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J L Misset

Publications and source records attributed to J L Misset.

At least 37 records · Page 2Linked to original sources
PubMed2000

Dramatic tumor response of bulky liver metastases following treatment with CPT-11 and a chronomodulated 4-day infusion of 5-fluorouracil, folinic acid and oxaliplatin every 2 weeks in a colorectal cancer patient.

Three active antitumor agents, i.e. 5-fluorouracil (5-FU), oxaliplatin and CPT-11, are available for the treatment of advanced colorectal cancer (CRC) patients and have been successfully combined in two-drug regimens. Hence, CRC has become a chemosensitive disease, but the optimal combination of these agents in first-line treatment remains to be determined. We report the first case of the combination of CPT-11 with oxaliplatin, 5-FU and folinic acid (FA) as first-line chemotherapy for a patient with a pre-occlusive sigmoid adenocarcinoma and synchronous bulky liver metastases. CPT-11 was given at 125 mg/m2, prior to the start of a chronomodulated 4-day infusion of oxaliplatin 25 mg/m2/day, 5-FU 800 mg/m2/day and FA 300 mg/m2/day repeated every 2 weeks. The doses could be escalated to 150 mg/m2 for CPT-11 and 900 mg/m2/day for 5-FU. After six cycles of chemotherapy 70% reduction in tumor size was documented in the liver. The primary tumor was no longer detectable by barium enema. The toxicity included three episodes of grade 4 neutropenic fever, and two episodes of severe diarrhea and vomiting with dehydration. A cumulative grade 2 neurosensory toxicity was observed after six cycles. Following surgery of the primary tumor, because of the major hepatic tumor response and of the absence of extra-hepatic metastases, the patient might be registered for a liver transplantation program. This first report of combining the three active agents in CRC every 2 weeks led to a high dose intensity of each agent and was associated with a dramatic tumor response of a very advanced disease in a patient with already altered performance status. The antitumor activity in this patient suggests that a three-drug intensified regimen might be feasible and active. A prospective study appears warranted to further examine the efficacy and toxicity of this therapeutic approach, and to determine whether it may increase the fraction of advanced CRC patients becoming resectable. This aggressive chemotherapy program may contribute to a re-examination of the usefulness of liver transplantation in patients with metastatic CRC confined to the liver.

Adenocarcinoma↗
PubMed2000

Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer.

PURPOSE: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)-leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m(2)/d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m(2), as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. RESULTS: Grade 3 to 4 toxicity from 5-FU-LV occurred in </= 5% of the patients (</= 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU-LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P <. 001). The median progression-free survival time was 6.1 months with 5-FU-LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU-LV (P =.048). Median survival times were 19.9 and 19.4 months, respectively. CONCLUSION: By chronomodulating 5-FU-LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen.

Adult↗
PubMed2000

Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients.

PURPOSE: To identify predictive factors for efficacy and safety in advanced breast cancer (ABC) patients treated in the French compassionate-use docetaxel program. PATIENTS AND METHODS: A total of 825 ABC patients treated with docetaxel (100 mg/m(2) every 3 weeks) were source-reviewed and analyzed for prognostic factors associated with overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), febrile neutropenia, mucositis, and severe fluid retention syndrome by univariate and multivariate analysis. RESULTS: The ORR was 22.9% (95% confidence interval, 20.2% to 26.2%). The median TTF and OS were 4.0 and 9.8 months, respectively. By multivariate analysis, secondary anthracycline-resistant disease was significantly associated (P <. 05) with lower ORR and shorter TTF and OS, whereas anthracycline-refractory disease was associated with shorter OS. Poor performance status was associated with lower ORR, shorter TTF, and shorter OS. Liver dysfunction (transaminase levels > 1.5 times the upper limit of normal [ULN] and alkaline phosphatase [AP] level > three times ULN) and time since first relapse less than 24 months were associated with shorter TTF and OS. Other significant correlations included the following: elevated CA 15-3 serum level with lower ORR; more than two involved sites, and minor transaminase and AP level abnormalities with shorter OS; and no previous chemotherapy for ABC with shorter TTF. According to multivariate analysis, ORR, TTF, and OS were not decreased in patients with liver metastases but without liver dysfunction. CONCLUSION: Docetaxel activity was maintained in heavily pretreated ABC patients and in those with liver metastasis; docetaxel must be used cautiously, however, in patients with liver dysfunction in whom high morbidity risk necessitates strict adherence to dose-adaptation guidelines.

