Biomedical subjects
Publications and source records attributed to H M Prince.
We describe a unique case of a patient with a three-year history of idiopathic CD4(+) T cell lymphopenia (HIV negative) who presented with stage IV diffuse large cell non Hodgkin's lymphoma with t(8;22). Despite the severe lymphopenia, the patient tolerated intensive chemotherapy well and at 18 months, remains in complete remission.
We have analyzed 25 patients with primary testicular large-cell non-Hodgkin's lymphoma managed at our institution from 1972-1998. The median age was 69 years, with bilateral testicular involvement in 16%. The disease stage was I in 56%, II in 32%, and IV in 12%. Twenty-four patients received further therapy after orchiectomy, including chemotherapy in 18 and radiation therapy in 11 (encompassing regional nodes in 8 and the contralateral testis in 6), with 5 patients receiving both modalities. The complete remission rate was 88%, but a continuous pattern of recurrence is evident up to 10 years, when only 23% of patients are predicted to be in ongoing remission. The dominant sites of first failure were extranodal (91%), with prominent involvement of the contralateral testis and cerebral parenchyma. The 10-year overall survival rate is 32%, and the median overall survival is 4.4 years. Within the entire cohort, adverse prognostic factors for treatment failure were serum albumin < or = to 3.5 g/dL (P = 0.02), advanced age, advanced stage, and lack of anthracycline-containing chemotherapy (each P < or = to 0.3). Among patients with locoregional disease, albumin < or = to 3.5 g/dL (P = 0.08), no anthracycline-containing chemotherapy (P = 0.15), and fewer than 6 cycles of chemotherapy (P = 0.03) remained predictive. Based on this analysis, we are prospectively evaluating a treatment program for patients with testicular non-Hodgkin's large-cell lymphoma comprising (1) 6 cycles of anthracycline-based chemotherapy, (2) prophylactic radiation therapy to the contralateral testis, and (3) central nervous system prophylaxis with both intrathecal chemotherapy and systemic high-dose methotrexate.
Central nervous system (CNS) involvement by mycosis fungoides (MF) is rare and is usually seen in advanced stages with lymph node or visceral involvement. We describe a patient with advanced stage MF in large-cell transformation who presented with profound hearing loss after chemotherapy. Despite an initial differential diagnosis of vincristine-related neurotoxicity based on clinical, audiometric, and MRI investigations, CSF examination revealed lymphomatous leptomeningeal involvement. This case illustrates the importance of an awareness of the possibility of CNS involvement by MF and underlines the need for a complete neurologic evaluation including CSF examination in a patient with underlying MF who presents with a new neurological problem.
We prospectively evaluated docetaxel (100 mg/m2) with G-CSF (10 microg/kg S.C., daily) for mobilization efficiency in 26 patients with breast cancer. The minimum target yield was >4.5 x 10(6) CD34+ cells/kg (optimum = 9 x 10(6)/kg), sufficient to support the subsequent three cycles of high-dose therapy (HDT). The peak days for peripheral blood (PB) CD34+ cells were day 8 and day 9. Seven collections began on day 7, 16 on day 8 and three on day 9. The median peripheral blood progenitor cell (PBPC) CD34+ cell content ranged from 1.2 to 5.9 x 10(6)/kg per day during days 7 to 11 with a median CD34+ content of the total 72 PBPC collections of 3.4 x 10(6)/kg (0.07-15.6). Fifteen patients obtained a PBPC collection exceeding 5 x 10(6)/kg on a single day of collection. Following a median 3 days collection for each patient (range 2-4), the median total CD34+ for all individual sets of collections was 9.7 x 10(6)/kg (range 1.0-28.4). We were able to achieve the minimum CD34+ cell target yield in 22 of 26 patients with one cycle of mobilisation chemotherapy and in two of these patients a second collection yielded sufficient cells. Twenty-two patients have subsequently received repetitive HDT and PBPC transplantation with 57 cycles of HDT having been delivered. For all 57 cycles, the median time to absolute neutrophil count (ANC) >0.5 x 10(9)/l and 1.0 x 10(9)/l was 10 days (range 8-22) and 11 days (range 8-23), respectively. The median time to platelets greater than 20 x 10(9)/l, 50 x 10(9)/l and 100 x 10(9)/l was 13 days (range 11-23), 17 days (range 12-53) and 23 days (range 18-70), respectively. We conclude that docetaxel with G-CSF effectively mobilises PBPCs with apheresis needing to be commenced approximately 8 days after docetaxel administration.
This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). The planned treatment was three cycles of high-dose cyclophosphamide, thiotepa and docetaxel delivered every 35 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. Eighteen patients were entered into this trial. Of the planned 54 treatment cycles, 44 were delivered and 11 patients completed all three cycles. The dose-limiting toxicities were interstitial pneumonitis and mucositis with moderately severe diarrhea (n = 3) and rash (n = 3). There were no treatment-related deaths. Of the 17 patients with evaluable disease, 16 patients responded with six patients achieving a complete remission and an additional four patients achieving no detectable disease (negative restaging including PET scan) but a persistently abnormal bone scan. At a median follow-up of 12 months, median progression-free survival was 11 months with the median overall survival not reached. The recommended doses for phase II/III studies are cyclophosphamide (4 g/m2), thiotepa (300 mg/m2) and docetaxel (100 mg/m2).
