Fracture surfaces of granular pastes.

Granular pastes are dense dispersions of non-colloidal grains in a simple or a complex fluid. Typical examples are the coating, gluing or sealing mortars used in building applications. We study the cohesive rupture of thick mortar layers in a simple pulling test where the paste is initially confined between two flat surfaces. After hardening, the morphology of the fracture surfaces was investigated, using either the box counting method to analyze fracture profiles perpendicular to the mean fracture plane, or the slit-island method to analyze the islands obtained by cutting the fracture surfaces at different heights, parallel to the mean fracture plane. The fracture surfaces were shown to exhibit scaling properties over several decades. However, contrary to what has been observed in the brittle or ductile fracture of solid materials, the islands were shown to be mass fractals. This was related to the extensive plastic flow involved in the fracture process.

Tackiness and cohesive failure of granular pastes: mechanistic aspects.

Granular pastes are dense dispersions of non-colloidal grains in a simple or a complex fluid. Typical examples are the coating, gluing or sealing mortars used in building applications. We study the rupture of a thick layer of mortar paste in a simple pulling test where the paste is confined between two flat surfaces. It is shown that, depending on the rheological properties of the paste and the plate separation velocity, two main failure modes are obtained. The first mode is the inwards shear flow of the paste with viscous fingering instabilities, similarly to what has been observed with Newtonian fluids and with non-Newtonian colloidal suspensions or polymer solutions. The second failure mode is stemming from the expansion of bubbles, similarly to what has been observed in soft adhesive polymer layers and, more recently, in highly viscous fluids. It is shown that the crossover between the two failure modes is determined by the conditions required to generate a pressure drop able to trigger the growth of pre-existing micro-bubbles smaller than the inter-granular distance.

6-Day continuous infusion of high-dose ifosfamide with bone marrow growth factors in advanced refractory malignancies.

Ifosfamide is an analogue of cyclophosphamide active in the treatment of numerous tumours. Although its use by continuous infusion seems to be responsible for less toxicity, differences of efficacy and toxicity, observed according to its doses and schedules of administration, still remain debated. The objective of this study was to assess the toxicity of high-dose ifosfamide given by continuous infusion over 6 days and its therapeutic activity in various advanced tumours. Twenty-six patients were treated with 14 g/m2 ifosfamide, an equal dose of MESNA, and routine granulocyte- or granulocyte/macrophage-colony-stimulating factor during the intercycle. Courses were repeated every 3 weeks until disease progression or unacceptable toxicity occurred; 75 cycles were administered. The mean number of cycles per patient was 3 (range 1-11). Extrahaematological toxicity was manageable in most patients, WHO grade II or more neurological (5 patients) and renal (5 patients) toxicities occurring in those heavily pretreated with platinum compounds and presenting peritoneal disease. WHO grade III or more neutropenia occurred in 60% of cycles, while grade III-IV thrombocytopenia and anaemia were observed in 19% of them. Three partial responses (germ-cell tumour, chondrosarcoma, soft-tissue sarcoma) and one complete response (metastatic osteosarcoma) were assessed, all in patients with tumours refractory or resistant to standard-dose ifosfamide, which underlines the possibility of circumventing the resistance to ifosfamide given in conventional schedules. The present results confirm previous reports of changes in the therapeutic index of ifosfamide according to its dose and administration schedule.

Oxaliplatin, 5-fluorouracil, and folinic acid (Folfox) in patients with metastatic renal cell carcinoma: results of a pilot study.

We report the results of a chemotherapy regimen combining oxaliplatin, 5-fluorouracil, and folinic acid in patients with metastatic renal cell carcinoma. The objective of this pilot study was to define the potential efficacy of this second-line combination in patients previously treated with interleukin-2 alone or in combination with interferon alpha. Fourteen patients with metastatic renal cell carcinoma in failure after immunotherapy were included in this trial. During treatment, patients received six chemotherapy courses (Folfox regimen) administered every 2 weeks. Each cycle combined oxaliplatin day (D) D1 and folinic acid plus 5-fluorouracil D1 and D2. At completion of treatment, no objective response was observed and two patients presented stable disease. This chemotherapy schedule in patients with metastatic renal cell carcinoma previously treated with immunotherapy does not seem to be effective.

[Immunoenzymatic determination of free immunoglobulin light chains in the cerebrospinal fluid: its value in the biological diagnosis of multiple sclerosis]. / Dosage immunoenzymatique des chaînes légères libres d'immunoglobulines dans le liquide céphalorachidien: intérêt dans le diagnostic biologique de la sclérose en plaques.

