Search PubMed⌕ Search

Biomedical subjects

C Jasmin

Publications and source records attributed to C Jasmin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.

CONTEXT: Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy. OBJECTIVE: We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible. PATIENTS AND METHODS: From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team. RESULTS: In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61). CONCLUSION: This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

Adult↗
PubMed1999

Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of docetaxel in combination with doxorubicin, and to evaluate the activity in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-two women with untreated metastatic breast cancer (79% with visceral metastases; 52% with prior adjuvant anthracycline therapy) were treated with doxorubicin (40-60 mg/m2) i.v. bolus followed one hour later by docetaxel (50-85 mg/m2) one-hour i.v. infusion every three weeks, without G-CSF support. RESULTS: The MTD occurred at the dose level combining 85 mg/m2 of docetaxel and 50 mg/m2 of doxorubicin, with the DLT being neutropenic sepsis. Neutropenia and/or its complications were manageable and no grade 3-4 or severe non-hematological toxicities were observed. Fluid retention was frequent but never severe. With a median cumulative dose of doxorubicin of 392 mg/m2 (240-559 mg/m2) and a median follow-up time of 29 months (9(+)-41), no congestive heart failure was observed. High activity was observed at all dose levels, particularly the last four, with a response rate of 81% (95% confidence interval (95% CI): 62.5-92.5). Median time to progression was 46 weeks (6(+)-62). Two-year survival was 66%, and median survival has not yet been reached. CONCLUSIONS: Docetaxel-doxorubicin is feasible, safe and highly active. The incidence of febrile neutropenia without G-CSF requires careful monitoring but is acceptable in this setting. There does not appear to be an increase in the cardiac toxicity of doxorubicin. The recommended doses is either docetaxel 75 mg/m2 and doxorubicin 50 mg/m2 or docetaxel 60 mg/m2 and doxorubicin 60 mg/m2, administered every three weeks.

Adult↗
PubMed1999

Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia.

Blockage in myeloid differentiation characterizes acute myeloid leukemia (AML); the stage of the blockage defines distinct AML subtypes (AML1/2 to AML5). Differentiation therapy in AML has recently raised interest because the survival of AML3 patients has been greatly improved using the differentiating agent retinoic acid. However, this molecule is ineffective in other AML subtypes. The CD44 surface antigen, on leukemic blasts from most AML patients, is involved in myeloid differentiation. Here, we report that ligation of CD44 with specific anti-CD44 monoclonal antibodies or with hyaluronan, its natural ligand, can reverse myeloid differentiation blockage in AML1/2 to AML5 subtypes. The differentiation of AML blasts was evidenced by the ability to produce oxidative bursts, the expression of lineage antigens and cytological modifications, all specific to normal differentiated myeloid cells. These results indicate new possibilities for the development of CD44-targeted differentiation therapy in the AML1/2 to AML5 subtypes.

Acute Disease↗
PubMed1999

Decreased topotecan platelet toxicity with successive topotecan treatment cycles in advanced ovarian cancer patients.

The dose-limiting toxicities of the DNA topoisomerase I inhibitor topotecan are hematological. We prospectively analyzed the platelet toxicity pattern in patients receiving topotecan to optimize the clinical management of topotecan hematotoxicity. Twenty-one advanced ovarian cancer patients, all pretreated with cisplatin and paclitaxel, were treated with 1.25 mg/m2/day topotecan as a 30 min infusion for 5 days, every 3 weeks. No prophylactic granulocyte colony stimulating factor (G-CSF) was given. No topotecan dose reduction was planned according to hematologic toxicity. One hundred and thirty-three topotecan courses were administered (median per patient 6; range: 1-15). Despite no dose reduction, the mean platelet nadir values were significantly less pronounced at cycle 2 than at cycle 1 (82 versus 46 x 10(3)/mm3, p=0.0007). Similar differences were found between cycle 1 and any following cycle. The percent of patients experiencing grade 4 thrombocytopenia decreased from 43% at the first cycle, to 15 and 19% at the second and third courses, respectively (p=0.058). We conclude that the currently recommended topotecan schedule is feasible in heavily pretreated ovarian cancer patients without prophylactic G-CSF. The severity of topotecan-induced thrombocytopenia is maximal at the first cycle but significantly decreases from the second cycle in the absence of dose reduction.

