Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2.

BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. RESULTS: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. CONCLUSION: The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.

[Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase: similarity and differences]. / Inhibiteurs de tyrosine kinase (TKI) de l'EGFR: similitudes et différences.

Tyrosine kinase inhibitors (TKI) of EGFR are used in advanced non-small cell lung cancer (NSCLC) in 2(nd) and 3(rd) line, and for gefitinib in first line in case of EGFR mutations. These drugs are particularly active in presence of these mutations, with response rate around 60-70%. Pharmacological data suggest an equivalent effect of erlotinib and gefitinib. One phase II study has directly compared the two drugs in 2(nd) line, with a non significant advantage for gefitinib in term of response and progression-free survival. However, skin tolerance profile was statistically better with gefitinib. Indirect comparisons between erlotinib and gefitinib in the phase III trials vs chemotherapy 1(st) line have to be interpreted, with caution and take under consideration the impact of the chemotherapy arm on the Hazard Ratio for Progression-free and overall survival. However, response rates seem to be equivalent. Cohort and phase IV studies have shown no significant difference for response and survival, and a similar tolerance profile.

Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients.

PURPOSE: The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. METHODS: Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s). RESULTS: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. CONCLUSIONS: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8.

Optimization of cisplatin doses in a testicular cancer patient with acute renal failure.

Although testicular cancers are highly curable malignancies, conventional cisplatin based therapy often causes important toxicities, not often easily manageable. Nephrotoxicity occurs in almost all patients, and is potentialized in patients suffering from renal failure. Monitoring of residual levels of unbound platinum was used to define guidelines for cisplatin administration. Monitoring of cisplatin was initiated in a patient treated for metastatic testicular cancer and acute renal failure. Reduced doses of cisplatin were first administered in conjunction with hemodialysis. Unbound and total platinum levels were determined by flameless atomic absorption spectrophotometry. The data found allowed us to adapt and increase sequentially cisplatin doses, accordingly with the renal function. Full regimen doses were eventually administered when useful renal function returned. This simple approach may be useful in monitoring cisplatin administration during acute renal failure.

Effect of ABCB1 C3435T polymorphism on docetaxel pharmacokinetics according to menopausal status in breast cancer patients.

BACKGROUND: It can be hypothesised that inherited polymorphisms in the drug-transporter ABCB1 gene may interfere with interindividual variations in drug response in breast cancer patients. Docetaxel is a substrate for ABCB1 whose function has been shown to be modulated by oestrogen and progesterone. METHODS: Whether ABCB1 polymorphisms including T-129C, A61G, C1236T, G2677T/A and C3435T polymorphisms could account for variations in the disposition of docetaxel and whether menopausal status at the time of diagnosis might interact with this effect were analysed in women receiving neoadjuvant chemotherapy for breast cancer (n=86). RESULTS: A highly significant association was observed, but restricted to premenopausal women (n=53), between the pharmacokinetics of docetaxel and C3435T polymorphism, as patients with CC genotype had lower mean values of the area under the plasma concentration-time curve (AUC) of docetaxel than patients with CT and TT genotypes (P<0.0001). Comparison between pre- and postmenopausal women with the same C3435T genotype yielded a significant difference in docetaxel AUC only for CC genotype (P<0.0001). CONCLUSION: These results suggest that C3435T polymorphism genotyping and menopausal status at the time of diagnosis might be useful when considering chemotherapy regimens including docetaxel in breast cancer patients.

Antiproliferative activity of PEP005, a novel ingenol angelate that modulates PKC functions, alone and in combination with cytotoxic agents in human colon cancer cells.

PEP005 is a novel ingenol angelate that modulates protein kinases C (PKC) functions by activating PKC delta and inhibiting PKC alpha. This study assessed the antiproliferative effects of PEP005 alone and in combination with several other anticancer agents in a panel of 10 human cancer cell lines characterised for expression of several PKC isoforms. PEP005 displayed antiproliferative effects at clinically relevant concentrations with a unique cytotoxicity profile that differs from that of most other investigated cytotoxic agents, including staurosporine. In a subset of colon cancer cells, the IC(50) of PEP005 ranged from 0.01-140 microM. The antiproliferative effects of PEP005 were shown to be concentration- and time-dependent. In Colo205 cells, apoptosis induction was observed at concentrations ranging from 0.03 to 3 microM. Exposure to PEP005 also induced accumulation of cells in the G1 phase of the cell cycle. In addition, PEP005 increased the phosphorylation of PKC delta and p38. In Colo205 cells, combinations of PEP005 with several cytotoxic agents including oxaliplatin, SN38, 5FU, gemcitabine, doxorubicin, vinorelbine, and docetaxel yielded sequence-dependent antiproliferative effects. Cell cycle blockage induced by PEP005 in late G1 lasted for up to 24 h and therefore a 24 h lag-time between PEP005 and subsequent exposure to cytotoxics was required to optimise PEP005 combinations with several anticancer agents. These data support further evaluation of PEP005 as an anticancer agent and may help to optimise clinical trials with PEP005-based combinations in patients with solid tumours.