Anthracyclines↗
PubMed2000

Lack of efficacy of 2-chlorodeoxyadenoside in the treatment of splenic lymphoma with villous lymphocytes.

Splenic lymphoma with villous lymphocytes (SLVL) is a B-cell chronic lymphoproliferative disorder. Splenectomy and/or chlorambucil (CLB) are usually regarded as the most effective treatment in SLVL patients. However, a few patients relapse and the second line therapy remains questionable. Although 2-Cda has been evaluated in patients with chronic lymphoid leukemia (CLL) and hairy cell leukemia (HCL), it has been reported as the treatment of SLVL in only one case report. Therefore, we have evaluated its efficacy and toxicity in 7 SLVL patients. The median duration between diagnosis and treatment was 18 months (range, 1 to 59). The patients received 2-CdA (0.1 mg/kg/d) by venous infusion for 7 days with a median number of 1 cycle (range, 1 to 2) either as a first line therapy (one patient) or after a failure of other therapies (splenectomy, chemotherapy). Two patients achieved a complete response. The first one maintained his CR during a follow-up of 9 months and then relapsed; the second patient remained in CR after a follow-up of 20 months. Four patients achieved a partial response and relapsed after a median follow-up of 3.5 months (range, 1 to 4). One patient had no response. The treatment was not well tolerated with many infectious events. In the limits of our study, 2-Cda does not appear to be efficient therapy for SLVL and is not well tolerated for patients in relapse after splenectomy or resistant to CLB.

Adenosine Triphosphate↗
PubMed2000

Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status.

The rest/activity circadian cycle has been used as a reference for chemotherapy administration at specific times to improve tolerability and efficacy. Because cancer processes may be associated with alterations of circadian rhythms, the rest/activity cycle was monitored noninvasively to assess its relationship with tumor response, survival, and quality of life in 200 patients with metastatic colorectal cancer. Patients wore an actigraph, a wristwatch that records the number of accelerations per minute, for 3 days before receiving chronomodulated chemotherapy. The circadian rhythms in activity were estimated by two robust parameters: the autocorrelation coefficient at 24 h (r24), and the dichotomy index (I<O) for comparing amounts of activity when in bed and out of bed. Accurate data for inclusion, quality of life, response, and survival were available for 192 patients. Survival at 2 years was 5-fold higher (P = 10(-4)) in patients with marked activity rhythm (I<O in upper quartile) than in those with rhythm alteration (I<O in lower quartile). These results were supported by the multivariate Cox analysis. Multivariate regression analysis showed that circadian rhythms in activity (I<O; P = 3 x 10(-4)) and in WBCs (P = 0.03) as well as performance status (P = 0.02) were jointly prognostic of response. Patients with marked rest/activity rhythms also had better quality of life and reported significantly less fatigue. The individual rest/activity cycle provides a novel independent prognostic factor for cancer patients' survival and tumor response as well as a quantitative indicator for quality of life.

Adult↗
PubMed2000

[Evaluation of the effect of pathology slide review on clinical practice in an oncology center].

Our aim was to evaluate the clinical impact of pathology review in an oncology center, in which review is not performed for every patient. This retrospective study involved 100 consecutive patients, whose slides were reviewed in our center. A standardized data sheet was filled out by oncologists for each patient. Pathology review was considered as responsible for a major (35%), moderate (40%), or mild or no (25%) modification of clinical practice. Modification concerned either initial investigations, treatment or medical follow up, and was independent of the reason for which review was performed. Eleven patients underwent a second biopsy. Whatever the possible discrepancies between initial and review diagnosis, our results show that pathological review has a major influence on clinical practice in patients with cancer.