Adult↗
PubMed1999

Continuous delivery of venous 5-fluorouracil and arterial 5-fluorodeoxyuridine for hepatic metastases from colorectal cancer: feasibility and tolerance in a randomized phase II trial comparing flat versus chronomodulated infusion.

High-dose chemotherapy combining regional hepatic artery infusion (HAI) of fluorodeoxyuridine (HAI FUDR) and systemic venous infusion of 5-fluorouracil (i.v. 5-FU) was delivered against liver metastases from colorectal cancer. The hypothesis that chronomodulation of delivery rate along the 24 h time scale would improve the tolerable doses of both drugs was tested. Combined HAI FUDR (80 mg/m2/day) and i.v. 5-FU (1200 mg/m2/day) were administered for five consecutive days every 3 weeks, either as a constant rate infusion (schedule A, 27 patients) or as chronotherapy (schedule B, 29 patients). This latter regimen consisted of a sinusoidal modulation of the delivery rate over the 24 h scale with a maximum at 16:00 for FUDR and 4:00 for 5-FU. Intrapatient dose escalation up to the individual maximum tolerated doses (MTD) was planned for both drugs in the absence of any previous grade 3 or 4 toxicity. All patients had metastatic colorectal cancer, with adjuvant or palliative chemotherapy given to six patients (22%) on schedule A and 12 patients on schedule B (41%). Severe stomatitis occurred in 71% of the patients and was dose limiting. No hepatic toxicity was encountered. Dose reductions of 5-FU and/or FUDR were required for 17 of 27 patients on schedule A (63%) as compared to 11 of 29 patients on schedule B (38%), following reaching the individual MTD (p<0.05). Over the first six cycles, patients on schedule B received higher doses (mg/m2/cycle; FUDR: 522 +/- 85 versus 499 +/- 50, p=0.004 and 5-FU: 5393 +/- 962 versus 5136 +/- 963, p=0.009) and higher dose intensities (mg/m2/week; FUDR: 164 +/- 46 versus 151 +/- 52, p=0.018 and 5-FU: 1652 +/- 478 versus 1553 +/- 535, p<0.041) of both drugs than patients on schedule A. As a result the number of courses with doses of 5-FU above 1200 mg/m2/day and/or FUDR above 110 mg/m2/day was larger in group B than in group A (5-FU, A: 67 of 268, 25% versus B: 133 of 321, 41% and FUDR, A: 86 of 268, 32% versus B: 155 of 321, 48%; p<0.001). Objective responses were observed in 13 patients on schedule A (48%) and 11 patients on schedule B (38%). The results support the need for further exploration of chronotherapy of colorectal cancer liver metastases with combined arterial and venous fluoropyrimidine chemotherapy.

Adult↗
PubMed1998

Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma.

Airway hyperresponsiveness leading to subepithelial fibrosis is mediated by inflammatory cells activated by T helper (Th) 2-derived cytokines such as IL-4 and IL-5. By analyzing the phenotype and response of human lung fibroblasts derived from either fetal (ICIG7) or adult (CCL202) tissue as well as from a Th2-type stromal reaction (FPA) to IL-4 and IL-13, we provide evidence that human lung fibroblasts may behave as inflammatory cells upon activation by IL-4 and IL-13. We show that the three types of fibroblasts constitute different populations that display a distinct pattern in cell surface molecule expression and proinflammatory cytokine and chemokine release. All fibroblasts express functional but different IL-4/IL-13 receptors. Thus, while IL-4 receptor (R) alpha and IL-13Ralpha1 chains are present in all the cells, CCL202 and FPA fibroblasts coexpress the IL-13Ralpha2 and the IL-2Rgamma chain, respectively, suggesting the existence of a heterotrimeric receptor (IL-4Ralpha/IL-13Ralpha/IL-2Rgamma) able to bind IL-4 and IL-13. Stimulation with IL-4 or IL-13 triggers in the fibroblasts a differential signal transduction and upregulation in the expression of beta1 integrin and vascular cell adhesion molecule 1 and in the production of IL-6 and monocyte chemoattractant protein 1, two inflammatory cytokines important in the pathogenesis of allergic inflammation. Our results suggest that when activated by IL-4 and IL-13, different subsets of lung fibroblasts may act as effector cells not only in the pathogenesis of asthma but also in lung remodeling processes. They may also differentially contribute to trigger and maintain the recruitment, homing, and activation of inflammatory cells.