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BACKGROUND: Quantitation of peripheral blood (PB) CD34(+) cells is now an established method for timing PBPC harvesting. Recent refinements to the dual-platform ISHAGE gating strategy for CD34(+) cells has seen the introduction of microbeads to enable absolute counting of cells on a single instrument platform. This eliminates the need for total WBCC performed on an automated hematology analyzer and potentially increases the analytical precision of the methodology. At the same time, alternative methods for CD34(+) cell enumeration have started to emerge, notably microvolume fluorimetry, which forms the basis of the fully-automated STELLer CD34 method using the Imagn 2000. METHODS: We performed a three-way evaluation of these methods. Sixty-eight samples of PB from 42 patients undergoing PBPC mobilization were analyzed by all three methods and correlations between all three calculated. The two-platform ISHAGE method was used as the reference method. RESULTS: Precision and linearity of the single-platform and STELLer CD34 assays were excellent. Correlation with the dual-platform reference method was also excellent (single-platform method slope = 1.03, intercept = -0.03 and R(2) = 0.9325, STELLer CD34 assay slope = 0.827, intercept = 4.27, R(2) =0.8215). Bias, determined by Bland-Altman analysis, was 1.16 and -1.62 for single platform and STELLer CD34 assay respectively. CONCLUSION: The three methods of CD34(+) cell enumeration gave equivalent results. The single-platform methodology negated the need for a separate white cell analyzer, while the STELLer CD34 methodology was technically the simplest.
We report three cases of women with breast cancer who developed renal impairment following treatment with high-dose ifosfamide. All the women underwent renal biopsy, which demonstrated severe interstitial damage with tubular changes by light and electron microscopy. Although reversible acute tubular dysfunction is well recognised with ifosfamide therapy, the long-term outcome of ifosfamide-induced renal injury remains unclear. The results of the current study suggest that ifosfamide can cause severe irreversible renal tubulointerstitial injury and should be used with caution even when there is initially normal renal function.
BACKGROUND: The viability stains propidium iodide (PI) and 7-amino-actinomycin D (7-AAD) are excited at 488 nm, as are the commonly used antibody conjugates fluorescein isothiocyanate (FITC), phycoerythrin (PE), and cyanine 5 dye covalently coupled to R-phycoerythrin (RPE-Cy5). When excited by a single laser, spectral overlap in the emission of PI and 7-AAD with RPE-Cy5 precludes the use of these viability stains for three-color immunophenotyping, particularly when evaluating low levels of marker expression in viable target cells. The ultraviolet excitable dye hydroxystilbamidine methanesulfonate (Fluoro-Gold, or FG) binds to DNA at the A-T-rich regions of the minor groove in permeabilized or dead cells. We assessed the suitability of this dye as a viability stain. METHODS: The ability of FG to detect nonviable cells in fresh and cryopreserved human apheresed peripheral blood cells was compared with that of PI and 7-AAD. The stability of FG staining and the effects of dye and cell concentration on the discrimination of nonviable cells was determined by measuring changes in the median fluorescence of viable and nonviable cells. RESULTS: FG labeling at dye concentrations of 2-8 microM is stable for at least 3 h over a wide range of cell concentrations (4 x 10(5) to 4 x 10(7) cells/ml). Costaining studies and linear regression analysis show that cell viability as determined by FG is strongly correlated with estimates using PI (r = 0.9636) and 7-AAD (r = 0.9879). CONCLUSIONS: FG is a reliable, alternative viability stain that can be used in conjunction with fluorochromes including FITC, PE, and RPE-Cy5 for multicolor analysis using dual-laser instruments.
Until recently, the collection of peripheral blood progenitor cells (PBPC) has been semi-automated by using the COBE Spectra, with the operator manually maintaining the position of the white cells being collected. The COBE Spectra Version 6.0 apheresis device offers the user an automated program for the collection of PBPC. In this study, we compared the new software Version 6.0 to that of Version 4.7. Patients (n = 46) undergoing PBPC collection were allocated to cell processing with either Version 4.7 (n = 24) or Version 6.0 (n = 22). The CD34+ cell count, mononuclear cell (MNC) count, white cell count (WCC), hemoglobin (Hb), and platelet content in the autograft product by using the two versions were compared. We divided the analysis into three subsets according to peripheral blood (PB) CD34 content: <10x10(6)/L, 10-50x10(6)/L and >50x10(6)/L. Analysis of the three subsets showed no statistical difference between results obtained when the starting PB CD34+ cell count was 10-50x10(6)/L (P=0.08) or >50x10(6)/L (P=0.4065). At lower starting PB CD34+ cell counts of <10x10(6)/L, Version 4.7 was superior (P=0.0167). However, autograft platelet contamination of the autograft was significantly higher using Version 4.7 (P=<0.0001).
