Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

Pyridinium cross-links in multiple myeloma: correlation with clinical parameters and use for monitoring of intravenous clodronate therapy--a pilot study of the German Myeloma Treatment Group (GMTG).

The relevance of quantitative determinations of urinary deoxypyridinolines (DPY) and pyridinolines (PY), and of serum type I collagen carboxyterminal cross-linked telopeptides (ICTP), has been evaluated for patient monitoring in multiple myeloma (MM). In 178 untreated MM patients, a clear correlation was found between ICTP concentrations, bone destructions and serum calcium levels. Furthermore, serum ICTP, urinary DPY and PY concentrations were estimated before and during treatment in a further 33 MM patients randomly allocated to four groups receiving intravenous melphalan/prednisone (MivP) chemotherapy alone, or MivP in combination with three different doses of i.v. clodronate. 1800 mg of i.v. clodronate combined monthly with MivP induced a rapid and sustained reduction in bone resorption parameters to the normal range, a result not obtained with either MivP alone, or with a lower clodronate dose. While confirming the relevance of determining pyridinium cross-links for estimating bone resorption in MM, our data indicate that measurements of these parameters could be useful for dose finding and monitoring of bisphosphonate therapy.

[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.

Treatment of refractory acute lymphoblastic leukemia in adults with high dose cytosine arabinoside and mitoxantrone (HAM).

In a clinical phase II study the combination of high dose cytosine arabinoside and mitoxantrone (HAM) was applied to 24 patients with refractory acute lymphoblastic leukemia (ALL). All patients had received a standardized first line treatment and were considered refractory against conventional chemotherapy as defined by nonresponse to induction treatment (n = 8), nonresponse to an alternative salvage regimen at first relapse (n = 9), second and third relapses (n = 5) and relapse after bone marrow transplantation (n = 2). Therapy consisted of HD-araC 3 g/m2 q 12 hr days 1-4 and mitoxantrone 10 mg/m2/d days 2-5 or 2-6. Twelve of the 24 patients (50%) achieved a complete remission (CR), one patient had a partial remission, and five patients were nonresponders. Five patients died in aplasia due to infections, one additional patient succumbed to HD-araC related CNS toxicity. Nonhematologic side effects consisted predominantly in infection, nausea and vomiting, mucositis and diarrhea. Recovery of blood counts occurred at a median of 28 days from the onset of treatment; the median time to CR was 33 days. Three of the 12 responders underwent subsequent bone marrow transplantations and one is alive disease free at 40+ months. The median remission duration for the remaining nine patients is 3.5 months, with one case in ongoing CCR at 36+ months; the median survival time is 5 months. Considering the selection of a highly unfavorable group of patients, these data demonstrate a significant antileukemic activity of HAM in refractory ALL and support its application as consolidation treatment during first line ALL therapy.

High-dose cytosine arabinoside in combination with mitoxantrone for the treatment of refractory acute myeloid and lymphoblastic leukemia.

In the present study 55 patients with refractory acute myeloid leukemia (AML) (n = 44) and acute lymphoblastic leukemia (ALL) (n = 11) were treated with high-dose cytosine arabinoside (HD-ara-C) and mitoxantrone (HAM) to assess the toxicity and antileukemic activity of the two-drug combination. All patients had received a standardized first-line therapy according to the corresponding multicenter trials of the German AML and ALL cooperative groups and were considered refractory to conventional treatment. Therapy consisted of HD-ara-C 3 g/m2 every 12 hours on days 1 to 4; mitoxantrone was started at 12 mg/m2/d on days 3, 4, and 5 and was escalated to four and five doses of 10 mg/m2/d on days 2 to 5 and 2 to 6. From the 44 patients with AML, 24 (54%) achieved a complete remission, two a partial remission, and five were nonresponders. Thirteen patients died of infections (n = 11), pericardiac effusion, or acute cardiomyopathy. In refractory ALL, seven of 11 patients (64%) went into a complete remission, one patient was resistant, and three patients were early deaths. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. More severe CNS symptoms were encountered during five treatment courses. The median time to complete remission was 36 days. Excluding five patients who underwent bone marrow transplantations, the median remission duration was 4.5 months in AML and 2.3 months in ALL. The median survival time was three months for all patients and nine months for responders only. These data emphasize a high antileukemic activity of HAM in refractory AML and ALL and support the incorporation of the HAM regimen into first-line treatment.

High-dose cytosine arabinoside and mitoxantrone (HAM) for the treatment of refractory acute lymphoblastic leukemia.

In a clinical phase-II study 11 patients with refractory ALL were treated with high-dose AraC and mitoxantrone in combination (HAM). Refractoriness was defined as: 1. primary resistance against the BMFT induction protocol; 2. first relapse with non-response to the B-ALL/NHL regimen as salvage treatment; 3. second and subsequent relapses. Therapy consisted of HD-AraC 3 g/m2 every 12 h by a 3-h infusion on days 1-4 and mitoxantrone 10 mg/m2/d on days 2-6. Seven of the 11 patients achieved a complete remission, 1 patient was refractory against 2 HAM cycles and 3 patients died during bone marrow aplasia. Toxicity was acceptable, consisting mainly of nausea and vomiting, mucositis and diarrhea. One patient who had completed the prophylactic CNS treatment with intrathecal MTX and cranial irradiation immediately before entering the HAM protocol developed severe signs of cerebral toxicity. These data indicate a significant activity of HAM in refractory ALL and suggest that the combination should be applied at earlier stages of ALL treatment.

