High-dose chemotherapy and autologous stem cell transplantation for breast cancer.
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Antineoplastic Agents↗
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Results for “Cancer stemness”
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Telomere maintenance in clinical medicine.
Telomeres, the ends of linear chromosomes, shorten with each round of DNA replication. Loss of telomeric DNA can lead to senescence, a state in which cells no longer divide, and crisis, which triggers cell death. To prevent these phenomena, cancer and stem cells must maintain their telomeres, for example, by expressing telomerase, an enzyme that can extend telomeres. As our knowledge of telomere maintenance increases, opportunities arise for translating telomere biology into clinical medicine. Areas of current investigation include the development of diagnostic and prognostic markers for cancer; the development of chemotherapeutic agents based on telomerase inhibition, an immune response to telomerase, or telomerase-based gene therapy; and engineering rejuvenated tissues by restoring telomerase expression.
Biomarkers, Tumor↗
Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience.
Community respiratory viruses (CRVs) are an important cause of morbidity and mortality among recipients of hematopoietic stem cell transplants (HSCT). At the Fred Hutchinson Cancer Research Center, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) infections in HSCT recipients have been studied intensively for more than a decade. Over time, mortality from these infections has declined as the approach to diagnosis has become more aggressive and more stringent preventive measures have been instituted. However, mortality among HSCT recipients with RSV or PIV pneumonia remains high. Uncontrolled studies at our center suggest that prompt therapy with aerosolized ribavirin has reduced mortality from RSV pneumonia but does not appear to affect the course of established PIV pneumonia. Two controlled clinical trials of ribavirin therapy for RSV infection in HSCT recipients are in progress.
Clinical Trials as Topic↗
Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results.
PURPOSE: To evaluate the feasibility and safety of nonmyeloablative allogeneic stem-cell transplantation in patients with metastatic renal cell cancer (RCC) and to evaluate efficacy with respect to engraftment and tumor regression. PATIENTS AND METHODS: Between February 1999 and June 2001, patients with refractory, metastatic RCC were screened for enrollment. A fludarabine and cyclophosphamide-based conditioning regimen was used. Patients received granulocyte-macrophage colony-stimulating factor-mobilized, unmanipulated stem cells from a 6/6 HLA-matched sibling donor. Prophylaxis against graft rejection and graft-versus-host disease (GVHD) included tacrolimus and mycophenolate mofetil. RESULTS: A total of 284 patients with metastatic RCC were seen during this time period. Eighty-four patients who had siblings available for HLA typing were actively screened for enrollment, and 15 patients have undergone treatment. Durable donor engraftment was achieved in one of the first four patients treated. Patients no. 5 through 15 received a more immunosuppressive conditioning regimen, and all have achieved sustained donor engraftment. In the 12 patients with at least 180 days of follow-up, acute GVHD has occurred in two patients and chronic GVHD in six patients, with four transplant-related mortalities. Four partial responses have been observed (response rate, 33% in all patients; 44% in the nine patients with sustained donor engraftment). CONCLUSION: Nonmyeloablative allogeneic stem-cell transplantation is feasible for a minority of patients with metastatic RCC. Adequately immunosuppressive conditioning is required for sustained donor engraftment, which is required for an antitumor response. Acute and chronic GVHD are the major causes of substantial morbidity and mortality. Metastatic RCC is susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell transplantation.
Adenocarcinoma, Clear Cell↗
A phase II study of repetitive cycles of dose-intense carboplatin plus paclitaxel chemotherapy and peripheral blood stem cells in metastatic breast cancer.