Humans↗
PubMed2000

Pharmacokinetics and pharmacodynamics of the novel marine-derived anticancer agent ecteinascidin 743 in a phase I dose-finding study.

Ecteinascidin (ET) 743 is an anticancer agent derived from the Caribbean tunicate Ecteinascidia turbinata. Preclinical studies revealed activity of ET-743 against different tumor types. A Phase I clinical trial was designed with ET-743 to identify the maximum tolerated dose and dose-limiting toxicities (DLTs). Furthermore, the pharmacokinetics of ET-743 and relationships with pharmacodynamics were evaluated. Adult patients with solid, resistant tumors received ET-743 as a 24-h i.v. infusion every 21 days. Blood samples were obtained during the first treatment course and in several consecutive courses. Noncompartmental pharmacokinetic analysis was performed. Relationships between pharmacokinetics and hepatic and hematological toxicities were explored. Fifty-two patients were treated at nine dose levels (50-1800 microg/m2). The DLTs, neutropenia and thrombocytopenia, were experienced at 1800 microg/m2. Twenty-five patients were treated at the recommended Phase II dose of 1500 microg/m2. At this dose, the mean value +/- SD for total body clearance was 59 +/- 31 liters/h, and the mean t(1/2) was 89 +/- 41 h. Pharmacokinetics were linear over the dose range tested. Prior exposure to ET-743 did not alter the pharmacokinetics in subsequent courses. The percentage of decrease in WBC count and absolute neutrophil count was correlated to the area under the plasma concentration versus time curve (AUC). Hepatic toxicity, defined as rise in alanine aminotransferase and aspartate aminotransferase, increased with dose and AUC but was reversible and not dose limiting. In conclusion, ET-743 administered as a 24-h i.v. infusion at a dose of 1500 microg/m2 is clinically feasible; severe thrombocytopenia and neutropenia are the DLTs.

Adult↗
PubMed1999

Hepatocellular carcinoma cell lines from diethylnitrosamine phenobarbital-treated rats. Characterization and sensitivity to endothall, a protein serine/threonine phosphatase-2A inhibitor.

Primary hepatocellular carcinoma (HCC) is probably one of the most common fatal forms of liver cancer. We have established permanent cell lines from diethylnitrosamine/phenobarbital induced primary rat liver carcinomas to study new anticancer therapies. The rat hepatocellular carcinoma cell lines (HR-2, HR-3, and HR-4) have been maintained in culture for over 3 years. They form tumors when transplanted sc or im into young syngeneic rats. Immunocytology (alpha-fetoprotein, albumin), biochemical (gamma-glutamyl transferase), and histochemical (glycogen) marker studies and electron microscopy (biliary canaliculi) showed unique, stable differentiation patterns in these tumor lines. They overproduced the c-met protooncogene product and formed colonies spontaneously in semisolid culture with high cloning efficiency (HR-2: 50%-80%, HR-3: 35%-50% and HR-4: 50%-65%). The sensitivity of these cell lines to inhibitors of protein ser/thr phosphatase-2A (PP2A), a key enzyme in the control of G1/S and G2/M cell cycle phase transitions in eukaryotes, was studied in vitro. The specific, weak inhibitor of PP2A, endothall, caused dose- and time-dependent cytostasis specifically in G2/M. The cells died later by apoptosis, which was confirmed by cytology (annexin V-FITC labeling, propidium iodide painting of apoptotic bodies) and by fluorescent activated cell sorter (FACS) DNA measurements. The HR-2, HR-3, HR-4, and Zajdela hepatocellular carcinomas were most sensitive to endothall (IC50 of 1.7, 1.2, 0.9, and 1.7 microg/mL), whereas newborn rat hepatocytes growing exponentially in primary culture (IC50 = 6.2 microg/mL), rat DHD/K12 colon carcinoma cells (IC50 = 3.6 microg/mL), or human HT-29 colon carcinoma cells (IC50 = 4.9 microg/mL) were less sensitive. Thus, endothall inhibits preferentially HCC growth and these new rat hepatocellular carcinoma lines may be useful for further biochemical and pharmacological studies on PP2A inhibitors, and for testing new forms of treatment of hepatic cell carcinomas.

