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Patrice Viens

Publications and source records attributed to Patrice Viens.

At least 37 records · Page 2Linked to original sources
PubMed2004

Comparative multi-methodological measurement of ERBB2 status in breast cancer.

The ERBB2 transmembrane tyrosine kinase receptor is both a prognostic marker and a therapeutic target in breast cancer. Accurate determination of ERBB2 status is a prerequisite for the establishment of prognostic significance and for the selection of ERBB2-overexpressing breast tumours for specific treatment. Unfortunately, there is no complete agreement on how this determination should be performed. This study has compared four methods of assessment of ERBB2 status. Two global, extraction-based methods using real-time quantitative PCR on DNA (Q-PCR) or RNA (RQ-PCR) and two non-global, tissue-based methods, ie fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), were used. The 94 breast cancers tested were enriched in cases scoring 2+ using the IHC scoring system currently in use and for which the actual ERBB2 status remains ill defined. To determine the best parameters and reagents for assessment, two protocols for FISH and five anti-ERBB2 antibodies were used, and both FISH and IHC were carried out on the same tissue microarrays (TMAs). It is shown that the combination of the two tissue-based methods gives the best results. The use of either PCR-based method did not improve the results significantly. A new combined IHC score based on the association of two selected anti-ERBB2 antibodies (HercepTest trade mark and TAB250) and a dual scale for improved assessment of ERBB2 protein expression, particularly in 2+ cases, are proposed.

Breast Neoplasms↗
PubMed2004

CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: Acute graft-vs-host disease (aGVHD) remains an important cause of morbidity after reduced-intensity conditioning (RIC) allogeneic transplantation (allo-SCT). It has been shown that antithymocyte globulin (ATG) dose infused during RIC is a major determinant for the likelihood of developing aGVHD. The ATG modulation on aGVHD is likely related to in vivo T-cell depletion. PATIENTS AND METHODS: We therefore investigated the relationship between the cellular composition of the allograft and clinical outcome in 57 patients who received allogeneic peripheral blood stem cells from HLA-identical siblings following an ATG-based RIC. RESULTS: In a multivariate analysis, the CD8+ T cell dose infused was the only parameter associated with the risk of aGVHD (p=0.031; RR=1.96; 95% CI, 1.1-3.6). When looking at the extremes, patients experiencing grade III-IV aGVHD received a median of 143 x 10(6)/kg CD8+ T cells, while patients without aGVHD received a median of 96 x 10(6)/kg CD8+ T cells (p=0.021). None of the different cell subtypes contained in the allograft was associated with a significant probability of developing chronic GVHD. Patients with grade II aGVHD who received an intermediate dose of CD8+ T cells (median, 111 x 10(6)/kg) had a significantly better overall survival in comparison to patients with grade 0-I or grade III-IV aGVHD (p=0.009). CONCLUSION: In comparison to myeloablative allo-SCT, these results demonstrate that a cautious monitoring of the number of cells infused, at least in the context of ATG-based RIC, may represent an important predictive indicator of early transplant-related events and outcome after RIC allo-SCT.

Acute Disease↗
PubMed2003

Loss of FHIT protein expression is a marker of adverse evolution in good prognosis localized breast cancer.

The FHIT tumor suppressor gene, which encompasses the fragile site FRA3B at 3p14.2, is altered frequently in many types of human cancers. To determine its importance as a prognostic marker in breast cancer, the expression of the FHIT protein was studied in a series of 452 breast carcinomas by using immunohistochemistry on sections of tissue microarrays. Three distinct levels of FHIT expression were observed: in 154 cases (34.1%) expression was unchanged as compared to normal level; in 78 (17.2%) no expression was found; in the remaining 220 cases (48.7%), expression was intermediate. Overall, two-thirds of the cases had abnormal levels of the protein. Absence of FHIT was significantly associated with a higher grade (p < 0.01) and absence of hormone receptors (p < 0.001). The patients were separated into Group I (153 node-negative good prognosis patients who did not receive adjuvant chemotherapy) and Group II (226 high-risk patients treated by adjuvant chemotherapy) according to the St.-Gallen conference consensus. The median follow-up was 48 months. Among Group I but not Group II patients, a multivariate analysis showed that FHIT expression was significantly associated with disease-free survival. The relative risk of recurrence for FHIT-negative Group I patients was 2.37 (1.21-4.64; p = 0.03). Thus, among the patients who present with tumors of apparent good prognosis, FHIT is an independent prognostic factor that distinguishes a subgroup of patients who could benefit from adjuvant treatment.

