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At least 1,063 records · Page 59Linked to original sources
PubMed2000

Tacrolimus does not abrogate the increased risk of acute graft-versus-host disease after unrelated-donor marrow transplantation with allelic mismatching at HLA-DRB1 and HLA-DQB1.

One hundred patients of median age 34 years (range, 14-53) received bone marrow transplants from unrelated donors serologically matched for human leukocyte antigen HLA-A, HLA-B, and HLA-DR using tacrolimus and minimethotrexate for prevention of acute graft-versus-host disease (GVHD). Sixty-eight patient-donor pairs had allelic matches at HLA-DRB1 and HLA-DQB1, 20 pairs had a single mismatch at HLA-DRB1 or HLA-DQB1, and 12 were mismatched at both HLA-DRB1 and HLA-DQB1. Minimum follow-up time was 6 months. Grades 2 to 4 GVHD occurred in 43% of patients with matched donors, 69% with single allele-mismatched donors, and 71% with double allele-mismatched donors; grades 3 to 4 GVHD occurred in 22%, 43%, and 64%, respectively. On multivariate analysis, the relative risk of grades 2 to 4 GVHD was 2.2 (95% CI, 1.1-4.5; P = .03) with a single allele mismatch and 2.7 (95% CI, 1.2-6.0; P = .02) with a double allele mismatch. The relative risks of grades 3 to 4 GVHD were 3.0 (95% CI, 1.2-7.6; P = .02) and 5.0 (95% CI, 1.9-12.6; P = .001), respectively. Day 100 treatment-related mortality was also adversely affected by allelic mismatching, occurring in 21% of those with matched donors, 50% with single allele-mismatched donors, and 42% with double allele-mismatched donors (P = .02), but overall survival at day 180 did not differ significantly among the 3 groups. Tacrolimus does not abrogate the adverse impact of allele mismatching at HLA-DRB1 and HLA-DQB1 on the risk of moderate-to-severe acute GVHD.

Acute Disease↗
PubMed2001

[Quantitative expression of the adhesion receptors VLA-4, VLA-5, L-selectin, MAC-1, and ICAM-1 on the surface of CD34+ cells].

The aim of this work was to quantify by flow cytometry the main adhesion receptors on CD34+ cells. These cells were isolated from bone marrow (BM) or mobilized peripheral blood (PB). The proportions of CD34+/CD49d+ and CD34+/CD49e+ are weaker on PB cells, without quantitative expression variation. This phenotypic variation may induce CD34+ cells exist from BM into circulation, promoting the mobilization. The homing to the BM implicate the CD62L receptor, which expression was found more frequently and stronger on PB cells than on BM. The CD11b, CD18 and CD54 receptors are implicated in CD34+ cells adhesion to BM micro-environment. No significant variation in CD34+/CD11b+ and CD34+/CD18+ cells frequency was noted. Moreover, CD54 receptor was more frequently expressed on PB cells. Quantitative analysis revealed that CD18 was more strongly expressed on BM than on PB cells. This quantitative variation could promote progenitor adhesion by interacting with stromal cells. Finally, quantitative expression of the main receptors on CD34+ cells provides an original option for studying CD34+ cells during the mobilization, the homing or the adhesion to BM micro-environment.

Antigens, CD↗
PubMed2003

The development of supportive-care agents for patients with cancer.

As the population ages, a dramatic increase in the number of cases of cancer is expected and the need for supportive-care agents, those used to ameliorate some of the side effects of cancer or its treatment, becomes more urgent. At present, supportive-care products are available and new agents are being developed with novel mechanisms of action or modifications of existing agents that improve performance. Because of the urgent need for such products, efficient development is required to deliver useful products to patients as rapidly as possible. This chapter uses actual examples to illustrate the stages of drug development, phase I through phase 3.

Anemia↗
PubMed2005

Chemotherapy-induced anaemia during adjuvant treatment for breast cancer: development of a prediction model.