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Ifosfamide: pharmacokinetic properties for central nervous system metastasis prevention.

The incidence of central nervous system (CNS) recurrence in patients with lymphoma is about 5%. Nevertheless, this complication is very serious because it is almost always fatal. Its incidence is not sufficiently high to warrant the use of CNS prophylaxis in all patients. The identification of subgroups for whom CNS prophylaxis may be of benefit is therefore important and the age-adjusted international prognostic index (aa-IPI) may be useful in this respect. Ifosfamide (IFO) is a widely used antitumor agent, requiring activation to isophosphoramide mustard (IPM) for DNA alkylation. IFO anabolism occurs through the hepatic microsomal cytochrome P450 system. As with the majority of antineoplastic agents, IFO has toxic side-effects. These include neurotoxicity due to the chloroacetaldehyde (CAA) catabolite. However, the incidence of neurotoxicity is low when IFO is administered as a continuous intravenous infusion. Both inactive IFO and active IPM cross the blood-brain barrier, making IFO treatment effective in the prevention of CNS metastasis in lymphoma patients at high risk of recurrence. The benefit/risk ratio for such patients should evaluated.

Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol.

Topotecan has demonstrated activity in ovarian carcinomas. In order to increase the tumour response rate and to define the maximum tolerated dose (MTD) of topotecan, we decided to develop a high-dose phase I regimen supported by stem cell support. High-doses schedules using a 1-day single administration have MTDs of 10.5 (24 h continuous infusion (CI)) or 22.5 mg/m2 (30 min infusion). Five-day CI induces grade IV mucositis at high doses (MTD<12 mg/m2). We chose to administer topotecan in a 5-day schedule with a 30 min daily infusion. Patients were scheduled to receive one cycle of therapy. The first dose level was 4.0 mg/m2/day x 5 days. Limiting toxicities were defined as toxic death, grade IV non-haematopoietic or haematopoietic toxicity >6 weeks. From August 1998 to April 2002, 49 patients were included. Forty-three patients have completed one course and 15 have received two cycles. One patient treated at level 7 mg/m2/day died of sepsis. Median duration of grade IV neutropenia was 9 days. Two episodes of grade IV diarrhoea were observed at level 9.5 mg/m2/day. Pharmacokinetic data were linear within the dose range of 4-9.0 mg/m2/day. The MTD was reached at 9 mg/m2/day x 5 days.

Drug-induced cardiotoxicity studied by longitudinal B-type natriuretic peptide assays and radionuclide ventriculography.

BACKGROUND: To study the longitudinal variations of plasma B-type natriuretic peptide (BNP) with reference to left ventricular ejection fraction (LVEF) during and after chemotherapy with cardiotoxic drugs. PATIENTS AND METHODS: We prospectively measured plasma BNP using an immunoradiometric assay in 12 anthracycline-treated breast cancer patients monitored for a mean time of 880+/-293 days (pilot group). Prior to each cycle and throughout the following year, LVEF and cardiac output were measured by radionuclide ventriculography. Anthracycline pharmacokinetics was studied during the first cycle. Relationships between serial observations were analysed with the general linear mixed effects model. Identical methods were subsequently applied to a test group of 67 anthracycline or trastuzumab-treated patients. RESULTS: Five out of 70 (6.33%) patients developed anthracycline-induced heart failure. BNP concentrations were found to be positively correlated to anthracycline cumulative dose and negatively to LVEF values. Variables entering the mixed models were cumulative anthracycline dose, time and cardiac output. CONCLUSION: An infra-clinical cardiotoxicity of anthracyclines as defined by BNP elevation is frequent but reversible. Patients who developed heart failure showed a continuous BNP increase and concentrations over 100 ng/ml.

A phase I clinical and pharmacokinetic study of capecitabine (Xeloda) and irinotecan combination therapy (XELIRI) in patients with metastatic gastrointestinal tumours.

