Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK)

Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.     

On the generation of test patterns for multiple faults

This article presents a new method to generate test patterns for multiple stuck-at faults in combinational circuits. We assume the presence of all multiple faults of all multiplicities and we do not resort to their explicit enumeration: the target fault is a single component of possibly several multiple faults. New line and gate models are introduced to handle multiple fault effect propagation through the circuits. The method tries to generate test conditions that propagate the effect of the target fault to primary outputs. When these conditions are fulfilled, the input vector is a test for the target fault and it is guaranteed that all multiple faults of all multiplicities containing the target fault as component are also detected. The method uses similar techniques to those in FAN and SOCRATES algorithms to guide the search part of the algorithm, and includes several new heuristics to enhance the performance and fault detection capability. Experiments performed on the ISCAS'85 benchmark circuits show that test sets for multiple faults can be generated with high fault coverage and a reasonable increase in cost over test generation for single stuck-at faults.     

Mechanical response of novel SiOC glasses to high temperature exposition

The presented work describes mechanical properties of materials prepared by the pyrolysis of polysiloxane resins. The polymeric precursors have different chemical composition. Materials under investigation are predetermined for high temperature resistant applications usually in composite form, i.e. accompanied by some reinforcement. Instrumented hardness tests were employed for material characterisation. The Vickers hardness, Martens hardness and indentation elastic modulus were the key parameters, determined either from the standard optical technique or load–indentation depth curves. The influence of mechanical properties on the monomers ratio was established. The exposition to the temperature between 1200 °C and 1500 °C in air was applied to observe damage caused by these severe conditions.     

Fatty acid and phytosterol accumulation during seed development in three oilseed species

This study was carried out to compare the kinetic accumulation of bioactive lipids during seed development in three oil crops rapeseed, sunflower and woad. Field experiments were conducted under organic conditions during 3 years. After flowering, seeds were collected each 4–5 days until harvest. The three species differed by the quantity and quality of both fatty acids and sterols. Higher levels of phytosterols and fatty acids were reached between 20 and 40 days after flowering (DAF) in sunflower, 40 and 60 DAF in rapeseed and 25 and 45 DAF for woad. The modification of lipid composition during the grain filling depends on species. Knowledge of the composition and accumulation of fatty acids and phytosterols in sunflower, rapeseed and woad seeds would assist in efforts to achieve industrial applications. These seeds may give an interesting source of bioactive lipids.     

Dyeing of leather with microencapsulated acid dye

CI Acid Black 210 was microencapsulated into liposomic systems, and the effects of the microencapsulation on dyebath exhaustion, depth of shade, colour fastness properties and through‐dyeing of chrome‐tanned leather were studied. In comparison with the original dyestuff form, the microencapsulated dye showed a deeper shade and a greater depth of through‐dyeing. Exhaustion and colour fastness values were the same.     

Is preoperative chemotherapy in locally advanced non-small-cell bronchial carcinoma of value?

Although surgeons are able to resect completely locally advanced non-small cell lung cancer with mediastinal lymph node involvement (stage IIIA), the majority of patients succumb from metastatic disease. Therefore, neoadjuvant therapy was introduced in the management of this disease in order to eradicate distant metastases at an early stage. Phase II trials with preoperative chemotherapy in stage IIIA patients have shown that the pathological response (amount of tumour necrosis) and the clearance of mediastinal lymph node correlate with a better survival and is the best predictor for eradication of distant metastases. Indeed, three small randomised phase III studies have demonstrated a survival advantage for preoperative chemotherapy compared to surgery alone. Further studies are required to determine the best neoadjuvant regimen inducing the largest amount of tumour necrosis.     

A novel gene expressed in rat ameloblasts codes for proteins with cell binding domains

Two variants of an mRNA sequence are identified that are expressed at high levels in rat ameloblasts during the formation of the enamel matrix. The sequences contain open reading frames for 407 and 324 amino acid residues, respectively. The encoded proteins, which we call amelins, are rich in proline, glycine, leucine, and alanine residues and contain the peptide domain DGEA, an integrin recognition sequence. The sequences coding for the C-terminal 305 amino acid residues, the 3' nontranslated part, and a microsatellite repeat at the nontranslated 5' region are identical in both mRNA variants. The remaining 5' regions contain 338 nucleotides unique to the long variant, 54 common nucleotides, and 46 nucleotides present only in the short variant. Eleven nucleotides have the potential to code for 5 amino acids of both proteins in different reading frames. The reading frame of the longer variant includes codons for a typical N-terminal signal peptide. The amelins are likely to be constituents of the enamel matrix and the only proteins that have so far been implicated in binding interactions between the ameloblast surface and its extracellular matrix.