Acid Anhydride Hydrolases↗
PubMed2003

Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma.

BACKGROUND: The current Phase II study investigated the clinical benefit, impact on quality of life (QOL), and tolerability of weekly docetaxel in symptomatic patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: Patients received weekly docetaxel 35 mg/m(2) intravenously for 6 consecutive weeks followed by a 2-week rest repeatedly for a maximum of 24 weeks of treatment. Clinical benefit evaluations, based on Karnofsky performance status (KPS) and pain, were assessed weekly during therapy. A clinical benefit response was defined as a sustained (> or = 4-week) improvement in at least one of these parameters without worsening in the other. Patient-assessed QOL (using the European Organization for Research and Treatment of Cancer QLQ-C30), changes in prostate-specific antigen (PSA) levels, tumoral response, and toxicity also were evaluated. RESULTS: Thirty men (median age, 67 years), 15 of whom had received previous chemotherapy, were treated. Overall, 46% of patients achieved a positive pain response and 48% achieved a 50%-or-greater reduction in PSA. KPS was high at baseline (80%), and no significant changes in this parameter were observed. Compared with baseline, all scores improved after the first cycle of therapy, particularly emotional (P = 0.015), pain (P = 0.001), constipation (P = 0.001), and global QOL (P = 0.011) scores. After the second cycle, dyspnea scores decreased (P = 0.010). At the last QOL assessment, there also was deterioration in terms of fatigue (P = 0.013), dyspnea (P = 0.010), and physical functioning (P = 0.017). Toxicity was mild and included neutropenia (Grade 3-4, n = 2). CONCLUSIONS: Of these elderly symptomatic patients with HRPC, half had received previous chemotherapy. Weekly docetaxel was found to be associated with improvements in clinical benefit response and in QOL and was well tolerated.

Aged↗
PubMed2003

Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors.

In this prospective multicenter program, we investigated allogeneic stem cell transplantation (ASCT) from HLA-identical siblings following reduced-intensity conditioning (RIC) regimen for patients with refractory metastatic solid tumors (STs). Fifty-seven patients, of whom 39 had a progressive disease (PD) at time of ASCT, received an RIC ASCT combining fludarabine, antithymocyte globulin (ATG), and busulfan. Patients were analyzed in terms of engraftment, transplant-related mortality (TRM), disease response, and outcome. In this setting, RIC was associated with rapid engraftment and low overall TRM (9% [95% confidence interval (CI), 1%-16%]). The cumulative incidence of objective responses (ORs) reached 14% (95% CI, 6%-30%) with this being significantly higher in patients without PD (44% [95% CI, 21%-67%] versus 0; P <.0001) at time of ASCT. Achievement of OR translated into a significantly better overall survival (OS). In multivariate analysis, OS was significantly influenced by disease status at time of ASCT (odds ratio, 4.88; P <.001) and chronic graft-versus-host disease (GVHD) occurrence (odds ratio, 2.86; P <.01). Overall, these results showed that OR can occur after RIC ASCT for resistant ST with a relatively low TRM and potential benefit especially in patients with slowly progressive disease. Further studies are warranted in patients with less advanced ST.

Acute Disease↗
PubMed2003

Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen.

Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P =.0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P =.0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P =.02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.

Acute Disease↗
PubMed2003

Breast cancer revisited using DNA array-based gene expression profiling.