Capecitabine is a highly active oral fluoropyrimidine that is an attractive alternative to 5-fluorouracil in colorectal cancer treatment. The current study, undertaken in 27 patients with gastrointestinal tumours, aimed to assess the toxicity and potential for significant pharmacokinetic interactions of a combination regimen incorporating capecitabine with 3-weekly irinotecan (XELIRI). Irinotecan (200 and 250 mg m(-2)) was administered as a 90-min infusion on day 1 in combination with escalating capecitabine doses (700-1250 mg m(-2) twice daily) administered on days 2-15 of a 3-week treatment cycle. Pharmacokinetics were characterised on days 1 and 2 of the first two cycles. A total of 103 treatment cycles were administered. The principal dose-limiting toxicities were diarrhoea and neutropenia. Capecitabine 1150 mg m(-2) twice daily with irinotecan 250 mg m(-2) was identified as the maximum-tolerated dose and capecitabine 1000 mg m(-2) with irinotecan 250 mg m(-2) was identified as the recommended dose for further study. Analyses confirmed that there were no significant pharmacokinetic interactions between the two agents. The combination was clinically active, with complete and partial responses achieved in heavily pretreated patients. This study indicates that XELIRI is a potentially feasible and clinically active regimen in patients with advanced gastrointestinal cancer.

Phase I population pharmacokinetics of irofulven.

Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration-time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35-0.45, 0.80 and 1-1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

Efficacy of prenatal ultrasonography in confirmed club foot.

Club foot can be diagnosed by ultrasound of the fetus in more than 60% of cases. We have correlated the accuracy of the prenatal findings in 281 ultrasound surveys with the physical findings after birth and the subsequent treatment in 147 children who were born with club foot. The earliest week of gestation in which the condition was diagnosed with a high degree of confidence was the 12th and the latest was the 32nd. Not all patients were diagnosed at an early stage. In 29% of fetuses the first ultrasound examination failed to detect the deformity which subsequently became obvious at a later examination. Club foot was diagnosed between 12 and 23 weeks of gestation in 86% of children and between 24 and 32 weeks of gestation in the remaining 14%. Therefore it can be considered to be an early event in gestation (45% identified by the 17th week), a late event (45% detected between 18th and 24th weeks) or a very late event (10% recognised between 25th and 32nd weeks). We cannot exclude, however, the possibility that the late-onset groups may have been diagnosed late because earlier scans were false-negative results. The prenatal ultrasonographic findings were correlated with the physical findings after birth and showed that bilateral involvement was more common than unilateral. There was no significant relationship between the prenatal diagnosis and the postnatal therapeutic approach (i.e., conservative or surgical), or the degree of rigidity of the affected foot.

Identification of cultured progenitor cells from human marrow stroma.

The marrow stromal cells (MSC) are essential for regulation of bone remodeling and hematopoiesis. It is of prime importance to isolate MSC and to expand the proliferating cells ex vivo. In this study, we analyzed cultured MSC for various cellular parameters, including cell morphology, cell cycle, and expression of cell surface antigens by flow cytometry. MSC were divided based on cell size to small (S-cells) and large (L-cells) and were visualized by light and electron microscope. The S-cells were proliferating cells correlated with G0/G1 phase of cell cycle, and expressed cFOS. The expression of surface markers CD-34, -44, -51, -61, -62E, -62P, -62L was quantified using flow cytometry. CD-44 was ubiquitously expressed by S and L cells, CD-51 and -61 were expressed by 30%-38% of S-cells. CD-34 and -62 expressed 20% positive of the analyzed cells that were of the proliferating progenitors (S-cells). This study enables the identification of subpopulations from MSC with special attention paid to the proliferating cells from ex vivo cultures of marrow stroma.

Topotecan preceded by oxaliplatin using a 3 week schedule: a phase I study in advanced cancer patients.

Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P<0.004). In conclusion, the recommended doses of oxaliplatin 110 mg/m(2) and topotecan 1 mg/m(2)/day, every 3 weeks can be administered to patients with a favourable general status and pretreatment characteristics and a phase II study is worthwhile in ovarian cancer patients.

Phase I-II and pharmacokinetic study of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer and ovarian carcinoma.

