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Biomedical subjects

H Holte

Publications and source records attributed to H Holte.

At least 37 records · Page 2Linked to original sources
PubMed2001

Combination chemotherapy containing mitoguazone, ifosfamide, methotrexate, etoposide (MIME) and G-CSF efficiently mobilize peripheral blood progenitor cells in heavily pre-treated relapsed lymphoma patients.

In this study we explored whether a standard chemotherapy regimen consisting of mitoguazone, ifosfamide, methotrexate and etoposide (MIME) combined with 5 micrograms/kg or 10 micrograms/kg G-CSF was capable of mobilizing peripheral blood progenitor cells (PBPC) in lymphoma patients. Thirty-three patients with Hodgkin's disease (HD) and 108 patients with non-Hodgkin's lymphoma (NHL) were mobilized with MIME/G-CSF. Most patients were heavily treated with different chemotherapy regimens receiving a median of 11 cycles (range 3-40) of chemotherapy prior to mobilization. Eight of 141 patients failed to mobilize PBPC and bone marrow was harvested. In addition, 10 patients obtained a harvest of < 2.0 x 10(6) CD34+ cells/kg. More than 2.0 x 10(6) CD34+ cells/kg were achieved in all HD patients and in 83% of the NHL patients. Fifty-eight per cent of the patients harvested > or = 5 x 10(6) CD34+ cells/kg. Eleven per cent of the patients developed neutropenic fever during the mobilization and 3% had nadir platelet values below 20 x 10(9)/L. An inverse correlation was observed in high-grade NHL (H-NHL) patients between the number of chemotherapy cycles given before mobilization and yield of CD34+ cells. Such an association was not seen among patients with HD, transformed and low-grade NHL. When G-CSF 10 micrograms/kg was used in combination with MIME, this correlation was no longer seen in patients with H-NHL. There was also association between CD34+ cell yield and prior radiotherapy in patients with HD or transformed NHL or low-grade NHL. These results demonstrate that an ordinary salvage chemotherapy regimen, such as MIME combined with G-CSF, can be successfully used to mobilize PBPC. Although no significant effect of increased dose of G-CSF was found, our data suggest that MIME/G-CSF 10 micrograms/kg should preferentially be used to mobilize PBPC in H-NHL patients pre-treated with > or = 12 cycles of chemotherapy, in irradiated HD patients and in all low-grade and transformed lymphomas.

Adolescent↗
PubMed2000

Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study.

BACKGROUND: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support. METHODS: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat. FINDINGS: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome. INTERPRETATION: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer.

Acute Disease↗
PubMed2000

Oncogenic aberrations in the p53 pathway are associated with a high S phase fraction and poor patient survival in B-cell Non-Hodgkin's lymphoma.

The implications of aberrations in the p53 pathway for induction of apoptosis and regulation of S phase entry, and for patient survival, were investigated in 83 B-cell Non-Hodgkin's lymphomas. Eight cases had missense mutations in exons 5, 7, 8 and 9 as revealed by constant denaturant gel electrophoresis and sequencing. Fifteen cases had lost 1 TP53 allele as revealed by fluorescent in situ hybridization and comparative genomic hybridization. Ten cases expressed high levels of p53 as assessed by immunoblotting and immunohistochemistry. S phase fractions were higher, apoptotic fractions were the same and survival times were shorter in all aberration groups compared with the cases with no TP53/p53 aberrations. Since many tumors had more than one TP53/p53 aberration, the tumors were divided into groups with the following characteristics: no TP53/p53 aberrations; loss of one TP53 allele only (9 cases), TP53 point mutation (8 cases), high-level p53 expression and no TP53 mutation (3 cases). Tumors from the 3 latter groups had higher median S phase fractions (5%, 7.6%, and 5%, respectively, p<0.02) than the cases without any aberrations (1.1%), and survival time for these patients was much shorter (relative risks of 5.9, 8.9, and 6.6, respectively, p<0.003). Apoptotic fractions were similar in all these groups (p=0.09). Multivariate analysis showed that the presence of TP53/p53 aberrations is a strong and independent prognostic parameter in B-cell Non-Hodgkin's lymphoma.

Adult↗
PubMed2000

Prognostic factors in 140 adult patients with non-Hodgkin's lymphoma with systemic central nervous system (CNS) involvement. A single centre analysis.

