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PubMed2001

Longitudinal effects of high-dose chemotherapy and autologous stem cell transplantation on quality of life in the treatment of metastatic breast cancer.

This study determined the effects of high-dose chemotherapy (HDCT) with autologous blood stem cell transplantation (ASCT) on quality of life (QL) in women with metastatic breast cancer prior to, and during treatment, and up to 1-year post-ASCT. Thirty-three women diagnosed with metastatic breast cancer participated in a phase 1 clinical trial of a new combination of cyclophosphamide (CTX) and mitoxantrone (MXT), with dose escalation of paclitaxel. Longitudinal QL data were collected using the functional living index-cancer (FLIC) and symptom scales at seven time periods: pre-induction chemotherapy (CT), post-induction CT, post-high dose CT (HDCT), and at 3, 6, 9 and 12 months post-ASCT. FLIC scores indicated that the worst problems for patients were feelings of hardship on themselves and their families, followed by psychological functioning and physical functioning problems. The time around diagnosis of the metastatic disease and following HDCT were the worst times for all levels of quality of life, but anxiety and depression symptoms continued to increase in severity across the entire follow-up period. The symptoms that were most problematic were worry about the future, loss of sexual interest, anxiety about the treatment, general worrying, and joint pain. These data highlight the problems that women with metastatic breast cancer encounter at different stages of the disease and treatment process, and can be used to tailor psychosocial interventions appropriate for treating the relevant issues at different points in time.

Adolescent↗
PubMed1998

Tracing cell fates in human colorectal tumors from somatic microsatellite mutations: evidence of adenomas with stem cell architecture.

Occult aspects of tumor proliferation are likely recorded genetically as their microsatellite (MS) loci become polymorphic. However, MS mutations generated by division may also be eliminated with death as noncoding MS loci lack selective value. Therefore, highly polymorphic MS loci cannot exist unless mutation rates are high, or unless mutation losses are inherently minimized. Mutations accumulate differently when cell fates are determined intrinsically before or extrinsically after division. Stem cell (asymmetrical division as in intestinal crypts) and random (asymmetrical and symmetrical division) proliferation, respectively, represent simulated cell fates determined before or after division. Whereas mutations regardless of selection systematically persist once inherited with stem cell proliferation, mutations are eliminated by the symmetrical losses of both daughter cells with random proliferation. Therefore, greater genetic diversity or MS variance accumulate with stem cell compared with random proliferation. MS loci in normal murine intestinal mucosa and xenografts of cancer cell lines accumulated mutations, respectively, consistent with stem cell and random proliferation. Tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC) demonstrated polymorphic MS loci. Overall, three of five adenomas and one of six cancers exhibited high MS variances. Assuming mutation rates are not significantly greater in adenomas than in cancers, these studies suggest the stem cell proliferation and hierarchy of normal intestines persists in many HNPCC adenomas and some cancers. An adenoma stem cell architecture can explain the complex polymorphic MS loci observed in HNPCC adenomas and account for many adenoma features. In contrast, cancers may lose intrinsic control of cell fate. These studies illustrate a feasible phylogenetic approach to unravel and describe occult aspects of human tumor proliferation. The switch from predominantly stem cell to random proliferation may be a critical and defining characteristic of malignancy.

Adenoma↗
PubMed2000

[Effective chemotherapy with docetaxel in a patient with breast cancer who had progressed after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (APBSCT)].

A 39-year-old female underwent mastectomy for breast cancer in December 1995. However, two years later, she relapsed with multiple bone metastases. Only a partial response was obtained despite tandem high-dose chemotherapy with autologous peripheral blood stem cell transplantation (APBSCT). Disease progression with bone pain and an increasing in the level of serum NCC-ST439 occurred 5 months after APBSCT. Salvage chemotherapy with docetaxel 60 mg/m2 reduced her symptoms, and the level of serum NCC-ST439 decreased to within the normal range. Ten cycles of docetaxel administration were repeated without severe adverse reactions in an outpatient setting for 10 months. There is little information regarding treatment after relapse from APBSCT for breast cancer. Docetaxel may be an effective agent for patients in such a setting.

Adult↗
PubMed1999

A randomized phase 3 study of peripheral blood progenitor cell mobilization with stem cell factor and filgrastim in high-risk breast cancer patients.