BACKGROUND: At present, oncologists prescribe chemotherapy according to standard dose schedules, and as a result many patients develop serious, dose-limiting toxic effects such as anaemia. We aimed to develop a prediction model for anaemia in patients with breast cancer who were receiving adjuvant chemotherapy. METHODS: We reviewed medical records of 331 patients who had received adjuvant chemotherapy for breast cancer. Patients were divided randomly into a derivation sample (n=221) and internal-validation sample (n=110). An external sample of 119 patients enrolled onto the control group of a randomised trial of epoetin alfa was used to validate the model further. Multivariable logistic regression was applied to develop the initial model. We then developed a risk-scoring system, ranging from 0 (low risk) to 50 (high risk), based on the final regression variables. A receiver operating characteristic (ROC) curve analysis was done to measure the accuracy of the scoring system when applied to both validation samples. FINDINGS: The risk of anaemia increased as the pretreatment haemoglobin concentration decreased and was reduced with successive chemotherapy cycles. Risk was also predicted by a platelet count of 200x10(9) cells/L or less before chemotherapy, age 65 years or older, type of adjuvant chemotherapy, and use of prophylactic antibiotics. ROC analysis had acceptable areas under the curve of 0.88 for the internal-validation sample and 0.84 for the external validation sample. A risk score of > or = 24 to < 25 before chemotherapy was identified as the optimum cut-off for maximum sensitivity (83.5%) and specificity (92.3%) of the prediction model. INTERPRETATION: The application and continued refinement of this prediction model will help oncologists to identify patients at risk of developing anaemia during chemotherapy for breast cancer, and might enhance patient-centred care by the application of anaemia treatment in a proactive and appropriate way.

Aged↗
PubMed2005

Impact of uncertainty on cost-effectiveness analysis of medical strategies: the case of high-dose chemotherapy for breast cancer patients.

OBJECTIVES: The object of this study was to determine, taking into account uncertainty on cost and outcome parameters, the cost-effectiveness of high-dose chemotherapy (HDC) compared with conventional chemotherapy for advanced breast cancer patients. METHODS: An analysis was conducted for 300 patients included in a randomized clinical trial designed to evaluate the benefits, in terms of disease-free survival and overall survival, of adding a single course of HDC to a four-cycle conventional-dose chemotherapy for breast cancer patients with axillary lymph node invasion. Costs were estimated from a detailed observation of physical quantities consumed, and the Kaplan-Meier method was used to evaluate mean survival times. Incremental cost-effectiveness ratios were evaluated successively considering disease-free survival and overall survival outcomes. Handling of uncertainty consisted in construction of confidence intervals for these ratios, using the truncated Fieller method. RESULTS: The cost per disease-free life year gained was evaluated at 13,074 Euros, a value that seems to be acceptable to society. However, handling uncertainty shows that the upper bound of the confidence interval is around 38,000 Euros, which is nearly three times higher. Moreover, as no difference was demonstrated in overall survival between treatments, cost-effectiveness analysis, that is a cost minimization, indicated that the intensive treatment is a dominated strategy involving an extra cost of 7,400 Euros, for no added benefit. CONCLUSIONS: Adding a single course of HDC led to a clinical benefit in terms of disease-free survival for an additional cost that seems to be acceptable, considering the point estimate of the ratio. However, handling uncertainty indicates a maximum ratio for which conclusions have to be discussed.

Adolescent↗
PubMed1996

Affinity chromatography with immunochemical detection applied to the analysis of human methionyl granulocyte colony stimulating factor in serum.

An on-line, automated, HPLC method was developed for the separation and detection of recombinant human methionyl granulocyte colony stimulating factor (GCSF) and GCSF modified with poly(ethylene glycol) (PEG-GCSF) in rat serum. The automated method consists of an initial immunoaffinity chromatography step, a microbore reverse phase separation, and postcolumn immunochemical detection. Calibration curves were constructed with a lower limit of 1.5 ng of GCSF (80 fmol) and 7.5 ng of PEG-GCSF in 120 microL of rat serum. In vivo serum samples from rats dosed with PEG-GCSF were also analyzed. The development of the method is discussed as well as its general application to the detection of metabolites of recombinant proteins in body fluids.

Animals↗
PubMed1997

Phase I study of paclitaxel on a 3-hour schedule followed by carboplatin in untreated patients with stage IV non-small cell lung cancer.