We examined retrospectively the outcome of patients with non-Hodgkin's lymphoma (NHL) with systemic involvement of the central nervous system (CNS) registered at The Norwegian Radium Hospital (NRH) from 1980 to 1996, in order to evaluate our treatment strategy for these patients. 170 of 2561 patients (6.6%) had CNS involvement, 140 (5.5%) systemic CNS lymphoma (SCNSL) and 30 (1.2%) primary CNS lymphoma (PCNSL). Description of the patients, time of SCNSL diagnosis, symptoms at CNS diagnosis, treatment and survival were registered. The overall median survival for the 140 patients with SCNSL was 2.6 months (95% confidence interval (CI) 2.1-3.2), only 12 patients are alive in complete remission (CR). Patients with CNS involvement at diagnosis, relapse or progression during treatment for NHL had a median survival of 5.4 months (95% CI: 0.3-10.6), 3.8 months (95% CI: 0.0-9.1), and 1.8 months (95% CI: 1.0-2. 7), respectively (P=0.001). 5 of the 8 patients consolidated with high-dose therapy (HDT) are in CR. Paresis was the only symptom that predicted survival for SCNSL. Patients above 60 years of age with CNS involvement at progression or relapse and those with paresis at the time of CNS diagnosis have a dismal prognosis. For these patients supportive therapy only should be considered. For patients under 60 years of age with chemosensitive disease, the trend was toward better prospects, and they should be offered intensive chemo-radiotherapy including HDT with autologous stem cell support.

Adolescent↗
PubMed2000

Stage I high-grade non-Hodgkin's lymphoma.

We report long-term survival and prognostic factors in 252 patients with stage I high-grade lymphoma. Median patient age was 64 years and 49% of patients had extranodal lymphoma. Premenopausal women had less risk of extranodal lymphoma than older women or males (p < 0.002). Disease specific 5 and 15 years' survival in patients < 64 years was 83% and 76%, respectively; compared to 54% and 46% in patients > 64 years of age. Age, non-centroblastic histology, B-symptoms, and increased serum lactate dehydrogenase (LDH) were independently negative prognostic factors (p < 0.01), while extranodal, testicular, or bulky ( > 6 cm) lymphoma presentation were of no prognostic significance. A radiation dose of 40 Gy in 2 Gy fractions to the primary site prevented in-field relapse in 159 of 173 irradiated patients (92%) and only three of 173 patients (1.7%) had local relapse in the absence of systemic dissemination.

Adolescent↗
PubMed1999

c-MYC, RB-1, TP53, and centromere 8 and 17 copy number in B-cell non-Hodgkin's lymphomas assessed by dual-color fluorescence in situ hybridization.

Dual-color interphase FISH was performed to B-cell Non-Hodgkin's lymphomas to detect numerical genetic alterations in c-MYC, RB-1, TP53 and centromere 8 and 17. The probe combinations c-MYC/centromere 8, RB-1/centromere 8 and TP53/centromere 17 were applied, and the hybridization signals scored in a correlated fashion. Copy number aberrations was found in 24 of 45 lymphomas examined (53%). Nine tumors (20%) had increased c-MYC gene copy number (three to 8 copies). Seven of these nine had increase in c-MYC copies relative to centromere 8 copy number. Allelic loss of RB-1 was found in 9 tumors (20%), one tumor lacked both alleles. Nine cases (20%) showed hemizygous TP53 deletion. TP53 deletion was significantly associated with high-grade histology (P = 0.02). Numerical alterations in c-MYC and RB-1 were not associated with prognosis. Patients with hemizygous TP53 deletion had shorter survival (relative risk = 6.1, P<0.001) than the ones with two or more alleles.

Centromere↗
PubMed1999

Pharmacokinetics and metabolism of doxorubicin after short-term infusions in lymphoma patients.

PURPOSE/METHODS: Twenty-four patients (17 males and 7 females with a mean age of 54 years) with malignant lymphoma participated in a study of doxorubicin pharmacokinetics after 50 mg/m(2) as 10-min infusions. In addition to plasma samples, serial leukocyte samples and - in one subject - serial biopsy specimens from lymphoma infiltrates were obtained. The samples were analysed by reversed-phase high-performance liquid chromatography. RESULTS: In contrast to several previous studies, the data suggested that 7-deoxydoxorubicinolone, and not doxorubicinone, is a metabolite of doxorubicin in humans. Doxorubicin, but no metabolites, was present in significant and fairly constant concentrations in circulating leukocytes. These levels may reflect the drug levels in lymphoma infiltrates. The data further suggest that metabolism to 7-deoxydoxorubicinone is subject to large interindividual variation, possibly due to a genetic polymorphism, and that significant levels of a metabolic product which may be a doxorubicin glucuronide can be recovered from plasma of patients treated with doxorubicin.

