Substantial activity of budesonide in patients with irinotecan (CPT-11) and 5-fluorouracil induced diarrhea and failure of loperamide treatment.

BACKGROUND: Diarrhea is one of the most disturbing effects of chemotherapy, affecting quality of life on the one hand and limiting applicable doses on the other. Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are associated with an elevated risk of developing severe diarrhea. Standard therapy consists of high-dose loperamide, but is associated with frequent failure. Other therapeutic regimens are still experimental. Endoscopic examination of a patient with severe loperamide-resistant diarrhea after CPT-11 chemotherapy revealed an inflammation of the ileo-coecal region. Oral therapy with the topical corticosteroid budesonide was immediately effective. This led to a phase I study of budesonide in CPT-11- and 5-FU-induced and loperamide-refractory diarrhea. PATIENTS AND METHODS: Fourteen patients with CPT-11- and seven patients with 5-FU-induced grade 3-4 (NCI/WHO) diarrhea and loperamide failure were enrolled in this study. All patients had metastatic colorectal cancer. RESULTS: In 86% of the CPT-11- and 57% of the 5-FU-treated patients with grade 3-4 diarrhea and loperamide failure, treatment with budesonide resulted in a reduction of diarrhea severity by at least two grades. CONCLUSIONS: The orally administered topical active steroid budesonide is highly effective in the therapy of loperamide-refractory chemotherapy (CPT-11 or 5-FU)-induced diarrhea.

Schedule- and dose-intensified paclitaxel as weekly 1-hour infusion in pretreated solid tumors: results of a phase I/II trial.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been studied primarily on a 3-week schedule as a 3-, 24-, or 96-hour infusion at doses ranging from 135 to 250 mg/m2. The observed toxicity profile seems to be both dose and schedule dependent. Dose densification of paclitaxel given weekly over 6 weeks on a split-dose schedule for an overall increase in dose intensity was thought to improve the therapeutic index of paclitaxel in a variety of advanced malignancies and to be suitable for outpatient administration. For this study, chemotherapy consisted of a weekly 1-hour infusion of paclitaxel at a starting dose of 40 mg/m2/wk for 6 weeks, followed by a 2- to 3-week interval. Paclitaxel dosage was escalated in 10 mg/m2/wk increments in subsequent patients, to a maximum dosage of 90 mg/m2/wk. Intravenous dexamethasone, cimetidine, clemastine, and ondansetron were administered immediately before the paclitaxel infusion. Fifty patients participated in the study. The male to female ratio was 21 to 29, the median age was 53.2 years (age range, 33 to 74), and the median performance status was 1. All patients were chemotherapeutically pretreated. Overall response included five complete responses (10%), 15 partial responses (30%), 19 no change (38%), and 11 disease progressions (22%). Median dose intensity was 410 mg/m2/6 wk (range, 200 to 540 mg/m2/6 wk). Hematologic toxicity was mild, with no grade 3 or 4 toxicity up to 90 mg/m2/wk. No hypersensitivity reactions or neurologic or cardiac toxicities were documented. Dose-densified, weekly paclitaxel is concluded to be active in a variety of pretreated tumor entities. The overall low hematologic and peripheral toxicity profile suggests that further dose intensification of weekly paclitaxel and/or combination with other cytotoxic agents (eg, cisplatin/carboplatin, ifosfamide, etoposide) may be warranted. Paclitaxel can be given safely in the outpatient setting. Paclitaxel 90 mg/m2/wk is recommended for single-agent treatment. Dose-densified paclitaxel may be considered a valuable and promising alternative to standard 3-week treatment, with further options possible in combination chemotherapy.

[Acute intrahepatic bleeding in a male patient with focal nodular hyperplasia]. / Akute intrahepatische Blutung bei einem männlichen Patienten mit fokalnodulärer Hyperplasie.