This randomized study compared the number of leukaphereses required to collect an optimal target yield of 5 x 10(6) CD34(+) peripheral blood progenitor cells/kg, using either stem cell factor (SCF) at 20 micrograms/kg/d in combination with Filgrastim at 10 micrograms/kg/d or Filgrastim alone at 10 micrograms/kg/d, from 203 patients with high-risk stage II, III, or IV breast cancer. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield of CD34(+) cells had been reached or a maximum of 5 leukaphereses performed. By day 5 of leukapheresis, 63% of the patients treated with SCF plus Filgrastim (n = 100) compared with 47% of those receiving Filgrastim alone (n = 103) reached the CD34(+) cell target yield. There was a clinically and statistically significant reduction (P <.05) in the number of leukaphereses required to reach the target yield for the patients receiving SCF plus Filgrastim (median, 4 leukaphereses) compared with patients receiving Filgrastim alone (median, 6 or more leukapherses; ie, <50% of patients reached the target in 5 leukaphereses). All patients receiving SCF were premedicated with antihistamines, albuterol, and pseudoephedrine. Treatment was safe, generally well tolerated, and not associated with life-threatening or fatal toxicity. In conclusion, SCF plus Filgrastim is a more effective peripheral blood progenitor cell (PBPC)-mobilization regimen than Filgrastim alone. In addition to the potential for reduced leukapheresis-related morbidity and costs, SCF offers additional options for obtaining cells for further graft manipulation.

Adult↗
PubMed1999

A predictive model for relapse in high-risk primary breast cancer patients treated with high-dose chemotherapy and autologous stem-cell transplant.

High-dose chemotherapy (HDCT) is currently under evaluation for high-risk primary breast cancer (HRPBC), defined by extensive axillary nodal involvement or inflammatory breast carcinoma. Phase II studies of HDCT for HRPBC show that 30-40% of patients eventually relapse. We retrospectively reviewed 176 patients enrolled in clinical trials of HDCT for HRPBC at the University of Colorado and analyzed 23 potential predictive variables for relapse. All of the patients received the same regimen, with cyclophosphamide, cisplatin, and BCNU. Nine patients who experienced a toxic death were excluded from this analysis. The resulting predictive model was subsequently tested in an independent patient set treated at Duke University with the same HDCT regimen. Nodal ratio (number of involved nodes:number of sampled nodes), tumor size, grade, stage, estrogen receptor, progesterone receptor, and clinical inflammatory breast carcinoma correlated with risk of relapse. Nodal ratio, tumor size, and the combined estrogen receptor/progesterone receptor status were independent predictors. A scoring system using those three variables determines the risk of relapse, with a sensitivity and specificity of 60 and 90%, respectively, and a positive and negative predictive value of 65 and 88%, respectively. The differences in relapse-free survival and overall survival between high- and low-score patients were highly significant (P<0.000001). This model was subsequently validated in the Duke patient set. This model can identify two subgroups of HRPBC patients with low (12%) and high (65%) risk for recurrence after HDCT. Future research that tests new therapies will focus on those patients with a high score.

Adult↗
PubMed1999

Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: impact on the delivery of local-regional radiation therapy.

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. PATIENTS AND METHODS: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. RESULTS: Overall and disease-free survival rates at 18 months were 83% (+/- 4%) and 77% (+/- 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. CONCLUSION: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

Adult↗
PubMed1998

New developments in high-dose chemotherapy for breast cancer.