This study sought to determine the principal toxicities and feasibility of administering paclitaxel as a 3-hour infusion followed by carboplatin without and with granulocyte colony-stimulating factor (G-CSF) in chemotherapy-naive patients with stage IV non-small cell lung carcinoma (NSCLC), and to recommend doses for subsequent clinical trials. Twenty-three patients were treated with paclitaxel at doses ranging from 175 to 225 mg/m2 followed by carboplatin targeting area under the concentration-time curve (AUC) 7 or 9 mg/mL.min every 3 weeks. AUCs were targeted using the Calvert formula with estimated creatinine clearance as a surrogate for the glomerular filtration rate. A high rate of intolerable, mutually exclusive toxicities, consisting primarily of thrombocytopenia, as well as neutropenia, nausea and vomiting, and mucositis, precluded escalation of carboplatin above a targeted AUC of 7 mg/mL.min with paclitaxel 225 mg/m2, which approaches the maximum tolerated dose (MTD) of paclitaxel given as a single agent on a 3-hour schedule. Moderate to severe peripheral neurotoxicity occurred in several patients after multiple courses. Due to the heterogeneous nature of the principal toxicities and the ability to administer clinically-relevant doses of both agents in combination without G-CSF, further dose escalation using G-CSF was not performed. Nine of 23 (39%) total patients and 43% of 21 assessable patients had partial responses (PR). The recommended doses for subsequent clinical trials are paclitaxel 225 mg/m2 as a 3-hour infusion followed by carboplatin at a targeted AUC of 7 mg/mL.min. The ability to administer clinically-relevant single agent doses of paclitaxel and carboplatin in combination, as well as the significant antitumor activity noted in this phase I trial, indicate that further evaluations of this regimen in both advanced and early stage NSCLC are warranted.

Aged↗
PubMed2000

Evaluation of pre-radiotherapy cyclophosphamide in patients with newly diagnosed glioblastoma multiforme. Writing Committee for The Brain Tumor Center at Duke.

Cyclophosphamide is an alkylating agent that has shown activity in the treatment of pediatric brain tumors, including high-grade gliomas. This study was designed to evaluate the response of patients with newly diagnosed glioblastoma multiforme to pre-radiotherapy cyclophosphamide. Fourteen patients with glioblastoma multiforme were treated with high-dose cyclophosphamide (2 g/m2/day for 2 doses every 28 days) followed by either sargramostim or filgrastin. Sargramostim was given 250 microg/m2 subcutaneously twice a day continuing through the leukocyte nadir until the absolute neutrophil count was more than 1000 cells/microl for 2 consecutive days. The filgrastin dose was 10 microg/kg given subcutaneously once daily until the post nadir absolute neutrophil count was > or = 10,000 cells/microl. A total of 46 courses was given. Four patients received a total of 3 courses, 7 patients completed 4 courses and 3 patients received 2 courses. Three patients demonstrated complete response; 3 stable disease; and 8 progressive disease. The most common toxicity was hematologic, requiring platelet and packed red blood cell transfusions, with 13 admissions for neutropenia with fever. There were no deaths related to infection or bleeding. These results suggest that high-dose cyclophosphamide has modest activity with acceptable toxicity against newly diagnosed glioblastoma multiforme.

Adolescent↗
PubMed2001

Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients.

BACKGROUND: The majority of high-dose chemotherapy (HDC)-related complications results from bone marrow aplasia, but the graft infusion per se may cause adverse reactions due to the injection of both dimethyl sulfoxide (DMSO) and cell lysis products. We evaluated the feasibility of a two-step chemotherapy regimen with peripheral blood progenitor cell (PBPC) support in association with a novel procedure to remove DMSO and products of cell lysis from the cryopreserved cells. PATIENTS AND METHODS: Stage III and IV breast cancer patients received induction chemotherapy with three cycles of CEF (cyclophosphamide 600 mg/m2, epirubicin 100 mg/m2, 5-fluorouracil 600 mg/m2) followed by three cycles of HDC consisting of escalating doses of cyclophosphamide (dose range 1200 3000 mg/m2) and carboplatin (dose range 600-1000 mg/m2), supported by DMSO-free PBPC reinfusion. DMSO was removed by a washing/enzymatic digestion procedure. RESULTS: Twenty patients received induction chemotherapy and eighteen completed the entire chemotherapy program; a total of fifty-four cycles of HDC were administered. Dose limiting toxicity of HDC was long-lasting grade 4 neutropenia associated with documented infection. The maximum tolerated dose (MTD) was cyclophosphamide 3000 mg/m2 and carboplatin 600 mg/m2. No side effects related to PBPC reinfusion were observed. CONCLUSIONS: The proposed two-step chemotherapy regimen, associated with a novel washing/enzymatic digestion procedure, is feasible in advanced breast cancer patients in the absence of complications related to the specific toxicity of PBPC reinfusion.

Adult↗
PubMed2002

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone.

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.