HISTORY AND CLINICAL FINDINGS: A 45-year-old man had acute bouts of pain in the right lower thorax with radiation to the mid-thorax and upper abdomen. For 3 years he was known to have coronary heart disease, for 4 years arterial hypertension and for 8 months, as an accidentally discovered finding, a liver cyst 2.5 cm in diameter, as well as an inhomogeneous focal lesion, demonstrable only by sonography, lying dorsally and close to the diaphragm in the right lobe of the liver, 3.0 x 3.5 cm which was not detected by computed tomography or magnetic resonance imaging. Physical examination at admission detected epigastric pain on pressure but no other abnormalities. INVESTIGATIONS: Sonography showed the inhomogeneous hepatic lesion now to be 6.0 x 7.5 cm. Computed tomography demonstrated a space-occupying mass, 7.5 cm in diameter, dorsal to the hepatic cyst, partly hypo-, partly hyper-dense with marginal spotty enhancement after contrast-medium injection. TREATMENT AND COURSE: As acute bleeding into the focal hepatic lesion was suspected, a laparotomy was performed and liver segments VII and VIII resected. On inspection there was a sharply demarcated yellowish-white tumor with a central haemorrhagic softening. Histology revealed focal nodular hyperplasia (FNH) without signs of malignancy. CONCLUSION: In the case of a known but not definitively diagnosed focal hepatic lesion, acute upper abdominal pain can be a sign of acute bleeding into the lesion.

High-dose infusional 5-fluorouracil combination therapy of metastatic gastric and colorectal cancer.

To improve the therapeutic ratio of palliative chemotherapy in patients with metastatic colorectal and gastric cancer 5-fluorouracil (5-FU) was administered as weekly high-dose 24-hour continuous infusion in combination with leucovorin (LV) and interferon-alpha-2b (IFN) as biomodulating agents: Chemotherapy consisted of a weekly schedule of 500 mg/m2 leucovorin as a 2-hour infusion, followed by a 24-hour continuous infusion of 2500 mg/m2 5-FU. IFN was administered subcutaneously at a dose of 3 mio I.E. three times a week. In patients with gastric carcinoma, etoposide (VP) 100 mg/m2 as 30-minute bolus infusion was added. Eighty-five patients (colorectal: 55 points, gastric: 30 points) are evaluable for response, toxicity, and survival analysis. Colorectal: CP+PR: 19/55 (34.5%), NC: 25/55 (45.5%), PD: 11/55 (20.0%). Median duration of remission in months (90% confidence interval): 5.2 (3.1 to 9.2), median survival since the start of salvage chemotherapy: 13.9 months (12.3 to 20.1), from initial diagnosis of metastasis: 30.2 months (26.3 to 44.5). Gastric: CR: 8/30 (26.7%), PR: 14/30 (46.6), NC: 5/30 (16.7), PD: 3/30 (10.0%). Median duration of remission in months (90% confidence interval): 6.75 (1.5 to 16.2), median survival since start of chemotherapy: 15.1 months (90% confidence interval 11.8 to 20.3 months). Hematologic toxicity: hemoglobin: I: 20.0%, II: 10.0%, leukocytes: I: 13.3%, II: 33.3%, III: 16.6%, platelets: I: 10.0% and III: 3.3%. Hematologic toxicity was moderate to negligible, peripheral toxicity consisted mainly of tolerable stomatitis and diarrhea. Dose and schedule intensified weekly 5-FU combination therapy in metastatic colorectal and gastric cancer is highly active in terms of response and median survival time. Chemotherapy pretreated patients with colorectal cancer seem to have a substantial survival benefit with this salvage protocol.

[Results of preoperative radio-chemotherapy in locally advanced squamous epithelial cancer of the esophagus]. / Ergebnisse der präoperativen Radio-Chemotherapie beim lokal fortgeschrittenen Plattenepithelcarcinom des Oesophagus.

In a 4-year period (1988-1991) 122 patients with a squamous cell carcinoma of the esophagus were studied prospectively and analysed. 64 patients of them could be primary resected (primary resectability rate 52%), 36 patients were in general inoperable and 22 patients had an advanced stage of cancer with local inoperability. Due to a preoperative combined radiotherapy and chemotherapy 16 of the 22 patients with local inoperability had a clinical remission of the tumor (73%). 11 patients (50%) showed a histological verified down staging and 3 cases of them a complete remission (no primary tumor was found, no infiltration of the regional lymphnodes and no metastatic disease). Curative resection was possible in 14 of 16 patients with clinical remission (2 patients refused surgical treatment). So the resectability rate now increases from 52 to 63%. We conclude that there was no increased rate of postoperative complications or mortality in the combined radio-/chemotherapy group compared with the primary resected patients.