Antigens, Surface↗
PubMed1998

IL-15 is produced by a subset of human melanomas, and is involved in the regulation of markers of melanoma progression through juxtacrine loops.

IL-15 is a novel cytokine active through the IL-2R/betagamma. Since several human melanoma cell lines display functional IL-2Rs, we studied the IL-15/melanoma cells interactions. Ten out of 17 melanoma cell lines express the IL-15 transcript and four of them express levels of IL-15 mRNA similar to those detected in control activated monocytes. Nine out of ten cell lines also express two transcripts for the IL-15R alpha originated by the alternative splicing of exon'3'. Two melanoma cell lines, MELP and MELREO, derived from patients with rapidly progressive primary melanomas, co-express the two IL-15 transcripts, originated by alternative splicing of exon 'A'. Intracellular IL-15 protein was only detected in these two cells lines and it is mainly retained in the Endoplasmic Reticulum (ER). However, a small amount of IL-15 is also found in the Golgi apparatus and in the early endosomes, suggesting production and intercellular trafficking of endogenous IL-15 protein. Nevertheless, no biologically active IL-15 could be detected in the supernatant of all melanoma cells. The anti IL-15 blocking mAb M111 causes the up regulation of HLA Class I in dense MELP and MELREO cultures. These data suggest that IL-15 is probably active through juxtacrine loops negatively controlling HLA Class I molecules expression. These data offer, for the first time, a likely explanation to the controversial issue of IL-15 secretion and constitute a natural model for understanding IL-15 routing. Moreover, we identify a subset of melanoma cells producing IL-15, possibly involved in tumor escape mechanisms.

Biomarkers, Tumor↗
PubMed1998

A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia.

CD44 is a ubiquitous cell-surface glycoprotein that displays many variant isoforms (CD44v) generated by alternative splicing of exons 2v to 10v. The expression of variant isoforms is highly restricted and correlated with specific processes, such as leukocyte activation and malignant transformation. We have herein studied CD44v expression in acute myeloid leukemia (AML) and, for comparison, in normal myelopoiesis. Protein expression of total CD44 and of CD44-3v, -6v, and -9v isoforms has been measured using specific monoclonal antibodies and flow cytometry. The composition of variant exon transcripts has been analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction followed by Southern hybridization with exon-specific probes. Our data show that (1) CD44-6v isoforms are expressed on 12.0% +/- 2.5% of normal CD34(+) cells; this expression is sharply upregulated through monopoiesis and, inversely, downregulated during granulopoiesis. Also, CD44-3v and CD44-9v isoforms are detected on 10% and 14% of normal monocytes, respectively. (2) Sixty-nine from a total of 95 AML patients display a variable proportion (range, 5% to 80%) of CD44-6v+ leukemic cells. (3) A shorter overall survival characterizes the group of AML patients displaying more than 20% of CD44-6v+ leukemic cells (8 months v 18 months, P < .02). These data suggest, for the first time, that the protein expression of CD44-6v containing isoforms may serve as a new prognostic factor in AML.

Acute Disease↗
PubMed1998

IL-4 and IL-13 specifically increase adhesion molecule and inflammatory cytokine expression in human lung fibroblasts.