Breast cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. The resulting clinical heterogeneity makes current diagnostic and therapeutic strategies less than perfectly adapted to each patient. Pathological and clinical factors are insufficient to capture the complex cascade of events that drive the clinical behavior of tumors. High-throughput molecular technologies provide novel tools to tackle this complexity. In particular, DNA arrays allow the simultaneous and quantitative analysis of the mRNA expression levels of thousands of genes in a single assay. Potential applications are multiple in the cancer field and the first research results are promising; comprehensive gene expression profiles of breast tumors are providing insights into mammary oncogenesis and are revealing new tumor subgroups previously indistinguishable. Significant advances will be the identification of new diagnostic, prognostic and predictive biomarkers as well as the discovery of new potential therapeutic targets. This review presents recent applications of DNA arrays in breast cancer research and discusses some issues to address in the near future to allow the technology to reach its full potential.

Breast Neoplasms↗
PubMed2003

Nurses' repeat measurement of chemotherapy symptoms: feasibility, resulting information, patient satisfaction.

The aim of this study was to investigate the feasibility and acceptability of a repeated measurement of 5 major side effects (pain, nausea, vomiting, anxiety, and fatigue) experienced by patients during an entire course of chemotherapy. Forty-nine inpatients receiving intravenous chemotherapy in the Medical Oncology Department of the Institut Paoli-Calmettes (Marseilles, France) were included in the study. At the study entry and every 12 hours from beginning of chemotherapy course, nurses assessed symptoms using Visual Analogic Scales (except for vomiting measured in number of episodes). Patients' pretreatment characteristics and their degree of satisfaction with nursing assessment were also recorded. The mean number of symptom measures was 2.9 in courses of less than 3 days, 5.4 in courses of 3 days, and 7.5 in courses of more than 3 days. Symptom patterns varied according to length of course. Furthermore, patients' pretreatment characteristics (age, sex, marital status, education level, type of cancer) had an impact on symptom scores at baseline and during treatment. About 80% of patients judged the nursing assessment as not constraining and 55% considered that its impact on their care was positive. This study demonstrates that repeated measurement of chemotherapy side effects was feasible and provide useful information for symptom management that might increase patient treatment satisfaction.

Adult↗
PubMed2003

DNA arrays in clinical oncology: promises and challenges.

Cancer is a complex genetic disease characterized by the accumulation of multiple molecular alterations. Current diagnostic and prognostic classifications, based on clinical and pathologic factors, are insufficient to reflect the whole clinical heterogeneity of tumors. Most current anticancer agents do not differentiate between cancerous and normal cells, leading sometimes to disastrous adverse effects. Recent advances in human genome research and high-throughput molecular technologies make it possible finally to tackle the molecular complexity of malignant tumors. With DNA array technology, mRNA expression levels of thousands of genes can be measured simultaneously in a single assay. Oncology is benefiting on multiple fronts. Gene expression profiles are revealing new biologically and clinically relevant tumor subclasses previously indistinguishable and are identifying new diagnostic and prognostic biomarkers as well as new potential therapeutic targets. Here, we review the technology and present clinical applications for which promising results have been obtained. Finally, we discuss issues that must be resolved in the near future to allow DNA arrays to translate into benefits for cancer patients.

Gene Expression Profiling↗
PubMed2003

Can sequential administration minimise the cost of high dose chemotherapy? An economic assessment in inflammatory breast cancer.

OBJECTIVE: To evaluate the potential cost savings of using sequential high dose chemotherapy (HDC), with granulocyte colony-stimulating factor (filgrastim) and stem cell support, rather than single course administration of HDC with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). PERSPECTIVE: French public hospital perspective. METHODS: Direct medical costs of sequential treatment, estimated on the basis of physical quantities of resources consumed by 95 patients with inflammatory breast cancer (IBC) included in a French pilot multicentric trial (PEGASE 02), were compared with those of historical control groups of patients treated with single course HDC, either with BMT (n = 27) or PBSCT (n = 14). Costs were evaluated in 1998 French francs (1 Euro = 6.55957 French francs). RESULTS: The total cost of sequential HDC was significantly lower than that for single course HDC both with BMT (-29%; 22,755 Euros vs 32,284 Euros; p < 0.001) or PBSCT (-16%; 22,755 Euros vs 27,209 Euros; p = 0.026). This was mainly due to a reduction in the length of hospitalisation in transplantation units. CONCLUSION: According to our results, economic arguments cannot be used against the widespread use of sequential HDC for patients with IBC. However, further economic evaluations based on overall and disease-free survivals alongside a randomised clinical trial are still needed to definitively establish the cost effectiveness of sequential administration of HDC.