[Fluorouracil as monotherapy or combined with folinic acid in the treatment of metastasizing colorectal carcinoma]. / Fluorouracil als Monotherapie oder in Kombination mit Folinsäure in der Behandlung des metastasierten kolorektalen Karzinoms.

In a prospective randomized multicentre trial 139 patients with metastatic colorectal carcinoma (70 men, 69 women; age 35-81 years) were given palliative treatment with fluorouracil (400 mg/m2 daily for 5 days) alone or combined with folic acid (100 mg/m2 before each dose of fluorouracil). Both groups were comparable in respect of age, sex, Karnofsky index and number of localisations of metastases. The criterion for starting the treatment was progression of the malignancy or clinical symptoms caused by the tumour. Resulting remission rates (fluorouracil monotherapy vs combination with folic acid) were: complete or partial remission, 9 vs 16%; arrest of tumour growth, 20 vs 60%; progression 71 vs 24%. Peripheral side effects, such as stomatitis and diarrhoea, were similarly frequent with the two treatment regimens and reasonably tolerable. Median survival time for the fluorouracil monotherapy was 7.24 months from onset of treatment, and 9.1 months from the time that any metastases were diagnosed. The combination treatment with folic acid achieved a significantly longer median survival time (P less than 0.0001), 14.98 months from treatment onset and 16.3 months from metastasis diagnosis. The higher rate of response and the significantly prolonged survival time signify an improvement of the therapeutic profile of fluorouracil by addition of folic acid in the palliative therapy of colorectal carcinomas.

Ambulatory high-dose 5-day continuous-infusion ifosfamide combination chemotherapy in advanced solid tumors: a feasibility study.

The oxazaphosphorine analog ifosfamide (IFO) has demonstrated an increased therapeutic index in a variety of solid tumors and hematologic malignancies compared with its parent compound cyclophosphamide. A fractionated dose schedule over 5 days as continuous infusion in combination with the uroprotective agent sodium-2-mercapto-ethane-sulfonate (mesna) is considered to provide an improved therapeutic/toxic ratio. Stability data of IFO demonstrate long-term stability for use in disposable infusion pumps as outpatient treatment. In all, 52 patients with various malignancies were entered in a feasibility study to receive outpatient continuous infusion of IFO. All patients were required to have a subcutaneous venous port system implanted. The following drug combinations were used: IFO as single agent, IFO/mitoxantrone, IFO/carboplatinum/etoposide, IFO/etoposide/MTX, IFO/epirubicin. Mitoxantrone and epirubicin were given as continuous infusion together with IFO. Starting dose of IFO was between 1.6-2.0 g/m2/day x 5 and was increased in absence of major hematologic or peripheral toxicity. Mesna was given in combination with IFO as continuous infusion at a dose of 50% of that calculated for IFO. No renal, bladder or central nervous system toxicity was observed. In 247 courses of outpatient continuous ifosfamide infusion only few technical complications due to improper handling were documented.

Chemotherapy of advanced and relapsed squamous cell cancer of the head and neck with split-dose cisplatinum (DDP), 5-fluorouracil (Fura) and leucovorin (CF).

58 patients with locally advanced or relapsed squamous cell head and neck cancer were treated on 5 consecutive days with DDP 20 mg/m2/d IV-push, followed by CF 100 mg/m2/d IV-bolus and Fura 400 mg/m2/d IV-push 60 minutes later. Treatment was recycled on day 22(-29), according to toxicity. CF was added to the widely used DDP/Fura combination, because recent studies showed enhancement of Fura-activity by CF. 45/58 patients had no prior therapy and 13/58 pts were relapsed after chemotherapy and/or radiation therapy. All patients were evaluable for toxicity and response. After 3 courses of induction chemotherapy 23/45 pts in the previously untreated group had a complete response (CR); 20/45 a partial response (PR), 2/45 were restaged as no change (CR + PR: 95%). Induction chemotherapy was followed by radical surgery and postoperative radiation therapy. In the pretreated group 4/13 pts had a complete response; 6/13 a partial response; no change in 3/13 pts. Median duration of remission (MDR) has not been reached in the primarily untreated group, whereas in pretreated patients the MDR was 3.8 months (range 2.3 - 11.7 months). Hematologic and gastrointestinal toxicity was substantial but manageable and therapy was performed on an outpatient basis. The combination of DDP, CF and Fura has high activity in untreated and pretreated head and neck cancer patients. The obtained results are comparable to the widely used DDP/Fura continuous infusion regimen.