To assess the feasibility of administering sequential cycles of dose-intensive therapy, 14 patients without prior chemotherapy for metastatic breast cancer were registered to be treated with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) at an initial dose of 250 mg/m2 over 24 hours (day 1), followed by carboplatin dosed to an area under the concentration-time curve of 16 (calculated according to the Calvert formula), every 3 weeks for four cycles. This combination was supported with peripheral blood stem cells collected following granulocyte colony-stimulating factor with or without cyclophosphamide and paclitaxel. One patient failed to peripheralize CD34 cells after cyclophosphamide/paclitaxel therapy and was taken off protocol. The remaining 13 patients entered the paclitaxel/carboplatin phase of the program, and nine completed all four cycles. The median duration of severe neutropenia (absolute neutrophil count < 100/microL) was 6 days, despite the absence of routine use of granulocyte colony-stimulating factor. Only five of a total of 42 chemotherapy cycles (12%) were associated with febrile neutropenia requiring hospitalization. Most patients did not require platelet transfusions. The most significant nonhematologic toxicity was gastrointestinal (grade 3 in three patients, two of whom had received local radiation for relapse before chemotherapy). Most patients developed grade 1 or 2 sensory neuropathy by the final cycle. Of the nine patients who entered the paclitaxel/carboplatin phase and were evaluable for response, five achieved a complete remission. This doublet of high-dose therapy can be given in an entirely ambulatory setting and is associated with modest hematologic toxicity. The value of this option in the treatment of metastatic breast cancer compared with more conventional approaches to high-dose therapy will require a greater number of patients evaluable for response and longer follow-up.
Adult↗
Therapeutic implications of a stem cell model for human breast cancer: a hypothesis.
A model for human breast cancer is proposed in which a subpopulation of relatively undifferentiated tumor stem cells gives rise to clones of cells by a process of exponential division. The progeny progressively become more differentiated but lose their proliferative potential. The model implies that breast cancers are heterogeneous with respect to differentiation features such as hormone receptors, both between different clones and within individual clones. Therefore, endocrine therapies are preferentially directed towards differentiated cells and are unlikely to be curative either in advanced disease or in the adjuvant setting. The reduction of differentiated cells by hormonal maneuvers may leave a population of more actively dividing tumor stem cells which are more sensitive to chemotherapy. Hormonal therapy followed by cytotoxic chemotherapy may be more likely to kill tumor stem cells than either form of therapy given alone.
Breast Neoplasms↗
Micrometastases in apheresis products predict shorter progression-free and overall survival in patients with breast cancer undergoing high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ABSCT).
The presence of cancer cells in autografts of breast cancer patients has been described to have prognostic value or directly lead to relapse. Previously, we demonstrated that apheresis products (APs) collected after induction chemotherapy have a significantly lower likelihood of tumor cell contamination. Here, we examine the prognostic value of micrometastases in autografts. Data from 83 patients with breast cancer treated with autologous blood stem cell transplantation were analyzed. Pan-cytokeratin-FITC conjugated antibodies were used to detect contaminating breast cancer cells in the APs. Progression and survival data analyzed on the basis of three or fewer cancer cells showed no significant differences in outcomes. Of the 83 patients, 11 had more than three cancer cells detectable in their APs. In total, 72 patients were shown to have less than three cells detectable. When patients with more than three cells were compared to patients with 0-3, we found statistically significant differences in progression-free survival. We also found a significant difference in overall survival (OS) between the two groups. No difference was observed in OS since the time of diagnosis. We conclude that patients with more than three contaminating cells in their APs have micrometastases and represent a poor prognosis group.
Adult↗
Toxicities associated with cryopreserved and thawed peripheral blood stem cell autografts in children with active cancer.
To evaluate the safety of cryopreserved and thawed peripheral blood stem cell (PBSC) autografts in children with active cancer, a toxicity assessment was made of 54 PBSC transfusions to 52 children (aged 1-16 years; median, 9 years). Patients were conditioned with high-dose chemotherapy without total body irradiation. The volume of PBSCs transfused varied from 46 to 500 mL (219.6 +/- 118.4 mL, mean +/- SD), with a mean of 0.91 g per kg of dimethyl sulfoxide. Insignificant and transient toxicities included hemoglobinuria in 40 patients (74%), headache in 38 (70%), nausea in 37 (69%), and vomiting in 25 patients (46%). Significant shock developed in 8 patients (15%), but they recovered quickly, whether they had supportive therapy or not. Vomiting and hyperbilirubinemia were the only toxicities that showed a correlation with the amount of PBSCs transfused. The data suggest that transient toxicity associated with PBSC autografts is rather common in children, and close observation of patients for possible serious morbidity is required.