Animals↗
PubMed1999

Antitumoral activity of oxaliplatin/cisplatin-based combination therapy in cisplatin-refractory germ cell cancer patients.

PURPOSE: Only 20-30% of patient with advanced germ cell tumors, relapsing after standard first-line therapy, are curable with current second-line cisplatin-based regimens. New salvage combinations incorporating new active agents are needed. We report the toxicity/tolerance of a new salvage regimen based on the oxaliplatin (Eloxatin)/cisplatin combination, evaluated in patients with recurrent, mostly cisplatin-refractory germ cell tumors. PATIENTS AND METHODS: Thirteen patients were enrolled in this study. All except one had received cisplatin-based chemotherapy. Eight had progressive disease as the best response on their last platinum-based chemotherapy, and three had potentially sensitive tumors. The median interval since the last platinum-based chemotherapy was 6 months (range: 1-36 months). One untreated patient with poor prognosis was also enrolled. Twelve patients had pathological markers [median alpha-fetoprotein 14 800 ng/ml (58-10(6)), median human chorionic gonadotrophin beta subunit 7000 IU/ml (37-723 700)]. Patients received either oxaliplatin (130 mg/m(2)) and cisplatin (100 mg/m(2)) every 3-4 weeks (Bi regimen, four patients), or the same regimen combined with one to four of the following cytotoxic agents: ifosfamide, epirubicin, vinorelbine, methotrexate, dactinomycin, etoposide and bleomycin (BiC regimen, 9 patients). Treatment was individualized according to each individual patient's pretreatment and clinical characteristics. RESULTS: Seven objective responses were obtained (overall response rate = 54%), all with the BiC regimens (two complete and five partial responses). Two patients with recurrent disease achieved a long-term complete response lasting over 5 years. Four partial responders were seen in the eight cisplatin-refractory tumors, lasting 4-8 months. All objective responses had a corroborating major decrease in tumor marker blood levels (median decrease: 99.7%). The median survival for the whole group was 8 months. The commonest severe toxicity was hematological (grade 4 neutropenia in 78% and thrombopenia in 74% of the BiC cycles). CONCLUSION: Our combined salvage regimen induced significant antitumoral activity in recurrent, cisplatin-refractory germ cell tumors. Oxaliplatin merits further evaluation as a component of combination therapy for this disease.

Adolescent↗
PubMed1999

[Clinical imaging of osteo-condensed metastases].

INTRODUCTION: Due to the occurrence of osteoblastic metastases in the course of various cancers, particularly in the course of prostate cancer, we are faced with diagnosis and follow-up issues different from those associated with lytic metastasis. We therefore analyzed the respective advantages of imaging techniques. CURRENT KNOWLEDGE AND KEY POINTS: Most of the time, osteoblastic metastases are evidenced by standard radiography. Due to its ability to demonstrate metastases localization, extent and signs, CT scan is not only of value when osteoblastic metastases are suspected but also for patient's follow-up. MRI provides further information in regard to both the lesion content and osteoblastic degree. Though MRI must be performed after all other imaging procedures, it is of value for multiplanar study of the whole spine. FUTURE PROSPECTS AND PROJECTS: Studies focusing on either the lesion content and volume or helical CT are in progress and aim at better monitoring follow-up, while the objective of dynamic MRI studies is to better analyze lesion content.