Adult↗
PubMed1999

High-dose therapy supported with immunomagnetic purged autologous bone marrow in high-grade B cell non-Hodgkin's lymphoma.

From August 1987 to March 1995, 25 patients with high-grade B cell non-Hodgkin's lymphoma (NHL) were treated with high-dose therapy (HDT) followed by bone marrow purged with immunomagnetic beads. At the time of transplantation, 20 patients were in sensitive relapse and five in first complete or partial remission. Ten patients had secondary high-grade NHL transformed from low-grade NHL. The HDT consisted of TBI followed by high-dose cyclophosphamide. All patients engrafted, except for two patients with early treatment-related death. Eleven patients relapsed, of whom nine died of lymphoma, and two are alive in new CR. The estimated event-free and overall survivals at 5 years were 40% and 48%, respectively, with a median follow-up of 48 months (range 1-123). Eight of the tumours contained the translocation t(14;18) at the major breakpoint region (MBR) of BCL-2. In these patients the presence of tumour cells in the bone marrow graft before and after purging were assessed by PCR. Four of five patients infused with non-detectable minimal residual disease in their autografts are in complete remission, while two of three patients reinfused with t(14;18) positive cells after purging, experienced a fast and aggressive relapse. As found by others, our data suggest that reinfusion of tumour-free autografts obtained by efficient in vivo purging using chemotherapy before harvesting, and/or by in vitropurging of the stem cell products, influence the patients remission status after HDT.

Adolescent↗
PubMed1999

Do patients who are treated with stem cell transplantation have a health-related quality of life comparable to the general population after 1 year?

Health-related quality of life (HRQOL) in leukemia and lymphoma patients treated with high-dose chemotherapy followed by allogeneic (SCT) and autologous (ASCT) stem cell transplantation or receiving combination chemotherapy (CT) was prospectively assessed by the EORTC QLQ-C30 and compared with reference data from a general population sample. One year after transplant, the SCT group had functional scores which were close to population values except for lower social (P < 0.0001) and role function (P = 0.0004). More symptoms and problems were reported, especially appetite loss (P = 0. 001) and financial difficulties (P = 0.0001). The ASCT patients reported a less than optimal HRQOL relative to the population 1 year post transplant. Cognitive, physical, role, and social function, dyspnoea, financial difficulties and global quality of life were most impaired (P < 0.001). In the CT group, physical, role and social function, dyspnoea and financial difficulties were impaired 1 year after start of chemotherapy, compared with the general population (P < 0.001). The EORTC QLQ-C30 was supplemented by a high-dose chemotherapy module, the HDC-19, at the 1-year assessment, but no consistent differences were found across groups. Fifteen to 34% of the patients expressed fears of relapse and worries about future health, while 24-30% indicated no participation in sexual activities.

Adolescent↗
PubMed1999

Persistent changes in the immune system 4-10 years after ABMT.

The aim of the present study was to investigate whether the early changes in the immune system observed after ABMT would persist over years. Eighty-five patients with malignant lymphoma were treated with ABMT in Norway from 1987 until 1993. Of the 46 patients in CR by 1997, 36 were enrolled in our study. Median time from ABMT was 5 years (4-10 years). Immunophenotyping showed an increase in the median number of B cells (0.35 x 109/l in patients vs 0.28 x 109/l in controls), and a decrease in T cells (1.08 vs 1.35 x 109/l). Furthermore, a lower median count of CD4+ T cells (0.54 x 109/l in patients vs0.87 x 109/l in controls) resulted in reduced CD4/CD8 ratios (0.8 in patients vs 1.6 in controls). The subgroup of CD4+ T cells expressing the 'naive' phenotype CD45RA was 19.5% in patients vs 38% in controls. In contrast, the fraction expressing the 'memory' phenotype CD45RO was higher in the ABMT group (76% vs 54%). When stimulated, larger fractions of CD3+CD4+ cells in patients produced IFN-gamma (32% vs 16%) or IL-4 (7% vs 1%) compared to controls; thus a differentiation into the functionally separate subgroups Th1 and Th2, with a dominant Th2 response. Our data further suggest that the decrease in CD4+ T cell counts and the imbalance between CD45RA+ and CD45RO+ subsets persists 4-10 years after ABMT.