[Primary adenocarcinoma of the duodenum. Clinical picture and radiological findings]. / Primäres Adenokarzinom des Duodenums. Klinik und radiologische Befunde.

The clinical and radiological features of primary adenocarcinoma of the duodenum are demonstrated by seven histologically confirmed cases. Clinically, obstruction develops following a prolonged uncharacteristic prodromal stage. The radiological findings resemble those of a carcinoma in any other part of the gastro-intestinal tract: polypoid filling defects, ulcers, mural thickening and loss of elasticity. The radiological method of choice is hypotonic duodenography. Sonography and CT are complimentary methods and are of use in postoperative follow-up.

[Whipple's disease with severe gastrointestinal hemorrhage]. / Morbus Whipple mit schwerer Gastrointestinalblutung.

A case report is given of a 54 year old male patient, who had acute, relapsing, life threatening episodes of gastro-intestinal bleeding caused by hemorrhagic gastroduodenitis associated with Whipple's disease. The diagnosis was established by histological examination of duodenum biopsies, which contained the pathognomonic PAS-positive macrophages. The gastroduodenitis healed after treatment with tetracyclines und bleeding stopped consequently. Clinical, pathological, radiological and clinical chemistry findings of patients with Whipple's disease are discussed on the basis of literature.

[Treatment of duodenal ulcer with synthetic depot secretin - a double-blind study]. / Die Behandlung des Ulcus duodeni mit synthetischem Depot-Sekretin - eine Doppelblindstudie.

63 inpatients with duodenal ulcer disease were treated with either depot-secretin or placebo. Two different secretin-regimens were used. In group I 18 patients were given secretin twice daily. 11 ulcers from a total of 19 ulcers healed within 3 weeks. In group II 23 patients were given secretin once daily. 21 out of 28 ulcers healed within 3 weeks. In the placebo-treated group 24 ulcers were observed in 22 patients. Of these 15 healed within 3 weeks. There was no statistical difference in the healing rate between the 3 groups. However, depot-secretin significantly improved typical symptoms. Analgetics were used less frequently. Serious side effects did not occur.

[Clinical relevance of the "cockade phenomenon" in abdominal ultrasonic diagnosis]. / Zur klinischen Relevanz des "Kokardenphänomens" in der abdominellen Ultraschalldiagnostik.

The ultrasonic diagnosis "cockade sign" in patients with unexplained abdominal complaints was investigated by means of endoscopy and X-ray studies of the gastrointestinal tract. The following final diagnoses were established: gastric cancer in 24 patients (16,2%), colonic carcinoma in 31 patients (21%), intraabdominal tumor without infiltration of the GI-tract in 19 patients (12,8%), inflammatory bowel disease in 35 patients (23,6%). In 39 patients (26,4%) no inflammatory or neoplastic process of the GI-tract could be found. Most of these patients were suffering of a spastic colon. If a tumor of the gastrointestinal tract can be made visible by ultrasonography, this may shorten the diagnostic procedure. However, ultrasonic investigation of the abdomen cannot exclude an abdominal inflammatory or neoplastic process. Therefore, it is only useful as a screening procedure.

[Comparative treatment of gastroduodenal haemorrhage with secretin and cimetidine]. / Vergleichende Behandlung gastroduodenaler Blutungen mit Sekretin und Cimetidin. Eine multizentrische Studie.