Subepithelial fibrosis in the bronchi of asthmatics is the result of an irreversible lung fibroblast activation, triggered by cytokines secreted by IL-4- and IL-5-activated inflammatory cells. Here, we provide evidence that human lung fibroblasts (ICIG7 cells) express a single class of high-affinity IL-4 receptor (IL-4R). This receptor is functional and composed of at least the IL-4Ralpha and IL-13Ralpha1 chains in the absence of the IL-2Rgamma chain. The IL-4Ralpha is efficiently internalized at 37 degrees C within 15 min in the presence of IL-4, whereas this process is slower with IL-13. In ICIG7 cells, IL-4 triggers the tyrosine phosphorylation of at least two proteins (110 and 180 kDa), and up-regulates the transcription of c-fos, c-jun and c-myc proto-oncogenes. In addition, the secretion of several cytokines [IL-6, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor (GM-CSF)] as well as the expression of beta1 integrin and VCAM-1 adhesion molecules are augmented by IL-4. IL-13 displays similar biological activities, but less effectively than IL-4. On the other hand, ICIG7 cells could constitute a lung fibroblast population defined by the spontaneous release of several pro-inflammatory cytokines (IL-6, IL-11 and GM-CSF) and cell surface phenotype (CD4 and Thy-1). Through this peculiar cytokine pattern and the IL-4/IL-13-dependent activities, these cells could act as effector cells in the pathogenesis of asthma, triggering and maintaining the recruitment, homing and activation of bone marrow-derived inflammatory cells, and playing a role in the remodeling process of the airways.

Cell Adhesion Molecules↗
PubMed1997

Implication of a new molecule IK in CD34+ hematopoietic progenitor cell proliferation and differentiation.

HLA-DR is one of the markers associated with hematopoietic cell differentiation, since expression of this molecule is modulated throughout hematopoiesis. We have previously described and cloned the gene encoding factor IK, which inhibits both interferon gamma (IFN-gamma)-induced and constitutive HLA-DR expression. The current study demonstrates that IK gene transcripts are present in CD34+ cells purified from human umbilical cord blood. IK expression increased and was therefore inversely correlated with the gradual loss of HLA-DR during growth factor-induced CD34+ cell proliferation and differentiation. To study the possible role of IK in hematopoiesis, antisense probes were used. IK expression was specifically inhibited by an antisense oligodeoxynucleotide containing two phosphorothioate internucleotide linkages at each of the 3' and 5' ends and corresponding to the initiation site of IK mRNA. A control oligonucleotide was also tested in parallel. A specific decrease of IK transcripts was correlated with an increase of HLA-DR antigen expression level. In colony-forming assays, IK antisense oligonucleotide inhibited colony formation by multilineage early erythroid and granulomonocytic CD34+ progenitors. The mean colony size was decreased 70% by IK antisense oligonucleotide in comparison to controls. These results provide evidence that the IK molecule participates in the regulation of HLA-DR expression on hematopoietic cells and plays a role in growth factor-dependent CD34+ cell proliferation and differentiation by modulating HLA-DR expression.

Antigens, CD34↗
PubMed1997

Inhibitor (IK) of IFN-gamma induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line.

The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-gamma) on the majority of the non professional APCs (e.g. fibroblasts). We have recently characterised a new factor called IK which is an efficient inhibitor of IFN-gamma induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-gamma induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

B-Lymphocytes↗
PubMed1997

CD44-mediated adhesiveness of human hematopoietic progenitors to hyaluronan is modulated by cytokines.

Adhesive interactions between CD34+ hematopoietic progenitor cells (HPC) and bone marrow stroma are crucial for normal hematopoiesis, yet their molecular bases are still poorly elucidated. We have investigated whether cell surface proteoglycan CD44 can mediate adhesion of human CD34+ HPC to immobilized hyaluronan (HA), an abundant glycosaminoglycan of the bone marrow extracellular matrix. Our data show that, although CD34+ cells strongly express CD44, only 13.3% +/- 1.1% spontaneously adheres to HA. Short-term methylcellulose assay showed that HA-adherent CD34+ cells comprised granulo-monocytic and erythroid committed progenitors (19.6% +/- 2.5% and 7.3% +/- 1.0% of the input, respectively). More primitive progenitors, such as pre-colony-forming units, also adhered to HA. Moreover, we found that CD44-mediated adhesion of CD34+ cells to HA could be enhanced by phorbol 12-myristate 13-acetate (PMA), the function-activating anti-CD44 monoclonal antibody H90, and cytokines such as granulocyte-monocyte colony-stimulating factor, interleukin-3 (IL-3), and stem cell factor. Enhancement through PMA required several hours, was protein-synthesis-dependent, and was associated with an increase of CD44 cell surface expression, whereas stimulation of adhesion by H90 monoclonal antibody and cytokines was very rapid and without alteration of CD44 expression. H90-induced activation occurred at 4 degrees C and lasted for at least 2 hours, whereas activation by cytokines required incubation at 37 degrees C and was transient. These data, which show for the first time that CD34+ HPC can directly adhere to HA via CD44, point out that this adhesive interaction to HA is a process that may also be physiologically regulated by cytokines.