Based on previous data on free immunoglobulin light chains in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS), we evaluated free kappa and lambda light chains in the CSF from 3 patients groups: (a) 42 with MS, (b) 16 with other neurological inflammatory diseases (ONID) and (c) 42 with non inflammatory neurological diseases (NIND) used as control. The kappa and lambda light chains contents were evaluated using a specific and sensitive (0.5 mcg/ml) enzyme linked immunosorbent assay (ELISA). Whole CSF immunoglobulins G (CSF-IgG) concentrations were determined by an immuno-nephelometric method and CSF oligoclonal banding was assessed by agarose gel electrophoresis. Elevated free kappa light chains levels were found in 36 of the 42 (85.7%) MS-CSF, and only in 2 of the 16 (12.5%) ONID-CSF. Moreover, all MS-CSF with oligoclonal banding (21/42) exhibited detectable free kappa light chains. In contrast, elevated free lambda light chains or whole CSF-IgG concentrations were found not so specific. These results suggest that free kappa light chains measurement in MS-CSF may have an important diagnostic usefulness. This assay offers a reliable alternative to other available procedures and may constitute complementary technique in routine investigation of MS-CSF.

Deregulated expression of the keratin 18 gene in human colon carcinoma cells.

The keratin 18 (K18) gene is expressed at a normal level in cells of nontumorigenic clones derived from the SW613-S human colon carcinoma cell line, but is overexpressed in cells of tumorigenic clones. A high level of expression was also found in the cells from 10 of 15 other human colon carcinoma cell lines. The expression of the gene is downregulated in differentiating Caco-2 cells, resulting in a normal expression level. Determination of K18 mRNA half-life in growing and confluent Caco-2 cells indicated that this downregulation does not take place at a posttranscriptional level. The density of RNA polymerase molecules on the K18 gene, as measured in nuclear run-on experiments, is the same in growing and confluent Caco-2 cells, but the rate of synthesis of K18 transcripts in confluent Caco-2 cells, as determined by in vivo pulse-labeling, is 35% of that in growing cells. Nuclear run-on experiments carried out with nuclei prepared from growing or confluent Caco-2 cells treated with 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB) indicated that a reduction in both the initiation and elongation rates of RNA polymerase molecules occurs on the K18 gene in confluent Caco-2 cells. This leads to a decreased rate of K18 transcript production with no reduction in the polymerase density on the gene. Evidence is provided that the mechanisms responsible for the differential expression of the K18 gene between tumorigenic and nontumorigenic SW613-S cells and between growing and differentiating Caco-2 cells share some similarities.

A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies.

PURPOSE: Gemcitabine and vinorelbine are active drugs with broad spectrum of activity and manageable toxicity in clinical trials. The aims of this study were to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of gemcitabine and vinorelbine to be recommended for phase II studies in patients with advanced cancers. PATIENTS AND METHODS: Drugs were given as 30-min infusions on day 1 and 8 (vinorelbine before gemcitabine) every 3 weeks. Thirty-six patients (male:female ratio 25:11; mean age 54, PS > 60) were treated including 1 retroperitoneal sarcoma, 7 head and neck, 10 lung, 4 thyroid, 6 pancreatic, 1 bladder, 2 ovary, 2 gastric, 1 rectum, 1 unknown primary, and 1 renal cell carcinoma. Doses of gemcitabine/vinorelbine ranged from 800/20 mg/m2 to 1500/30 mg/m2. RESULTS: The dose-limiting toxicity was neutropenia. A transient grade 2-3 elevation of transaminases was frequently observed at several dose-levels, although this toxicity did not appear to be dose dependant and was reversible at day 21 before the next cycle. Other toxicities were mild and easily manageable, consisting of fatigue and flu-like syndromes. Since the MTD was not reach at the higher dose-level, the recommended dose level of the gemcitabine-vinorelbine combination was 1500/30 mg/m2. One toxic death due to hematologic toxicity was reported in a heavily pretreated patient who underwent prior chemotherapy and pelvic radiotherapy. A total of 12 patients were treated at the recommended dose level which was associated with grade 3-4 neutropenia in 3 of 12 patients and in 22.9% of cycles. CONCLUSIONS: This study estimates that the recommended dose for phase II studies of gemcitabine-vinorelbine is 1500/30 mg/m2 at day 1 and 8 every three weeks. A careful monitoring of the hematologic toxicity is recommended in heavily pretreated patients and in patients who received pelvic radiotherapy. Partial responses observed in a patient with an advanced cisplatin-5-fluorouracil-resistant pancreatic adenocarcinoma and in a patient with mesothelioma support further evaluation of this combination in patients with tumors refractory to classical antitumor agents.