High-dose chemotherapy with autologous stem cell support as applied to the treatment of breast cancer has shown promise for over 15 years. Three main approaches have been used: (1) standard-dose induction chemotherapy followed by one or two cycles of myeloablative therapy, (2) multicycle nonablative combination chemotherapy, and (3) high-dose sequential chemotherapy using single agents at the maximum tolerated doses in rapid sequence. Each of these approaches has a strong biological rationale and is being pursued in randomized trials. Unfortunately, comparative data are limited and there is only one fully published randomized trial of the use of high-dose chemotherapy in metastatic breast cancer. This small study from South Africa showed a significant improvement in response rate and survival for women receiving high-dose chemotherapy compared to those given standard dose treatment. It is anticipated that results from larger studies in the USA and Europe evaluating the use of high-dose chemotherapy in metastatic breast cancer and in adjuvant treatment of poor-prognosis early-stage disease will be available within the next 2-3 years. A potentially important and related issue is that of tumor contamination of bone marrow and apheresis collections. Current data suggest that finding epithelial tumor cells with sensitive techniques (such as immunohistochemistry or polymerase chain reaction) gives prognostic information. However, it is not clear whether reinfusion of these cells after high-dose chemotherapy contributes to relapse of breast cancer. Unfortunately, understanding of the data is marred by a lack of standardization of assay methodology. Further work is needed to develop a widely accepted method for the detection of circulating tumor cells before the clinical relevance of such a finding can be meaningfully interpreted.

Antineoplastic Agents↗
PubMed2001

Metaplasia, intraepithelial neoplasia and early cancer of the stomach are related to dedifferentiated epithelial cells defined by cytokeratin-7 expression in gastritis.

Cancer presumably arises from stem cells, preserved in an undifferentiated status since fetal development, or from a dedifferentiation of mature cells that return into a fetal phenotype with the potential for proliferation and renewal. Dedifferentiation in this context could represent a transient phase, passed through by cells, before they switch to redifferentiation, metaplasia or neoplasia. Cytokeratin-7 (CK7) is present in fetal, largely absent in normal adult, and transiently neoexpressed in metaplastic and neoplastic epithelial cells of the stomach according to previous observations. CK7 neoexpression in the stomach could, hence, define a fetal-like, dedifferentiated, cellular phenotype during the development of metaplasia and neoplasia. To test this hypothesis, we investigated CK7 expressions in fetal stomachs, non-neoplastic control stomachs, and neoplastic stomachs exhibiting metaplasia, intraepithelial neoplasia, and early cancer. Proliferation and beta-catenin expression of CK7-positive cells were also evaluated. The chronology of CK7 expression was studied during the experimental gastritis-cancer sequence in Mongolian gerbils. Our results show that metaplastic and neoplastic changes in the gastritis-cancer sequence are related to dedifferentiated epithelial cells which are defined by CK7 expression and can phenotypically be linked to fetal cells at the start of gastric pit development. The dedifferentiated cells exhibit a low proliferation and beta-catenin accumulation, similar to stem cells. Thus, the "stem cell" and "dedifferentiation" hypotheses for cancer origin could complement one another, and dedifferentiation-redifferentiation processes might be decisive for carcinogenesis in the stomach.

Adenocarcinoma↗
PubMed1997

High-dose chemotherapy with autologous stem cell support for the treatment of advanced ovarian cancer--initial experience in Uppsala and Turku.

BACKGROUND: With current standard-dose chemotherapy ovarian cancer is a chemosensitive but not chemocurable disease in the majority of cases. The widely used first-line chemotherapy including a platinum analogue combined with cyclophosphamide results in response rates of 60-80%. However, only 10-20% of patients with advanced disease are alive 5 years after the diagnosis. The efficacy of high-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is currently under intensive investigation. METHODS: We report here our initial experiences of the use of high-dose chemotherapy supported by ASCT for patients with high-risk ovarian cancer. Two patients were treated at Uppsala University Hospital in 1992 and four patients at Turku University Central Hospital in 1994. RESULTS: The first four patients treated either after heavy previous chemotherapy or recurrent disease relapsed within 5-10 months. Two patients received high-dose therapy as part of first-line treatment. One of them had a relapse 18 months after therapy, the other one has been disease free for 28 months. No toxic deaths occurred, but the patients had neutropenic febrile episodes and moderate to severe gastrointestinal toxicity. CONCLUSIONS: Coordinated efforts in Nordic countries are indicated to evaluate the usefulness of high-dose therapy supported by ASCT in the treatment of advanced ovarian cancer.

Adult↗
PubMed2006

Stem cells, senescence, neosis and self-renewal in cancer.