Adolescent↗
PubMed1999

FEC mobilized stem cells for high-dose therapy in breast cancer patients. SB6 9401 Study Group.

The feasibility of mobilizing peripheral blood stem cells (PBSC) using anthracycline containing polychemotherapy and G-CSF on the first 50 patients randomized to the high-dose arm in the adjuvant SBG 9401 is investigated. The patients were treated with standard FEC (5-fluorouracil 600 mg/m2, epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2) for two courses followed by a modified third FEC course with a C dose of 1200 mg/m2 supported with subcutaneous G-CSF (filgrastim) at 5 mg/kg followed by harvest around day 11. The mean yield of CD34+ cells per patient was 10.6x10(6)/kg (range 2.6-29.1). The side effects after the third course were low and only one patient developed an uncomplicated granulopenic fever. Our data indicated a correlation between number of transfused CD34+ cells and days to neutrophil and platelet recovery. In conclusion, the modified FEC regimen followed by G-CSF is a feasible method for PBSC mobilization in the adjuvant setting.

Antigens, CD34↗
PubMed1999

Prognostic value of lymphoma-specific S-phase fraction compared with that of other cell proliferation markers.

The proliferation-associated antigens Ki67 (immunohistochemistry) and proliferative cell nuclear antigen (PCNA) (immunohistochemistry and immunoblotting) were analysed together with DNA synthesis (3H-thymidine incorporation) and cell-cycle distribution (tumour-specific S-phase fraction determined by flow cytometry) in lymph node suspensions from 63 patients with newly diagnosed B-Cell non-Hodgkin's lymphomas. Details of clinical parameters, treatment and patient outcome were available for all patients, and retrospectively analysed. Of the proliferation-associated parameters, only high S-phase fraction (p < 0.00001) and high PCNA expression by immunoblotting (p = 0.012) were predictive of a poor prognosis. Of the conventional parameters, high-grade malignancy, high International Prognostic Index (IPI) score, bulky disease and presence of B symptoms predicted a patient for poor survival. High S-phase fraction was predictive of a short survival for the low-grade lymphomas analysed separately (p < 0.00001), as well as for patients treated with an Adriamycin- and a non-Adriamycin-containing regimen (p < 0.005 for both groups). In a multivariate analysis, S-phase fraction (p = 0.00006), IPI score (p = 0.015) and B symptoms (p = 0.017) had independent prognostic values, but not histological grade.

Adult↗
PubMed1999

Late medical sequelae after therapy for supradiaphragmatic Hodgkin's disease.

A total of 221 consecutive early stage Hodgkin's disease (HD) patients were given mantle field irradiation only or in combination with chemotherapy in 1971-1991. In 1994 these patients responded to a mailed self-report questionnaire covering items on late medical symptoms. Of 200 patients (91%) who reported that their thyroid function had been tested, 110 patients (55% of those tested) had thyroid hypofunction at follow-up in 1994. Ninety-five patients (86% of patients with biochemical hypothyreosis) had started hormonal substitution. In 1993 and 1994, 101 of these patients who had received mantle field irradiation in 1980-1988 were called in for interview, clinical examination and thyroid function tests. Eighteen patients (18%) had started hormonal substitution treatment earlier, but 58 (70%) of the other 83 patients were found to have biochemical hypothyreosis. Of the 221 patients who completed the questionnaire, 66 patients (30%) reported dyspnoea on exertion for more than 3 years after treatment, 8 patients (4%) reported a history of myocardial infarction, 6 patients (3%) reported pericardial disease and 25 patients (11%) heart valve disease. Increased expenses incurred for dental care were reported by 106 patients (48%), increasing to 55% when Waldeyer's ring had been irradiated. The consequences of late sequelae after mantle field irradiation for future treatment are discussed.

Adolescent↗
PubMed1998

[Primary non-Hodgkin's lymphoma of the brain].

Between 1980 and 1993, 26 patients were treated for primary lymphoma in the central nervous system at the Norwegian Radium Hospital. This is a rare disease with poor prognosis and thus represents a great therapeutic challenge. Immunocompromised, e.g. AIDS patients, are a group at high risk, but the incidence has increased among immunocompetent patients as well. Median patient age was 64 years; and none of the patients had any signs of immunodeficiency. 23 of the patients received radiation therapy. 13 of the patients received some form of chemotherapy. The overall median survival was 19 months. WHO performance status 0-2, unifocal lesion, absence of steroid dependency and normal serum levels of LDH were all associated with longer survival. Although complete remissions were achieved in most patients, relapses in the central nervous system were frequent.

