcinoma in situ or T1N0 cancer of the papilla and the peripapillary common bile duct are also considered to be indications for segmental resection of the peripapillary duodenum. A literature search for cystic neoplastic lesions and DPPHRt revealed the most frequent indications to be IPMN, MCN and SCA lesions and 28 % suffered from a cystic neoplasm with carcinoma in situ or a peripapillary malignoma. The hospital mortality rate was 0.52 %. Compared to the Whipple type resection the DPPHRt exhibits significant benefits with respect to a low risk for early postoperative complications and a low hospital mortality rate of <?1 %. Exocrine and endocrine pancreatic functions after DPPHR are not impaired compared to the Whipple type resection.     

Pancreatic trophism after truncal vagotomy in rats

Thirty-two rats had truncal vagotomy either with or without pyloroplasty. After 2 or 4 weeks, respectively, the pancreas was excised and weighed. Measurements of amylase, trypsin, lipase, total protein, and DNA were obtained from the homogenated pancreatic tissue. Isolated pancreatic lobules were incubated with and without ceruletide (5 X 10(-10) g/ml) during a 60 minute period. Amylase values were determined four times in the incubation medium. Morphometry was performed by light microscopy analysis. There was a significant increase in pancreatic weight, DNA content, and trypsin concentration 2 weeks after vagotomy with and without pyloroplasty. These changes were accelerated after 4 weeks. DNA, amylase, and total protein concentrations were unchanged. Lipase concentration decreased 2 weeks after vagotomy and pyloroplasty, whereas at 4 weeks, it decreased in both experimental groups. The in vitro incubation study revealed a significantly decreased amylase discharge under basal conditions, whereas the stimulated amylase discharge was unchanged in both experimental groups compared with the control group. Morphometry did not detect differences in exocrine cellular size. We conclude that vagotomy in rats induces pancreatic hyperplasia, enzyme dissociation, and decreased basal amylase discharge in vitro.     

EFFICACY OF RAMIPRIL VERSUS ENALAPRIL IN PATIENTS WITH MILD TO MODERATE ESSENTIAL HYPERTENSION

SUMMARY This double-blind, randomised, cross-over study investigated the antihypertensive efficacy of ramipril and enalapril was completed by 30 patients with mild-to-moderate essential hypertension. After a four-week placebo run-in phase, the patients received either 2.5mg ramipril or 10mg enalapril once daily for four weeks. The dosages were increased to 5mg ramipril and 20mg enalapril for a further four weeks. After a placebo washout phase of four weeks, the patients were crossed over to the alternative treatment. The decrease in average 24-hour ambulatory diastolic blood pressure from week 0 to week 8 was 1.6mmHg greater with ramipril than enalapril (90% confidence interval 0.6-2.7mmHg). The corresponding reduction in for systolic blood pressure was also greater with ramipril than enalapril by 2.4mmHg (90% confidence interval: 0.5-4.2mmHg). For the difference in the drop of 24-hour ambulatory diastolic blood pressure between ramipril and enalapril the lower level of the 90% confidence interval (CI) is above the clinically relevant difference of -3mmHg. This is an indication that ramipril (2.5 and 5mg dose) is at least as effective as enalapril (10 and 20mg dose) in decreasing blood pressure in patients with mild-to-moderate essential hypertension. The duration of adequate antihypertensive effect was relatively long for both ramipril and enalapril; however, ramipril tended to have a more prolonged antihypertensive effect. Ramipril had a higher diastolic and systolic trough/peak ratio than enalapril, resulting in a more uniform antihypertensive effect over the 24-hour treatment period. Both ramipril and enalapril were well tolerated and the two treatment groups had similar safety profiles.     

Pre-B cells and other possible precursor lymphoid cell lines derived from patients with X-linked agammaglobulinemia

A group of unique Epstein-Barr virus-containing cell lines was derived from the bone marrow of three patients with X-linked agammaglobulinemia. Efforts to obtain cell lines from the peripheral blood of these patients were uniformly unsuccessful. Immunofluorescence analyses as well as biosynthetic studies with [(35)S]methionine indicated unusual patterns of Ig synthesis in many of these bone marrow derived lines. Seven of the lines were of particular interest in that two produced no Ig of any type; two others showed no Ig by fluorescence but small amounts by [(35)S]methionine labeling; one expressed only cytoplasmic μ chains without any evidence of light chain synthesis, and two produced primarily μ chains with only slight amounts of light chains. One of the lines without membrane or cytoplasmic Ig studied in detail grew like a typical lymphoid line and was carried in intermittent culture over a period of 2 yr without Ig expression. One line grew quite differently and resembled the round cell type described previously, which has been obtained from a variety of sources. The cell line with cytoplasmic μ chains and no light-chain expression had the characteristic properties of pre-B cells. Three normal type Ig-producing cell lines also were obtained from the patients. The accumulated evidence obtained in the present study indicates that these unusual cell lines represent normal precursor cells of the B-cell lineage; these grew out in these cases because of the virtual absence of mature B cells that ordinarily overgrow the culture system. However, the possibility that in certain instances they reflect abnormal Ig synthesis characteristic of the disease has not been ruled out.