Bone Neoplasms↗
PubMed2004

High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

The aim of the present study was to evaluate the role of a weekly preoperative chemotherapy in locally advanced, unresectable gastric cancer. In all, 82 patients with an Eastern Oncology Cooperative Group PS <or=2 and normal cardiac function were enrolled onto the study. Surgical unresectability was confirmed in 52 patients (63%) at laparotomy, and in 30 (27%) cases by CT scan of the abdomen and endoscopic ultrasonography. Chemotherapy treatment was: cisplatin 40 mg x m(-2); 5-fluorouracil 500 mg x m(-2); epidoxorubicin 35 mg x m(-2); 6S-leucovorin 250 mg x m(-2) and glutathione 1.5 g x m(-2) (PELF). One cycle consisted of 8 weekly treatments. Response to chemotherapy was observed in 40 of 82 patients (49%): six (7%) complete and 34 (41%) partial responses, and in four (5%) cases a complete pathological response was confirmed. Of the 40 responding patients, 37 (45%) had potentially curative surgery. Grade 3/4 leucopenia and thrombocytopenia occurred in three and two patients. At a median follow-up of 48 months, 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free. The median and 4-year survival for the whole group was 17 months and 31%, respectively. The median survival was 12 months for inoperable patients and it was not reached in resected patients.

Adult↗
PubMed1999

Stage III and oestrogen receptor negativity are associated with poor prognosis after adjuvant high-dose therapy in high-risk breast cancer.

We report on the efficacy and toxicity of a sequential high-dose therapy with peripheral blood stem cell (PBSC) support in 85 patients with high-risk stage II/III breast cancer. There were 71 patients with more than nine tumour-positive axillary lymph nodes. An induction therapy of two cycles of ifosfamide (total dose, 7.5 g m(-2)) and epirubicin (120 mg m(-2)) was given, and PBSC were harvested during G-CSF-supported leucocyte recovery following the second cycle. The PBSC-supported high-dose chemotherapy consisted of two cycles of ifosfamide (total dose, 12,000 mg m(-2)), carboplatin (900 mg m(-2)) and epirubicin (180 mg m(-2)). Patients were autografted with a median number of 3.7 x 10(6) CD34+ cells kg(-1) (range, 1.9-26.5 x 10(6)) resulting in haematological reconstitution within approximately 2 weeks following high-dose therapy. The toxicity was moderate in general, and there was no treatment-related toxic death. Twenty-one patients relapsed between 3 and 30 months following the last cycle of high-dose therapy (median, 11 months). The probability of disease-free and overall survival at 4 years were 60% and 83%, respectively. According to a multivariate analysis, patients with stage II disease had a significantly better probability of disease-free survival (74%) in comparison to patients with stage III disease (36%). The probability of disease-free survival was also significantly better for patients with oestrogen receptor-positive tumours (70%) compared to patients with receptor-negative ones (40%). Bone marrow samples collected from 52 patients after high-dose therapy were examined to evaluate the prognostic relevance of isolated tumour cells. The proportion of patients presenting with tumour cell-positive samples did not change in comparison to that observed before high-dose therapy (65% vs 71%), but a decrease in the incidence and concentration of tumour cells was observed over time after high-dose therapy. This finding was true for patients with relapse and for those in remission, which argues against a prognostic significance of isolated tumour cells in bone marrow. In conclusion, sequential high-dose chemotherapy with PBSC support can be safely administered to patients with high-risk stage II/III breast cancer. Further intensification of the therapy, including the addition of non-cross resistant drugs or immunological approaches such as the use of antibodies against HER-2/NEU, may be envisaged for patients with stage III disease and hormone receptor-negative tumours.

Adult↗
PubMed1999

First-line high-dose sequential chemotherapy with rG-CSF and repeated blood stem cell transplantation in untreated inflammatory breast cancer: toxicity and response (PEGASE 02 trial).

Despite the generalization of induction chemotherapy and a better outcome for chemosensitive diseases, the prognosis of inflammatory breast cancer (IBC) is still poor. In this work, we evaluate response and toxicity of high-dose sequential chemotherapy with repeated blood stem cell (BSC) transplantation administered as initial treatment in 100 women with non-metastatic IBC. Ninety-five patients (five patients were evaluated as non-eligible) of median age 46 years (range 26-56) received four cycles of chemotherapy associating: cyclophosphamide (C) 6 g m(-2) - doxorubicin (D) 75 mg m(-2) cycle 1, C: 3 g m(-2) - D: 75 mg m(-2) cycle 2, C: 3 g m(-2) - D: 75 mg m(-2) - 5 FU 2500 mg m(-2) cycle 3 and 4. BSC were collected after cycle 1 or 2 and reinfused after cycle 3 and 4. rG-CSF was administered after the four cycles. Mastectomy and radiotherapy were planned after chemotherapy completion. Pathological response was considered as the first end point of this trial. A total of 366 cycles of chemotherapy were administered. Eighty-seven patients completed the four cycles and relative dose intensity was respectively 0.97 (range 0.4-1.04) and 0.96 (range 0.25-1.05) for C and D. Main toxicity was haematological with febrile neutropenia ranging from 26% to 51% of cycles; one death occurred during aplasia. Clinical response rate was 90% +/- 6%. Eighty-six patients underwent mastectomy in a median of 3.5 months (range 3-9) after the first cycle of chemotherapy; pathological complete response rate in breast was 32% +/- 10%. All patients were eligible to receive additional radiotherapy. High-dose chemotherapy with repeated BSC transplantation is feasible with acceptable toxicity in IBC. Pathological response rate is encouraging but has to be confirmed by final outcome.