Adolescent↗
High-dose chemotherapy and autologous stem cell transplantation for breast cancer.
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Agranulocytosis↗
Cardiac conduction abnormalities in patients with breast cancer undergoing high-dose chemotherapy and stem cell transplantation.
Cardiac toxicities in 39 consecutive patients with breast cancer receiving high-dose chemotherapy (HDC) with stem cell transplantation were reviewed. All 39 patients received various anthracycline-containing regimens in adjuvant settings and/or for metastatic disease before HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for 3 consecutive days. No immediate fatal toxicities were observed, but one patient developed chronic congestive heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another three patients. ST-T abnormalities during HDC were observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with uncontrolled vomiting. No relationship was observed between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that abnormalities in the conduction system during HDC may be more frequent than previously reported. Vagal reflex secondary to emesis may play an important role in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185-189.
Adult↗
Performance limitations and participation restrictions among childhood cancer survivors treated with hematopoietic stem cell transplantation: the bone marrow transplant survivor study.
BACKGROUND: Hematopoietic stem cell transplantation (HCT) may result in important disease- and treatment-related late effects. This study estimated physical, emotional, and educational limitations (performance limitations) and restrictions in the ability to perform personal care or routine daily activities (physical participation restrictions) and restrictions in the ability to participate in social roles (social participation restrictions) in a cohort of cancer survivors treated with HCT during childhood. METHODS: Study participants included 235 persons who had a malignancy or hematologic disorder, were treated with HCT before the age of 21 years, and survived at least 2 years after transplantation. A comparison group was recruited and frequency matched for age, sex, and ethnicity. Medical data were abstracted, and patients or parents (if <18 years at survey completion) completed a mailed 24-page questionnaire. RESULTS: Adult survivors of childhood cancer were more likely than the comparison group to report limitations in physical (prevalence odds ratio [OR], 2.2; 95% confidence interval [CI], 1.3-3.7) and emotional domains (OR, 2.9; 95% CI, 1.4-5.8) and to report physical participation restrictions (OR, 3.9; 95% CI, 1.9-8.2). Adult survivors were also less likely than the comparison group to be married (OR, 0.4; 95% CI, 0.2-0.6). Child survivors were more likely than similarly aged children to have participated in special education (OR, 3.0; 95% CI, 1.5-6.0), to report physical participation restrictions (OR, 10.8; 95% CI, 2.2-53.9), and to have behaviors that indicated impaired social competence (OR, 2.0; 95% CI, 0.9-4.2). CONCLUSION: This study demonstrated that persons treated with HCT as children were at increased risk for performance limitations that restricted participation in routine daily activities and interpersonal relationships.
Activities of Daily Living↗
Effect of prior therapy and bone marrow metastases on progenitor cell content of blood stem cell harvests in breast cancer patients.
This study was designed to examine the relationship of prior therapy, bone marrow metastases, mobilization, and blood progenitor/stem cell (BSC) collection in breast cancer patients. Cells were collected from 19 breast cancer patients during steady state (nonmobilized group) and from 69 breast cancer patients after cytokine administration (mobilized group). Characteristics of the patients were compared with the cells obtained. A significant inverse association was found between the number of chemotherapy regimens the patients had received prior to BSC collection and the mononuclear cell (MNC) count of the product per liter of blood processed (LBP) with apheresis (P = .0006) and the granulocyte monocyte/macrophage colony-forming cell (GM-CFC) numbers per LBP (P = .0002). This association was evident in both mobilized and nonmobilized patients. Similar results were seen in those 25 patients who had received prior radiation therapy (MNC/LBP, P = .0003; GM-CFC/LBP, P = .0004). Patients in both the mobilized and nonmobilized groups with marrow metastases at the time of collection also had significantly lower levels of MNC/LBP (P = .0039) and GM-CFC/LBP (P = .0001) than did those without marrow metastases. The findings suggest that prior administration of radiation therapy and/or chemotherapy and the presence of marrow metastases all negatively impacted the collection of mobilized and nonmobilized progenitor cells from breast cancer patients. The mechanisms of this impact are not understood.