BACKGROUND: The aim of this study was to determine the toxicity profile, the recommended dose (RD) and the pharmacokinetic parameters, and to evaluate the antitumor activity of gemcitabine combined with oxaliplatin in patients with advanced non-small-cell lung cancer (NSCLC) and ovarian carcinoma (OC). METHODS: Gemcitabine was administered as a 30-min infusion followed by a 2-h infusion of oxaliplatin, repeated every 2 weeks. Doses of gemcitabine and oxaliplatin ranged from 800 to 1500 and 70 to 100 mg/m(2), respectively. RESULTS: Forty-four patients (26 males, 18 females; median age 55 years) including 35 NSCLC (five platinum pretreated) and nine OC patients (all platinum pretreated) received a total of 355 cycles. All patients were evaluable for toxicity. No dose-limiting toxicity at any dose level occurred during the first two cycles; therefore, the highest dose-level of gemcitabine (1500 mg/m(2)) and oxaliplatin (85 mg/m(2)) was considered as the RD. Hematological toxicity was moderate amongst the 22 patients treated (167 cycles) at that dose level. Thirteen cycles were associated with grade 3-4 non-febrile neutropenia in six patients, and eight cycles with grade 3-4 thrombocytopenia in two patients. Other toxicities were mild to moderate, consisting of asthenia and peripheral neurotoxicity. Four of the 35 patients treated with oxaliplatin 85 mg/m(2) experienced grade 3 neurotoxicity requiring treatment discontinuation at cycle 10. In the range of the doses used, gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine appeared not to be affected by oxaliplatin 70-100 mg/m(2). Of the 44 patients evaluable for activity, 12 NSCLC patients experienced objective responses (one complete and 11 partial responses) and three OC patients showed tumor stabilization lasting for 6 months with a 50% decrease of CA 125 level. Two partial responses (NSCLC) and one tumor stabilization (OC) occurred in platinum-resistant patients. CONCLUSIONS: The combination of gemcitabine and oxaliplatin could be safely administered on an out-patient schedule in patients with advanced NSCLC and OC. The RD was gemcitabine 1500 mg/m(2) and oxaliplatin 85 mg/m(2) every 2 weeks. Promising antitumor activity was reported in patients with NSCLC and platinum-pretreated OC, and thus, deserves further evaluation.

Exacerbation of oxaliplatin neurosensory toxicity following surgery.

Combination of chemotherapy and surgical resection of metastases is the most promising strategy to improve the fraction of long-term survivors and cured patients in metastatic colorectal cancer. We reproducibly observed evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection. Among 12 patients, seven (58%) patients reported immediate post-operative aggravation of the pre-existing neurotoxicity. At the time of surgery, we detected high intra-erythrocytic platinum concentrations in all patients (median: 1365 micro g/l, range: 820-2968 micro g/l). While ultrafilterable oxaliplatin was not detectable prior to surgery, it could be detected immediately after surgery and during 48 h. These results suggest that patients heavily pretreated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. This clinical observation might be the consequence of peroperative hemolysis.

Primary chronic sclerosing (Garré's) osteomyelitis in children.

Three children with unifocal nonpyogenic inflammatory bony lesions with a prolonged, fluctuating course are reported. The lesions were located at the metaphyseal region of long bones. Three was progressive sclerosis and hyperostosis in the tibia or femur, such as the changes described in Garré's osteomyelitis. No pus was released by exploration of the lesions. Tissue and blood cultures were negative. The histology was typical of chronic osteomyelitis: the symptoms returned intermittently over several years, together with the development of sclerosis but without disturbance of bone growth. It is not clear whether Garré's chronic sclerosing osteomyelitis is a different entity from chronic recurrent multifocal osteomyelitis.

Differential gene expression of cultured human osteoblasts.

Human cells with osteogenic capacity were studied for differential gene expression. In the first part of the study we compared gene expression of marrow stroma cells (MSC) in comparison to matured osteoblasts cultured from trabecular bone (TBC) that were analyzed by RT-PCR for series of messages. High expression was detected for PTH-r, TGFb1 and biglycan in TBC compared to MSC's. The messages for c-MYC, IL-6, IL-11, M-CSF, osteonectin, and osteocalcin were expressed at the same level in the two populations of cells. In the second part of the study, we analyzed gene expression within the MSC derived from 25 donors (2.5-49 years old) with respect to donors' age and gender. Increased message levels for M-CSF and biglycan were measured in correlation with age of the donors. Gender differences did not affect the expression of cytokines studied (IL-6, IL-11, MCSF, TGFb1). We investigated the effect of Dexamethasone treatment on MSC and monitored an increased expression of IL-11, M-CSF, biglycan, and osteocalcin messages. This study employs primary cell systems (MSC and TBC) to illustrate differential gene expression by osteoblastic cells. The expression was correlated with maturation status of the cells with respect to differences between donors.