Biopsy↗
PubMed1999

Efficacy and safety of docetaxel (Taxotere) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience.

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received > 1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m2/cycle (75 mg/m2 in case of liver function impairment: transaminases > 1.5 x upper limit of normal (ULN), alkaline phosphatases > 3 x ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS > or = 2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received > 2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2-26.2%). Median time to treatment failure was 4 months (95% CI: 3.6-4.3) and median survival was 9.8 months (95% CI: 8.8-10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

Adult↗
PubMed1999

Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients.

BACKGROUND: Many patients with advanced NHL ultimately relapse and require salvage treatment. Oxaliplatin, a diaminocyclohexane (DACH) platinum, has shown a differential spectrum of cytotoxicity with cisplatin, with activity in primary or secondary cisplatin-resistant solid tumors (colon and ovarian cancer). We report the tolerance/activity of this platinum derivate in previously-treated NHL patients. PATIENTS AND METHODS: From July 1988 to February 1994, 22 patients (11 men, 11 women) with recurrent NHL received single-agent oxaliplatin (100-130 mg/m2 i.v. over two hours with antiemetic premedication, q three weeks). All had been previously treated (median number of prior chemotherapy regimens 2, range 1-7) > or = 1 alkylating agent: 22 patients, anthracyclines: 18 patients, cisplatin: four patients, and radiation: 11 patients. Fourteen patients (63%) had progressive disease as best response to their last chemotherapy, and were considered treatment-refractory. All histologies were centrally reviewed in accord with the R.E.A.L. Classification; they were: eight follicular, five MCL, three diffuse large cell, two MALT, one lymphoplasmocytoid, and three other. RESULTS: A total of 144 cycles were administered for a median number of 6 (range 1-30) per patient. The objective response rate was 40% (95%, CI: 21-64), including one CR (MCL) and eight PRs (four follicular, two MCL, two MALT). The median response duration was 27 months (range 5-44). Treatment-related toxicity was limited to grade 1-2 nausea/vomiting and reversible grade 1-2 peripheral neuropathy in most of the patients. CONCLUSION: Oxaliplatin is an active agent in relapsed/refractory NHL, including the MCL type. Its safety profile makes this agent a good candidate for the development of combined salvage regimens. Further phase II studies are needed to confirm these preliminary results.

Adult↗
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

Large scale recovery and characterization of stromal cell-associated primitive haemopoietic progenitor cells from filter-retained human bone marrow.

Bone marrow aspirates are composed of two cellular compartments, an abundant buffy coat suspension and a minor particulate fraction. The particulate fraction is routinely removed by filtration prior to transplantation in order to reduce the risk of embolism. This study shows that the filter-retained fraction includes many multicellular complexes, previously defined as haematons. A haematon is a finely arborized stromal-web which is tightly packed with haemopoietic progenitor cells and differentiated postmitotic cells. Comparison of the pooled buffy coat and the filter-retained materials from healthy donors showed that the haematon fraction contained 8-40 x 10(6) CD34+ cells, 20-115 x 10(3) high proliferative potential colony-forming cells (HPP-CFC) and 0.49-2.67 x 10(6) granulocyte-macrophage colony-forming unit (GM-CFU) which constituted 24+/-8% (10-36; n=8) of the total GM-CFU population harvested. Similar, but more variable recoveries of GM-CFU were obtained from the haematon fractions from patients with breast cancer (21+/-13%; n=10), Hodgkin's disease (33+/-19%; n=4), non-Hodgkin's lymphoma (21+/-18; n=7), but the recovery was lower from patients with acute myelogenous leukaemia (AML) (13+/-13%; n=6). The haematon fraction was enriched in CD34+ cells (2.5-fold), long-term culture initiating cells (LTC-IC/CAFC, week 5) (3.5-fold), HPP-CFC (2.8-fold) and GM-CFU (2.3-fold) over the buffy coat. Purified CD34+ cells expanded exponentially and produced 800 to 4000-fold more nucleated cells, 300 to 3500-fold more GM-CFU and 10 to 80-fold more HPP-CFC in stroma-free suspension culture with interleukin-1 (IL-1beta), IL-3, IL-6, GM-CSF and stem cell factor (SCF), than did the starting cell input. The haematon fraction produced significantly more progenitor cells than the buffy coat in long-term liquid culture (LTC). This was due to the higher frequency of LTC-IC/CAFC and to the presence of the whole spectrum of native, stroma cell-associated CAFC in haematons. Thus, the haematon includes the most productive haematogenous compartment in human BM. This simple enrichment strategy, using filter-retained haematons, provides a rational source of BM cells for large scale experimental and/or clinical studies on haemopoietic stem cells and on critical accessory stromal cells.