Adult↗
Autologous peripheral blood stem cell transplantation for lung cancer.
Lung carcinoma, the most frequent cause of cancer-related death in both men and women, remains a difficult therapeutic problem. Small-cell lung carcinoma, despite its high response rate to chemotherapy, is associated with a rapid recurrence and ultimately limited overall survival. In attempts to exploit tumour chemosensitivity, high-dose chemotherapy (HDC) combining several active drugs has been studied to improve outcome. In addition, haematopoietic stem cell support has been used to allow dose escalation without major myelosuppression. In contrast to small-cell carcinoma, non-small-cell carcinoma of the lung is generally not very responsive to chemotherapy, and results with dose intensity in unresectable tumour have so far been very disappointing. We review the results of HDC in terms of response and survival, and discuss potential strategies to improve the effectiveness of dose intensity.
Antineoplastic Combined Chemotherapy Protocols↗
High-dose chemotherapy with mitoxantrone + melphalan and autologous stem cell rescue in metastatic breast cancer patients: a study of feasibility and tolerability.
Hematological and extra-hematological toxicity of mitoxantrone-containing regimens with autologous stem cell rescue was evaluated in 32 metastatic breast cancer patients. The schedule was the final part of two high-dose chemotherapy programs, including an induction phase with three courses of conventional chemotherapy with epirubicin (120 mg/m2) and cyclophosphamide (600 mg/m2) plus three courses of docetaxel (100 mg/m2) and a first high-dose chemotherapy consisting of cyclophosphamide (6000 mg/m2), thiotepa (500 mg/m2) and carboplatin (800 mg/m2) or melphalan (160 mg/m2) plus thiotepa (600 mg/m2). The final second autograft phase included mitoxantrone (60 mg/m2) associated with melphalan (160 mg/m2) and autologous stem cell rescue infusion. The median duration of severe neutropenia and thrombocytopenia was 9 (range, 7-13) and 11.5 (range, 9-29) days. The median number of units of erythrocytes and platelets transfused was 1 (0-11) and 4 (1-9), respectively. Fever for a median of 2 (0-8) days developed in 71.8% of the patients. Mucositis was observed in 81.2% (WHO grade 3-4 in 25%). No acute or late cardiac toxicity was observed. One patient died because of a transplant-unrelated cause. The response according to the program phase showed an increased rate of complete response, from 12.5% at the end of conventional chemotherapy to 21.9% after the first high-dose chemotherapy course, to increase to 43.9% after the treatment with mitoxantrone-melphalan. We conclude that a conditioning regimen with high dose mitoxantrone-melphalan fits well within the high-dose chemotherapy program.
Adult↗
Potentially therapeutically relevant differences of antisense oligonucleotide uptake in CD34+ hematopoietic stem cells, leukemic blasts and cancer cells from patients.
Antisense oligonucleotide (ON) technology, e.g. against drug resistance or antiapoptotic factors, may play an important role in future cancer chemotherapy. An unanswered question in this field is the capacity for uptake of antisense molecules in normal and malignant patients' cells. Therefore, we examined the cellular uptake of FITC-labeled phosphorothioate modified ONs in: i) cells from the T-lymphoblastoid cell line CCRF-CEM, ii) CD34+ hematopoietic progenitors from healthy donors, iii) blasts from ALL or AML patients, iv) cells from the ovarian cancer cell line A2780 and v) cancer cells from malignant fluids. The cationic polymer ExGen was taken as a carrier for transfection, while FITC-ON uptake was evaluated by flow cytometry. We found marked differences between these cell types. Cancer cells from the cell line A2780 and from patients showed a distinctly enhanced uptake compared to hematopoietic progenitors and leukemic blasts. Since bone marrow toxicity substantially limits any conventional chemotherapeutic regimen, a better ON uptake in cancer cells compared to hematopoietic precursors might give an advantage for therapeutic approaches using e.g. ON-based chemosensitization.