[Role of computed tomography in extrapulmonary tuberculosis]. / Stellenwert der Computertomographie bei extrapulmonaler Tuberkulose.

A retrospective evaluation of 65 computed tomographic investigations on 27 patients with proven disseminated extrapulmonary tuberculosis showed no CT changes characteristic for tuberculosis, except for a higher density of tubercular abscesses. In the majority of cases the extent of tubercular manifestations could only be exactly established after the CT investigation. With the aid of this information together with the clinical course of the disease, the timing, type and extent of operative measures could be determined. Finally, in comparison with conventional X-ray and sonography, computed tomography has proved to be superior for control of therapeutic procedures.

Synchronous double primary malignant lymphoma of low grade malignancy and early cancer (collision tumor) of the stomach.

Collision tumors of the stomach are rare tumors, with about 32 cases reported in the English and German literature. In this report the case of a 65-year-old male with a synchronous primary malignant lymphoma (immunocytoma) and an early cancer of the stomach is presented. A total gastrectomy with esophago-jejunostomy was performed. Postoperatively the affected region was irradiated. 30 months later a re-evaluation did not reveal any recurrence of the disease. The diagnostic and therapeutic problems of collision tumors of the stomach and a possible relationship between the two tumors are discussed against the background of the literature.

Evidence for the participation of superoxide anion radical in altering the adhesive interaction between granulocytes and endothelium, in vivo.

The aim of this study was to characterize granulocyte behaviour, in venules, after enzymatic generation of free radicals on the surface of the hamster cheek pouch and to elucidate the role of superoxide anion radical (O2-), H2O2 and hydroxyl radical in these changes. A decrease in granulocyte velocity, which was dissociated from a concomitant increase in red cell velocity, was found while granulocyte rolling frequency and granulocyte adhesion increased in the venules studied. These alterations in granulocyte behaviour could be completely inhibited by superoxide dismutase, an enzymatic scavenger of O2-, but not by catalase, which decomposes H2O2 or by L-methionine which may scavenge OH. and quench singlet O2. Our results are consistent with the concept than an O2-dependent lipid hydroperoxide generated on the hamster cheek pouch by the xanthine oxidase system markedly alters granulocyte behaviour in vivo.

The role of calcium in liver cell damage. Comparative studies with carbon tetrachloride and D-galactosamine.

Female rats treated with D-galactosamine showed increased serum enzyme levels of lactate dehydrogenase, alanine transaminase and sorbitol dehydrogenase as well as moderately elevated liver calcium and decreased potassium contents 4 and 8 hours after drug administration. Slightly but significantly more calcium was sequestered in the liver when the animals were additionally pretreated with vitamin D3, while the other investigated factors were not altered by this treatment. A different pattern was found in carbon-tetrachloride-induced liver lesion. Liver calcium levels were also raised when animals with carbon tetrachloride were pretreated with vitamin D3, but in contrast to D-galactosamine injury, liver enzyme release and electrolyte shift were markedly inhibited under these conditions. Together with previously reported results these findings support our concept that an early rise in liver cell calcium content with a related protective effect is a specific phenomenon in carbon-tetrachloride-induced liver cell damage.

Free radicals as mediators of tissue injury.

Polymorphonuclear leukocytes and other inflammatory cells on exposure to appropriate stimuli release superoxide anion radical into the extracellular space. This results in the further generation of other activated oxygen species such as hydrogen peroxide, hydroxyl radical and singlet oxygen. We have assessed the influence of activated oxygen species, generated by substrate-xanthine oxidase systems, on the degradation of hyaluronic acid, human glial cells in culture and the microcirculation of the hamster cheek pouch. Hyaluronic acid degradation was observed and morphological changes, culminating in cell death, were seen in glial cells. Increased microvascular permeability and increased polymorphonuclear leukocyte-endothelial adhesion were also observed. The results suggest that a variety of alterations to macromolecular and cellular elements of tissues can be mediated by specific free radical species. Similar mechanisms may play a role in the structural and cellular injury occurring in the microcirculation during inflammation and other disease processes.

Relaxation of isolated taenia coli of guinea-pig by enantiomers of 2-azido analogues of adenosine and adenine nucleotides.

1 2-Azido photoaffinity analogues of adenosine 5'triphosphate (ATP), adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP), and adenosine have been synthesized and tested on guinea-pig taenia coli. 2 2-Azido-ATP and 2-azido-ADP were approximately 20 times more potent than ATP as relaxants of taenia coli, and required prolonged washout times before recovery of the muscle. 3 2-Azido-AMP and 2-azidoadenosine were 2 to 12 times more potent than ATP, but took much longer (up to 100 s) to reach maximal relaxation. This behaviour is different from that of AMP and adenosine which were much less potent than ATP. 4 L-Enantiomers of adenosine and adenine nucleotides were also tested. L-ATP and L-ADP were 3 to 6 times less potent than ATP and ADP, and L-AMP and L-adenosine were inactive. 2-Azido-L-ATP and 2-azido-L-ADP were approximately 120 times less potent than 2-Azido-ATP and 6 times less potent than ATP as relaxants of taenia coli. 2-Azido-L-AMP and 2-azidio-L-adenosine were almost inactive. 5 2-Azido derivatives are photolysed by u.v. irradiation to reactive intermediates. 2-Azido-ATP and 2-azidoadenosine might be suitable photoaffinity ligands for labelling putative P2 and P1 purine receptors respectively. 2-Azido-L-ATP and 2-azido-L-adenosine could be useful controls for nonspecific labelling.