Antigens, CD34↗
PubMed1999

Primary chemotherapy or hormonotherapy for patients with breast cancer.

Scientific rationale for primary treatment of breast cancer relies on experimental data showing that the incidence and growth of disease correlate with the primary tumour mass and tumoral angiogenesis. Although the strategy may be applied to both chemotherapy and hormonotherapy, only the first was extensively explored for patients with locally advanced breast cancer in order to improve survival and to avoid mastectomy through the achievement of a downstaging of the tumour. Encouraging results obtained in this clinically advanced setting combined with renewed interest for tumoral angiogenesis brought clinicians to apply this strategy to smaller tumours. Despite high clinical and radiological response rates, only pathologic information, carefully assessed in both the primary and axillae lymph nodes, stands out as the major source of prognostic information on patients' outcome. Recent developments in chemotherapy (dose-intensity, new drugs) do not seem to influence these results, indicating the possible limitations of recent developments in chemotherapy. Of 6 published randomized trials comparing primary vs adjuvant chemotherapy, none showed any significant impact of primary chemotherapy on survival, with a trend towards delayed/less distant recurrences in patients treated by primary chemotherapy in some. Some recent reports suggest that local relapse rate might be increased after conservative treatment following induction chemotherapy in subgroups analyse and this should cause oncologists to revise and define the role for conservative surgery after primary medical treatment without calling into question the global strategy. Through sequential samplings, neoadjuvant medical treatment provides indeed the opportunity (a) to identify molecular mechanisms associated with pathologic response and (b) to study the possibility to guide the choices for induction treatment and patient populations submitted to primary medical treatment.

Antineoplastic Agents↗
PubMed1999

Cellular pharmacology of the combination of oxaliplatin with topotecan in the IGROV-1 human ovarian cancer cell line.

The clinical development of combinations of cisplatin or carboplatin with DNA topoisomerase I (Topo I) inhibitors is based on their overlapping spectrum of antitumor activity and their in vitro synergy, but is limited by significant hematotoxicity. We studied the cellular interactions between oxaliplatin and topotecan in the IGROV-1 human ovarian cancer cell line prior to evaluating the combination in the clinic. Growth inhibition was studied after a 96 h exposure to oxaliplatin and topotecan. The analysis of the cytotoxicity by the isobolograms method revealed supra-additivity with maximal cytotoxicity obtained by giving oxaliplatin prior to topotecan. In the presence of topotecan, the formation of oxaliplatin-induced DNA interstrand crosslinks was not modified in cells, but their reversion was slower, as measured by alkaline elution. Successive topotecan exposures did not affect the level of Topo I-mediated DNA single-strand breaks (SSBs). Pre-exposure to oxaliplatin transiently increased Topo I-mediated SSBs, suggesting that DNA platination might stimulate Topo I DNA cleavage activity. Hence, the cellular pharmacology of oxaliplatin combined with topotecan appeared highly dependent on the schedule. Therefore, this study suggests that the combination of topotecan with oxaliplatin might exhibit sequence-dependent pharmacodynamic interactions in the clinic.

Adenocarcinoma↗