Adenocarcinoma↗
PubMed1997

Efficient peripheral blood stem cell mobilization with low-dose G-CSF (50 microg/m2) after salvage chemotherapy for lymphoma.

We compared the use of low-dose G-CSF (50 microg/m2/day), following salvage chemotherapy, for mobilization of PBSC with the results obtained in a comparable historical control group who received a standard dose of G-CSF (5 microg/kg/day, approximately 200 microg/m2/day). Thirty adult patients with relapsed or refractory lymphoma were treated with ifosfamide, VP-16, intermediate-dose Ara-C, methylprednisolone (IAPVP-16) and G-CSF 5 microg/kg/day (group A, n = 15) or 50 microg/m2/day (group B, n = 15) from day 6 until the end of leukaphereses. The duration of neutropenia and thrombocytopenia were equal in both groups. A median of two (1-3) leukaphereses were performed in both groups to harvest >3.5 x 10(6)/kg CD34+ cells. The numbers of circulating CD34+ cells on the first day of leukocyte recovery were similar in both groups in those patients mobilized after a first cycle of IAPVP-16. The numbers of circulating CD34+ cells were similar in patients mobilized after a first and after a second IAPVP-16 in group A. In the low-dose group (group B), however, the numbers of circulating CD34+ cells were significantly lower in those mobilized after a second than after a first course. Additionally, the product of the first leukapheresis contained significantly fewer CD34+ cells in those mobilized after a second course only in group B, with no differences in group A. Nevertheless, the final products harvested did not differ in the content of MNC, CFU-GM and CD34+ cells, suggesting that these differences are not clinically important. These results indicate that the use of low-dose G-CSF (50 microg/m2/day) is as effective as 5 microg/kg/day in accelerating neutrophil recovery and mobilizing CD34+ cells after a first cycle of IAPVP-16 salvage chemotherapy, resulting in a substantial decrease in costs, while more heavily pretreated patients may require higher doses of G-CSF for an equivalent mobilization.

Adolescent↗
PubMed1997

Mobilization of hematopoietic progenitors in patients with chronic myeloid leukemia.

Although the mobilization and harvesting of Philadelphia chromosome-negative progenitors has been proven feasible by a number of groups, it is not clear which techniques should be used with regard to the monitoring of purging and evaluation of stem cell yield. Therefore, we isolated CD34-positive cells from leukapheresis samples of seven CML patients after induction therapy. These cells were analyzed using the colony-forming unit granulocyte-macrophage (CFU-GM) and long-term culture-initiating cell (LTCIC) assays. In addition, we analyzed frequency and clonogenicity of single stem cells using the LTCIC assay at limiting dilution. Individual colonies derived from these assays were subsequently analyzed for the presence of the bcr-abl gene with interphase fluorescence in situ hybridization (FISH) and for the presence of bcr-abl mRNA with RT-PCR. We compared these results with the cytogenetic analysis of the leukapheresis material. Molecular analysis of individual colonies correlated well with the results of cytogenetic analysis. However, in nine out of 18 samples, cytogenetic analysis exclusively demonstrated the presence of either Philadelphia chromosome-positive or -negative cells whereas with the molecular analysis of individual colonies tumor contamination or the presence of residual normal cells could be substantiated. We concluded that molecular analysis of individual colonies should be employed to further optimize induction protocols. With regard to stem cell mobilization we demonstrated that about 67 CFU-GM colonies and clusters were generated by one single LTCIC both for the CML samples and the samples obtained from patients with non-hematologic malignancy. This number is important since until now most centres use a number of four colonies and clusters generated by one LTCIC. Dividing the CFU-GM output in the LTCIC assay by four to determine LTCIC frequency could thus lead to an almost 20-fold overestimation of the LTCIC frequency. It is concluded that stem cell frequency analysis is an important tool with regard to the interpretation of mobilization protocols.

Adult↗