We describe the basic tenets of the current concepts of cancer biology, and review the recent advances on the suppressor role of senescence in tumor growth and the breakdown of this barrier during the origin of tumor growth. Senescence phenotype can be induced by (1) telomere attrition-induced senescence at the end of the cellular mitotic life span (MLS*) and (2) also by replication history-independent, accelerated senescence due to inadvertent activation of oncogenes or by exposure of cells to genotoxins. Tumor suppressor genes p53/pRB/p16INK4A and related senescence checkpoints are involved in effecting the onset of senescence. However, senescence as a tumor suppressor mechanism is a leaky process and senescent cells with mutations or epimutations in these genes escape mitotic catastrophe-induced cell death by becoming polyploid cells. These polyploid giant cells, before they die, give rise to several cells with viable genomes via nuclear budding and asymmetric cytokinesis. This mode of cell division has been termed neosis and the immediate neotic offspring the Raju cells. The latter inherit genomic instability and transiently display stem cell properties in that they differentiate into tumor cells and display extended, but, limited MLS, at the end of which they enter senescent phase and can undergo secondary/tertiary neosis to produce the next generation of Raju cells. Neosis is repeated several times during tumor growth in a non-synchronized fashion, is the mode of origin of resistant tumor growth and contributes to tumor cell heterogeneity and continuity. The main event during neosis appears to be the production of mitotically viable daughter genome after epigenetic modulation from the non-viable polyploid genome of neosis mother cell (NMC). This leads to the growth of resistant tumor cells. Since during neosis, spindle checkpoint is not activated, this may give rise to aneuploidy. Thus, tumor cells also are destined to die due to senescence, but may escape senescence due to mutations or epimutations in the senescent checkpoint pathway. A historical review of neosis-like events is presented and implications of neosis in relation to the current dogmas of cancer biology are discussed. Genesis and repetitive re-genesis of Raju cells with transient "stemness" via neosis are of vital importance to the origin and continuous growth of tumors, a process that appears to be common to all types of tumors. We suggest that unlike current anti-mitotic therapy of cancers, anti-neotic therapy would not cause undesirable side effects. We propose a rational hypothesis for the origin and progression of tumors in which neosis plays a major role in the multistep carcinogenesis in different types of cancers. We define cancers as a single disease of uncontrolled neosis due to failure of senescent checkpoint controls.

Journal Article↗
PubMed1997

Role of tumor cells contaminating the graft in breast cancer recurrence after high-dose chemotherapy.

One of the possible drawbacks to autologous stem cell transplantation in breast cancer (BC) patients is the potential for tumor contamination in the transplanted product. We present a patient with advanced disease who received high-dose chemotherapy (HDC) and PBPC support as consolidation therapy after achieving complete remission with standard-dose first-line treatment, and suffered recurrence of the disease 6 months after transplantation. Retrospective analysis revealed the presence of contaminating cells in the leukapheretic product, and clinical evidence suggested a role for these cells in the tumor relapse.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2007

CD133 positive hepatocellular carcinoma cells possess high capacity for tumorigenicity.

Recently increasing reported data have suggested that only a small subset of cancer cells possess capability to initiate malignancies including leukemia and solid tumors, which was based on investigation in these cells displaying a distinct surface marker pattern within the primary cancers. CD133 is a putative hematopoietic and neuronal stem-cell marker, which was also considered as a tumorigenic marker in brain and prostate cancer. We hypothesized that CD133 was a marker closely correlated with tumorigenicity, since it was reported that CD133 expressed in human fetal liver and repairing liver tissues, which tightly associated with hepatocarcinogenesis. Our findings showed that a small population of CD133 positive cells indeed exists in human hepatocellular carcinoma (HCC) cell lines and primary HCC tissues. From SMMC-7721 cell line, CD133+ cells isolated by MACS manifested high tumorigenecity and clonogenicity as compared with CD133- HCC cells. The implication that CD133 might be one of the markers for HCC cancer stem-like cells needed further investigation.

AC133 Antigen↗
PubMed1999

Stem cell factor and granulocyte-macrophage-colony stimulating factor as candidates for tumour markers for non-small-cell lung cancer.