ADP-ribosyl Cyclase↗
PubMed1997

Comparative study of the expression of cellular proteins in uninfected and HIV infected U937 cells using two dimensional SDS polyacrylamide gel electrophoresis.

The cellular response to HIV infection was determined by analysing the expression of cellular proteins in uninfected and HIV-1 infected U937 cells using two-dimensional protein electrophoresis. HIV infected U937 cells constitute a useful model for the study of the chronic productive infection of cells of the monocyte/macrophage lineage by the human immunodeficiency virus. Our data suggest that the expression of 70 proteins is modified following HIV infection: the expression of approximately half of these proteins was found to be increased, while that of the other half was repressed. We estimate that the expression of around fifteen of these proteins was markedly changed following HIV infection. These results suggest that HIV infection results in the modified expression of approximately 0.5% of total cellular proteins. To our knowledge, this study represents the first global quantitative analysis of the cellular response to HIV infection in a model of chronic infection of cells of the monocyte-macrophage lineage.

Cell Line↗
PubMed1997

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.

Adolescent↗
PubMed1997

Oxaliplatin/cisplatin (L-OHP/CDDP) combination in heavily pretreated ovarian cancer.

The aim of this study was to evaluate the toxicity and the activity of two non-cross-resistant platinum compounds: oxaliplatin (L-OHP) and cisplatin (CDDP) in platinum pretreated ovarian cancer patients. Chemotherapy consisted of L-OHP and CDDP given sequentially as 2 h infusions on day 1 at their standard recommended dose (130 mg/m2 for oxaliplatin, 100 mg/m2 for cisplatin) every 3 weeks. Dose reductions (20-35%) were planned according to baseline haematological and renal status, but the dose ratio between L-OHP and CDDP was always maintained at 1.3. Cycles were repeated until progression or treatment limiting toxicities. From September 1992 to November 1994, 25 patients with pretreated ovarian cancer entered this salvage programme. They had received a median number of three previous chemotherapy lines (1-7), one at least platinum based. Previously cisplatin had been given to 22 patients at a median total dose of 600 mg/m2 (170-1175), while 18 had received carboplatin to a median total dose of 1135 mg/m2 (200-2450). 9 patients had also received and were resistant to taxanes (paclitaxel, 6 patients, docetaxel, 3 patients), while the rest were considered ineligible for simultaneously ongoing single-agent taxane phase II trials. 13 and 12 patients, respectively, were considered to have platinum refractory and potentially sensitive disease, according to Markman's criteria. 77 cycles of L-OHP/CDDP were given, with a median of three cycles/patient (range 1-6) and were evaluable for toxicity. The limiting toxicity of the L-OHP/CDDP combination was a cumulative, sensory peripheral neuropathy, severe (> or = grade 3 CTC) after more than three cycles, but reversible within a few months of its discontinuation. Grade 3-4 (WHO scale) neutropenia and thrombopenia were seen in 35-40% of cycles, with one neutropenic treatment-related death (septic shock). 22 patients with measurable/evaluable disease were assessable for antitumoral activity. Two complete responses (CR) (8%) (one proven histologically at laparotomy (pCR)) and 8 partial responses (PR) (32%) for an overall objective response rate (ORR) of 40% (95% CI, 21-61%) (intent to treat). The median duration of response was 4 months. Seven responses were seen among 12 potentially platinum-sensitive tumours (58%, CI 95% 28-85%), while 3/13 platinum refractory patients (23%, CI 95% 5-54%) had an objective response. These encouraging results are the basis for new first- and second-line combination treatment programmes in ovarian carcinoma.

Adult↗