Adolescent↗
PubMed2003

Phase I and pharmacokinetic study of escalating dose of docetaxel administered with granulocyte colony-stimulating factor support in adult advanced solid tumors.

PURPOSE: The purpose of our study was to assess the feasibility, toxicity, and pharmacokinetics of an escalating dose of docetaxel when administered with granulocyte colony-stimulating factor (G-CSF) support every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were treated with escalating doses of docetaxel as a 1-h infusion every 3 weeks, supported by s.c. administration of human recombinant glycosilated G-CSF Granocyte (lenograstim), 5 microg/kg/day (from day 4 until neutrophil count >0.5-10(g)/liter for two consecutive days). Plasma sampling was performed to characterize the pharmacokinetics of docetaxel at the new recommended high-dose level. RESULTS: Forty-seven patients were treated with 116 courses of docetaxel at eight dose levels ranging from 100-185 mg/m(2). Dose-limiting toxicities were nonhematologic and included mucositis and dermatitis. Severe skin toxicity observed at 185 mg/m(2) led to discontinuing the study, and 175 mg/m(2) was selected as the recommended dose of docetaxel + G-CSF for future Phase II studies. Analysis of multiple courses revealed dermatitis, mucositis, arthralgia/myalgia, and neuropathy as the main dose-related toxic events. At 175 mg/m(2) mean +/- SD values for docetaxel plasmatic peak, area under the curve, clearance, volume of distribution, and terminal half-life were 6.7 +/- 1.7 microg/ml, 9.7 +/- 4 microg.h/ml, 34.2 +/- 12 liters/h, and 122.7 +/- 124 liters, respectively. Of the 16 patients treated at 175 mg/m(2), 8 patients responded (7 breast cancer and 1 lung cancer patients) including one complete response (1 breast cancer patient). CONCLUSIONS: Using G-CSF support allows substantial dose escalation of docetaxel. Whether such a dose increase improves the response rate warrants further investigation. At the highest dose level studied, pharmacokinetic parameters seem to maintain a linear profile.

Adult↗
PubMed2003

[Risk of stage underestimation of breast cancer by sentinel lymph node biopsy method].

Sentinel lymph node (SLN) biopsy is fast becoming the standard for testing lymph node involvement in many institutions. However questions remain as to stage underestimation. The aim of this study was to analyse this specific risk in a retrospective study. Between 1975 to 1999, 1,636 patients underwent a breast cancer excision and an axillary lymph node dissection (ALND) for 437 T0, 766 T1 or 433 T2 < or = 30 mm breast cancer without axillary lymph node involvement (NO). We analyse this population because of similar characteristics with SLN biopsy present indication. Node involvement rate was analysed regarding predictive factors of lymph node involvement (LNI): pathologic diameter, grading, peritumoral vascular embols, hormonal receptors, menopause and age. Risk of no adjuvant chemotherapy indication in case of SLN biopsy method using was analysed for pre and post menopaused women. Overall lymph node involvement was 27% (444/1,636): 17% for TO stage (74/437), 26% for T1 stage (202/766), 39% for T2 < or =30 mm stage (168/433). LNI was similar for ductai and lobular invasive breast cancer respectively 27,4% (308/1,125) and 24,3% (52/214). On the other hand LNI rate was sign lower for tubular, medullar and colloids cancers: 15% (20/155). Univariate and multivariate statistical analysis showed LNI significative predictive factors: vascular embols, grade III, age < or = 50 years, tumor diameter > 30 mm. Lymph node involvement rate was defined regarding grading, vascular embols and tumor diameter with increasing rate according to different sub-groups. Among pre-menopaused patients with a false negative rate of SLN of 5%, SLN biopsy without ALND give a specific risk of wrong non-adjuvant chemotherapy indication of 1,4 case/1,000. Among menopaused patients SLN biopsy without ALND give a specific risk of 0,93 cases/1,000. Expected LNI regarding major predictive factors (vascular embols, grading and tumor diameter) allows SLN biopsy risk/benefit evaluation in different sub-groups. SLN biopsy indication could he improved according these data which could be obtain pre-operatively by micro-biopsy.