BACKGROUND: This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: The planned treatment was three cycles of high-dose ifosfamide, thiotepa and conventional-dose paclitaxel delivered every 28 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. RESULTS: Twenty-three patients were entered into this trial. Of the planned 69 treatment cycles, 59 were delivered and fifteen patients completed all three cycles. The dose-limiting toxicities were renal tubular acidosis, encephalopathy, mucositis and enterocolitis. There was one treatment-related hemorrhagic death. CONCLUSIONS: The recommended doses for phase II or III studies are ifosfamide (10 g/m2), thiotepa (350 mg/m2) and paclitaxel (175 mg/m2).
For patients with metastatic breast cancer (MBC) who undergo high-dose therapy with autologous peripheral blood progenitor cell (PBPC) transplantation, an important prerequisite is a mobilization regimen that efficiently mobilizes PBPCs while producing an effective anti-tumor effect. We prospectively evaluated ifosfamide-based chemotherapy for mobilization efficiency, toxicity and disease response in 37 patients. Patients received two cycles of the ifosfamide-based regimen; ifosfamide (5 g/m2 with conventional-dose cycle and 6 g/m2 with mobilization cycle) with either 50 mg/m2 doxorubicin (if limited prior anthracycline and/or progression more than 12 months after an anthracycline-based regimen) or 175 mg/m2 paclitaxel. For the mobilization cycle, all patients received additional G-CSF (10 microg/kg SC, daily) commencing 24 h after completion of chemotherapy. The target yield was >6x10(6) CD34+ cells/kg, sufficient to support the subsequent three cycles of high-dose therapy. The mobilization therapy was well tolerated and the peak days for peripheral blood (PB) CD34+ cells were days 10-13 with no significant differences in the PB CD34+ cells mobilization kinetics between the ifosfamide-doxorubicin vs. ifosfamide-paclitaxel regimens. The median PBPC CD34+ cell content ranged from 2.9 to 4.0x10(6)/kg per day during days 9-14. After a median of 3 (range 1-5) collection days, the median total CD34+ cell, CFU-GM and MNC for all 44 individual sets of collections was 9.2x10(6)/kg (range 0.16-54.9), 37x10(4)/kg (range 5.7-247) and 7.3x10(8)/kg (range 2.1-26.1), respectively. The PBPC target yield was achieved in 35 of the 37 patients. The overall response rate for the 31 evaluable patients was 68% with 10% having progressive disease. Thirty-three patients have subsequently received high-dose therapy consisting of three planned cycles of high-dose ifosfamide, thiotepa and paclitaxel with each cycle supported with PBPCs. Rapid neutrophil and platelet recovery has been observed. Ifosfamide with G-CSF in combination with doxorubicin or paclitaxel achieves effective mobilization of PBPC and anti-tumor activity with minimal toxicity.
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Acute myeloid leukemia developing secondary to prior cytotoxic chemotherapy (s-AML) encompasses a range of distinct entities. We report two cases of s-AML with inv(16)(p13q22) who had prior exposure to paclitaxel. Additionally, two previously reported cases of s-AML with inv(16) had prior paclitaxel exposure raising the possibility that the taxanes may predispose to this specific syndrome of s-AML. One of our patients received escalated-dose ara-C chemotherapy, achieving a complete remission (12+ months). We therefore examined the prognosis of previously reported cases of s-AML with inv(16) and analyzed the influence of escalated-dose ara-C (>/=400 mg/m2/day). A total of 25 evaluable cases were identified, with 96% attaining CR independent of ara-C dose. The estimated median remission duration was 40 months and the median survival has not been reached (actuarial 5-year survival 52 +/- 18%). Although not achieving statistical significance, patients treated with escalated dose ara-C (n = 15) had longer remission duration and overall survival than those treated with standard dose ara-C (n = 10) (P = 0.063 and 0.20, respectively). In univariate analysis, younger age, male gender, and the presence of additional cytogenetic abnormalities were associated with a tendency towards adverse outcomes (P< 0.1). Age and gender were equally distributed between ara-C dose cohorts, but more patients treated with standard-dose ara-C had additional cytogenetic abnormalities (P = 0.048). Within the limitations of this retrospective study, this analysis suggests that, similar to de novo AML with inv(16), secondary cases may also potentially benefit from treatment with escalated-dose ara-C. This is consistent with the premise that the underlying molecular defect, rather than the presence of prior cytotoxic drug exposure, may be the most important determinant of disease behavior and chemotherapy responsiveness in AML.
We report a case of fatal disseminated fungal infection by Scedosporium prolificans which occurred in a patient with acute leukemia during induction chemotherapy. Rapid clinical deterioration despite high-dose empirical amphotericin B highlights both the pathogenicity of this fungus in immunocompromised hosts and its resistance to standard antifungal therapy.
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