Antigens, CD34↗
Evaluation of the functional assessment of cancer therapy cognitive scale with hematopoietic stem cell transplant patients.
The current study evaluated a newly developed self-report measure of cognitive complaints with cancer patients, the Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog). Six or 12 months following hematopoietic stem cell transplantation, participants completed a psychosocial assessment that included the FACT-Cog and a neuropsychological assessment. Using a criterion of two or more times a week, an average of 12 of a total of 50 items were endorsed as complaints on the FACT-Cog. FACT-Cog total, domain, and subscale scores were significantly correlated with measures of depression, fatigue, anxiety, and physical and mental well-being. FACT-Cog scores, with the exception of one subscale, Other People Noticed Deficits, were not significantly correlated with cognitive performance. In general, the FACT-Cog and a commonly used measure of cognitive complaints (European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-C30 Cognitive Functioning Scale) demonstrated similar psychometric properties. However, the FACT-Cog assesses broader aspects of cognitive complaints, thereby providing greater information about the types of cognitive complaints patients are experiencing.
Adult↗
BRCA1 functions as a breast stem cell regulator.
BRCA1 is an important susceptibility gene for breast cancer, which confers substantial lifetime risks of breast cancer, particularly in the pre-menopausal age group. Typically, carriers of BRCA1 mutations develop breast tumours that grow rapidly and are high grade and oestrogen receptor negative. They also possess a basal epithelial phenotype, as defined by cytokeratin expression, that is not present in most breast cancers. It has recently been proposed that the adult breast stem cell expresses only basal keratins. Others have indicated a CD44 positive, CD24 negative phenotype for breast cancer stem cells. In this paper, I argue that the biology of human BRCA1 and its rodent homologues and the clinicopathological features of breast cancer related to BRCA1 support the notion that one of the key functions of BRCA1 is to act as a stem cell regulator. This has implications for the management of carriers of mutations of BRCA1, in part because support for the role of BRCA1 as a stem cell regulator would emphasise the distinct nature of breast cancer related to BRCA1.
Animals↗
Tissue-Level Transcriptomic Entropy Reveals Organ-Specific Aging Patterns and Predicts Cancer Progression.
Although aging and cancer share complex molecular mechanisms, distinguishing causative factors from byproducts remains challenging. Here, we investigated the role of tissue transcriptomic entropy-a measure of transcriptional disorder-in aging and cancer processes by analyzing RNA-sequencing data from over 25,000 samples from human and mouse tissues. We found that entropy changes during aging are highly tissue-specific, with some tissues showing increased entropy while others exhibit decreased or stable entropy levels. Moreover, transcriptomic entropy strongly correlates with age-related processes, showing positive associations with proliferation, cellular senescence, somatic mutation burden, and cellular reprogramming, whereas it negatively correlates with stemness. In cancer, we observed that primary tumors generally display higher entropy than normal tissue, with its levels further increasing in metastatic stages. Cancer treatment modulated entropy patterns in multiple contexts, with changes suggesting a role for transcriptional complexity in tumor plasticity and therapy resistance. Elevated entropy levels predicted poor survival outcomes in multiple cancer types, suggesting its potential as a prognostic marker. Furthermore, differential expression analysis revealed that entropy-associated genes are enriched in developmental processes and depleted in metabolic pathways, indicating a possible link to cellular dedifferentiation. Finally, we found increased entropy in various age-related disorders beyond cancer, suggesting that transcriptomic entropy may be a common feature in age-related diseases. Our findings establish transcriptomic entropy as a fundamental parameter in aging and cancer progression, offering new insights into disease mechanisms.
Humans↗