Breast Neoplasms↗
PubMed2003

[Inflammatory breast carcinoma: towards molecular characterization?].

Inflammatory Breast Carcinoma (IBC) is a rare but aggressive form of breast carcinoma. Characteristic clinical and pathological features are well documented. Pathological response to chemotherapy is currently the only identified prognostic factor. This high-grade tumor exhibits phenotypical features of an aggressive tumor: absence of hormonal receptors in 56 to 83% of cases, high proliferating index, p53 expressed in 30 to 69%, Immunohistochemistry (IHC) detection of HER2 over expression in 38 to 60%. Current work on IBC points out specific molecular mechanisms: adhesion molecules such as E-Cadherin, apomucin MUC1 and angiogenesis processes contribute to the IBC phenotype. So does a gene named WISP3. This gene has been recently cloned and sequenced. It has been shown to be lost in IBC and could control tumor growth, invasion, and angiogenesis. This paper summarizes current knowledge on IBC and describes a new basis for a molecular definition of IBC.

Breast Neoplasms↗
PubMed2002

Efficacy and tolerance of a scalp-cooling system for prevention of hair loss and the experience of breast cancer patients treated by adjuvant chemotherapy.

The applicability and efficacy of a scalp cooling system were studied in 105 breast cancer patients receiving four cycles of adjuvant chemotherapy with mitoxantrone + cyclophosphamide (NC chemotherapy). Women accepting the scalp-cooling system were compared for alopecia both against those who refused and against a "reference" group of 109 patients similarly treated but without being offered a scalp-cooling system. Hair loss in the 105 study patients was evaluated by nurses using World Health Organization (WHO) criteria at each cycle of chemotherapy. Concomitantly, tolerance and side-effects of the helmet were also recorded in 48 accepting patients. Similarly to reference group patients, a subsample of 27 accepting patients self-assessed hair loss using a specific questionnaire measuring its frequency and severity and the distress associated with this symptom. Nurses' ratings ( n = 105) indicated that hair loss frequency was constantly lower, at each cycle of chemotherapy, in study patients with scalp-cooling system ( n = 77) than in those without ( n = 28). Differences between the two groups were statistically significant at cycles 1 and 3 ( P < 0.05). When compared with those reported by reference group patients ( n = 109), study patients' self-measures of alopecia frequency ( n = 27) provided even more marked results than those achieved by nurses (cycles 1-3: P < 0.01; cycle 4: P < 0.05). Tolerance was generally good and no scalp metastasis was observed among the 77 accepting patients followed up. This study demonstrates that scalp cooling was an effective method of protection against hair loss caused by NC chemotherapy. Its routine use as part of adjuvant chemotherapy, especially in cancers with low prevalences of scalp metastasis, should be seriously considered.

Adult↗
PubMed2002

Gene expression profiles of poor-prognosis primary breast cancer correlate with survival.

The extensive heterogeneity of breast cancer complicates the precise assessment of tumour aggressiveness, making therapeutic decisions difficult and treatments inappropriate in some cases. Consequently, the long-term metastasis-free survival rate of patients receiving adjuvant chemotherapy is only 60%. There is a genuine need to identify parameters that might accurately predict the effectiveness of this treatment for each patient. Using cDNA arrays, we profiled tumour samples from 55 women with poor-prognosis breast cancer treated with adjuvant anthracycline-based chemotherapy. Gene expression monitoring was applied to a set of about 1000 candidate cancer genes. Differences in expression profiles provided molecular evidence of the clinical heterogeneity of disease. First, we confirmed the capacity of a 23-gene predictor set, identified in a previous study, to distinguish between tumours associated with different survival. Second, using a refined gene set derived from the previous one, we distinguished, among the 55 clinically homogeneous tumours, three classes with significantly different clinical outcome: 5-year overall survival and metastasis-free survival rates were respectively 100% and 75% in the first class, 65% and 56% in the second and 40% and 20% in the third. This discrimination resulted from the differential expression of two clusters of genes encoding proteins with diverse functions, including the estrogen receptor (ER). Another finding was the identification of two ER-positive tumour subgroups with different survival. These results indicate that gene expression profiling can predict clinical outcome and lead to a more precise classification of breast tumours. Furthermore, the characterization of discriminator genes might accelerate the development of new specific and alternative therapies, allowing more rationally tailored treatments that are potentially more efficient and less toxic.