In a prospective multicenter study 71 patients with acute, non-arterial gastroduodenal haemorrhage from ulcers or stress lesions were treated alternately with synthetic secretin (Hoe 0690 (n = 35) or with cimetidine (n = 36). Both medications were given by infusion over 48 hours. Prior to commencement of treatment the haemorrhage was verified gastroscopically. During infusion of secretin cessation of hemorrhage was achieved without recurrence in 30 out of the 35 patients within the 48-hour infusion time and in 3 patients with recurrence within the same period. Two patients failed to obtain discontinuation of haemorrhage within the infusion period. Cimetidine led to cessation of haemorrhage without recurrence within 48 hours in 20 out of 3 patients, 3 patients had recurrences. Haemorrhages could not be arrested in 13 patients within the two-day treatment period. Differences between success of treatment among the two groups are significant (P less than 0.01) favouring secretin.

[Acid secretion and gastrin release following stimulation with intragastric instillation of a peptone solution in healthy probands and patients with duodenal ulcer]. / Säuresekretion und Gastrinfreisetzung nach Stimulation durch intragastrische Instillation einer Peptonelösung bei gesunden Probanden und Patienten mit Ulcus duodeni.

In 19 DU-patients and in 15 control subjects acid secretion tests were performed by continuous aspiration or by intragastric titration. Pentagastrin (6 micrograms/kg subcutaneously) or a 20% peptone solution (intragastric instillation) were used for stimulation. In 10 control subjects pentagastrin stimulated acid secretion was within the normal range, hypersecretion (greater than 32 mmol/h) was found in the other 5. 14 DU-patients showed hypersecretion, 5 had normal acid secretion. In contrast to these findings intragastric peptone stimulation caused a very uniform acid secretion within each group. Based on these results ulcer patients and healthy controls could be discriminated more exactly. Acid secretion and serum gastrin concentration were significantly higher in DU patients than in controls. There was a significant correlation between maximal gastrin concentrations and peak acid output after peptone stimulation.

[Sonographic diagnosis in cholestasis (author's transl)]. / Ultraschalldiagnostik bei Cholestase. Ergebnisse einer prospektiven Studie.

In a prospective study, sonographic diagnosis was compared in 156 patients having jaundice or showing clinico-chemical signs of cholestasis, with the final diagnosis obtained via endoscopic-retrograde cholangiography, percutaneous transhepatic cholangiography, surgery or autopsy. The results show that in almost 90 per cent of the cases it is possible to differentiate between intrahepatic and extrahepatic cholestasis via sonography. The limitations of sonography concern the identification of prepapillary bile duct concrements which were present in 30 per cent of the patients. Hence, in most cases it was not possible to supply aetiological pointers towards determining the cause of the bile flow disturbance.

[A case each of complete duplication of the stomach and of the duodenum (author's transl)]. / Je ein Fall von vollständiger Duplikatur des Magens und des Duodenums.

Previous reports of the very rare observations concerning complete duplication of the stomach and of the duodenum are reviewed and such a case is described. Radiological examination and gastroscopy showed complete duplication of the stomach, the abnormal organ being situated dorsal to the normal stomach and communicating with it at three separate points--fornix, body and antrum, and also through a duodenal diverticulum. In addition the authors describe complete duplication of the bulb and descending part of the duodenum, connecting through a duodenal diverticulum. The pathogenesis of these duplications and their relationship to duodenal diverticula is discussed.

Inhibition of parietal cell function by human gammaglobulin containing gastric parietal cell antibodies.

Parietal cell antibodies (PCA) are found in up to 90% of sera from pernicious anaemia patients but it is often stated that they could represent an epiphenomenon without being directly responsible for the achlorhydria. In the present studies a direct effect of these antibodies on the secretory function of gastric acid-secreting cells has been demonstrated in two different experimental systems. In one set of experiments IgGs containing PCA activity were shown to inhibit acid secretion specifically in the living gastric mucosa of the bull frog suspended as a diaphragm between two chambers. The other system demonstrated their inhibition of carbonic anhydrase activity in a cytochemical bioassay for human G17-gastrin, suggesting a blocking effect on the gastrin receptors in the canalicular microvilli or the cell membrane. These experiments suggest a direct pathogenic role for PCA in autoimmune fundal gastritis and in pernicious anaemia.