Adult↗
PubMed1998

Socio-medical situation for long-term survivors of Hodgkin's disease: a survey of 459 patients treated at one institution.

We present the socio-medical situation for 459 adult disease-free long-term survivors of Hodgkin's disease (HD) 3-23 years after first line curative treatment. In 1994, 557 patients were sent a self-report questionnaire relating to their social status and 459 patients (82%) replied. Educational or professional plans were changed due to HD in 142 patients (32%). After 6, 12 and 18 months from start of treatment, 52, 82 and 95% of the patients, respectively, had returned to their job or education. The sum of full-time and part-time employment was in men 78% at diagnosis and 85% at follow-up, and in women 57% at diagnosis and 64% at follow-up. Only 2% of men and 3% of women did not have a job at follow-up in 1994. At diagnosis 2% of the patients were permanently disabled versus 19% at follow-up in 1994. Age > 40 years at diagnosis, increased the total score of psychological distress and fatigue and long-term disablement after first line treatment were predictors for permanent disablement. Transient or permanent sexual problems were reported in 16% and 13%, respectively. MVPP (mustine, vinblastine, procarbazine and prednisone) or LVPP (chlorambucil, vinblastine, procarbazine and prednisone) chemotherapy was responsible for most cases of early menopause in women older than 30 years, and of infertility in both men and women. In summary, most long-term HD survivors had adapted well to their socio-medical situation except a high number of permanently disabled patients. By focusing more on factors predisposing for permanent disablement and early treatment for these, more patients may be helped to return to their job.

Adolescent↗
PubMed1998

Proliferation and apoptosis in malignant and normal cells in B-cell non-Hodgkin's lymphomas.

We have examined apoptosis and proliferation in lymph node cell suspensions from patients with B-cell non-Hodgkin's lymphoma using flow cytometry. A method was developed which allowed estimation of the fractions of apoptotic cells and cells in the S-phase of the cell cycle simultaneously with tumour-characteristic light chain expression. Analysis of the tumour S-phase fraction and the tumour apoptotic fraction in lymph node cell suspensions from 95 B-cell non-Hodgkin's lymphoma (NHL) patients revealed a non-normal distribution for both parameters. The median fraction of apoptotic tumour cells was 1.1% (25 percentiles 0.5%, 2.7%). In the same samples, the median fraction of apoptotic normal cells was higher than for the tumour cells (1.9%; 25 percentiles 0.7%, 4.0%; P = 0.03). The median fraction of tumour cells in S-phase was 1.4% (25 percentiles 0.8%, 4.8%), the median fraction of normal cells in S-phase was significantly lower than for the tumour cells (1.0%; 25 percentiles 0.6%, 1.9%; P = 0.004). When the number of cases was plotted against the logarithm of the S-phase fraction of the tumour cells, a distribution with two Gaussian peaks was needed to fit the data. One peak was centred around an S-phase fraction of 0.9%; the other was centred around 7%. These peaks were separated by a valley at approximately 3%, indicating that the S-phase fraction in NHL can be classified as 'low' (< 3%) or 'high' (> 3%), independent of the median S-phase fraction. The apoptotic fractions were log-normally distributed. The median apoptotic fraction was higher (1.5%) in the 'high' S-phase group than in the 'low' S-phase group (0.8%; P = 0.02). However, there was no significant correlation between the two parameters (P > 0.05).

Adult↗
PubMed1998

Tumour cell proliferation, but not apoptosis, predicts survival in B-cell non-Hodgkin's lymphomas.

Tumour S-phase fraction, but not the apoptotic fraction, had prognostic value in 92 patients with B-cell non-Hodgkin's lymphoma (P < 0.0001 and P = 0.85 respectively). Multivariate analysis showed that S-phase fraction was the strongest prognostic indicator in all cases (P = 0.0003, relative risk 4.3; age: P = 0.16; grade: P = 0.81), as well as in the 63 primary biopsy cases (P = 0.0006, relative risk = 7.3; international prognostic index: P = 0.015, relative risk = 3.2; B symptoms: P = 0.017, relative risk = 3.3; bulkiness: P = 0.65; grade: P = 0.91).

Antineoplastic Combined Chemotherapy Protocols↗