Breast Neoplasms↗
PubMed2002

Distinct and complementary information provided by use of tissue and DNA microarrays in the study of breast tumor markers.

Emerging high-throughput screening technologies are rapidly providing opportunities to identify new diagnostic and prognostic markers and new therapeutic targets in human cancer. Currently, cDNA arrays allow the quantitative measurement of thousands of mRNA expression levels simultaneously. Validation of this tool in hospital settings can be done on large series of archival paraffin-embedded tumor samples using the new technique of tissue microarray. On a series of 55 clinically and pathologically homogeneous breast tumors, we compared for 15 molecules with a proven or suspected role in breast cancer, the mRNA expression levels measured by cDNA array analysis with protein expression levels obtained using tumor tissue microarrays. The validity of cDNA array and tissue microarray data were first verified by comparison with quantitative reverse transcriptase-polymerase chain reaction measurements and immunohistochemistry on full tissue sections, respectively. We found a good correlation between cDNA and tissue array analyses in one-third of the 15 molecules, and no correlation in the remaining two-thirds. Furthermore, protein but not RNA levels may have prognostic value; this was the case for MUC1 protein, which was studied further using a tissue microarray containing approximately 600 tumor samples. For THBS1 the opposite was observed because only RNA levels had prognostic value. Thus, differences extended to clinical prognostic information obtained by the two methods underlining their complementarity and the need for a global molecular analysis of tumors at both the RNA and protein levels.

Base Sequence↗
PubMed2002

Transient detection of beta-galactosidase activity in hematopoietic cells, following reinjection of retrovirally marked autologous blood progenitors in patients with breast or ovarian cancer receiving high-dose chemotherapy.

OBJECTIVE: The aim of this report is to demonstrate the feasibility and safety of genetically modifying autologous human blood CD34(+) cells in vitro, with a retroviral vector that encodes a marker gene. The fate of genetically modified cells and their progeny was followed in vivo, after reinfusion in patients treated with high-dose chemotherapy for poor-prognosis breast or ovarian carcinomas. PATIENTS AND METHODS: Six patients received genetically modified autologous peripheral blood progenitors, together with unmanipulated aphereses, following high-dose chemotherapy. CD34(+) cells were immunoselected from aphereses, and retrovirally transduced by coculture with the retroviral vector producing cell line, to express a nuclear localized version of E. coli beta-galactosidase, encoded by a defective Moloney-murine leukemia virus-derived retroviral vector. Cells were reinfused to the patients after myeloablation, without prior ex vivo selection. RESULTS: Five out of six patients showed the transient presence of low numbers of beta-galactosidase(+) cells, as detected with an immunocytochemical assay, in the peripheral blood, during the first month following infusion. One patient had beta-galactosidase(+) clonogenic progenitors in her marrow at two months after transplantation, including HPP-CFC; intriguingly, this patient had the lowest percentage of X-gal(+) cells in her graft. Patients experienced side effects that are often observed after high-dose chemotherapy. CONCLUSIONS: Feasibility and safety of genetic modification of human hematopoietic stem and progenitor cells are demonstrated by this study. Ex vivo or in vivo selection is not mandatory, even in clinical situations where transduced cells have no survival advantage over wild-type cells; however, significant improvements in gene transfer technology are needed to achieve potentially useful levels of expression in such clinical situations.

Aged↗