We have investigated the serum level of stem cell factor (SCF) and granulocyte-macrophage-colony stimulating factor (GM-CSF) in relation to a control group and commonly accepted tumour markers, such as carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1). Additionally, we have defined the diagnostic sensitivity, specificity, positive predictive value, negative predictive value and receiver-operating characteristics (ROC) curve of SCF and GM-CSF in non-small-cell lung cancer (NSCLC). The serum levels of cytokines were measured in 50 patients with NSCLC and in 20 healthy subjects. SCF and GM-CSF were determined using enzyme-linked immunosorbent assay (ELISA), CYFRA 21-1 was measured by radioimmunoassay and CEA by microparticle enzyme immunoassay. There were significant increases in circulating SCF and GM-CSF in the lung cancer patients compared to the control group. The diagnostic sensitivity of GM-CSF was higher (70%) than the sensitivity of CEA (62%) and CYFRA 21-1 (51%). The diagnostic specificity of GM-CSF was lower (65%) than SCF specificity (70%), but the GM-CSF predictive values were higher in relation to the predictive values of SCF. These results suggest a potential role of SCF and GM-CSF as tumour markers for NSCLC.

Adult↗
PubMed2002

Curing metastatic testicular cancer.

Our initial studies with cisplatin + vinblastine + bleomycin began 27 years ago in 1974, changing the cure rate for disseminated disease from 5 to 60%. Subsequently, through random prospective clinical trials, we have modified the treatment regimen to reduce both the duration and dosages of the chemotherapy drugs. Cisplatin + etoposide was first used at Indiana University as salvage chemotherapy in 1978, representing the first time that a solid tumor had been cured with second-line chemotherapy. We next did a clinical trial comparing bleomycin + etoposide + cisplatin (BEP) to cisplatin + vinblastine + bleomycin. The BEP regimen was proven to have less toxicity and a higher cure rate and therefore, since 1984, has been standard chemotherapy. More recent studies have evaluated the use of lesser chemotherapy to maintain the same cure rate for patients with good-prognosis disease. Standard therapy for these patients is either three courses of BEP or four courses of EP, and over 90% of these patients will be cured of their disease. Patients who are not cured with their initial BEP chemotherapy are usually treated with salvage chemotherapy. Approximately 50% of these testicular cancer patients will subsequently be cured with salvage chemotherapy with tandem transplant of high-dose chemotherapy with peripheral stem cell rescue. Testicular cancer has become a model for a curable neoplasm. In the early 1970s, metastatic testicular cancer was associated with only 5% survival. Today, with modern chemotherapy and surgery techniques, 80% of patients will survive their disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

High-dose carboplatin plus paclitaxel with granulocyte colony-stimulating factor and peripheral blood stem-cell support in non-small-cell lung cancer.

The treatment of non-small-cell lung cancer (NSCLC) has recently undergone major changes due to the availability of new drugs that demonstrate substantial activity in NSCLC patients. Although cure for the majority of stage III NSCLC and effectively all stage IV disease patients remains rare, a number of compounds, including carboplatin, paclitaxel, docetaxel, irinotecan, and vinorelbine, have proved useful in the treatment of these patients. Together with a number of phase II trials, phase I trials utilizing escalating doses of carboplatin and paclitaxel with growth factor or growth factor and blood stem-cell support have shown that substantial increases in dose intensity can be achieved. These studies in small numbers of patients have demonstrated that these regimens have encouraging activity and have formed the basis of a Cancer and Leukemia Group B (CALGB) phase II pilot study. This study will utilize two cycles of high-dose carboplatin and Taxol given at an AUC dose of 18 and a 24-h infusion dose of 250 mg/m2, respectively, with growth factor and stem-cell support to treat stage III NSCLC patients. Patients will also receive multimodality therapy, including radiation with or without surgery. It is hoped that this effort to intensify treatment in patients with limited-stage disease will improve survival and benefit the large number of patients with stage III tumors. This paper outlines the phase I results that formed the basis of the CALGB trial and reviews several recent reports of phase II or phase III trials of single-agent and combination regimens for NSCLC.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Indium-111-labelled donor-lymphocyte infusion by way of hepatic artery and radio-frequency ablation against liver metastases of renal and colon carcinoma after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: In patients with metastatic solid cancer, antitumor effects occur after allogeneic stem-cell transplantation (SCT). However, this treatment is not as effective in the liver as against pulmonary and lymph-node metastases. To intensify the effect of donor-lymphocyte infusions (DLI) against liver metastases, intra-arterial (IA) cell injection by way of the hepatic artery (HA) can be used. METHODS: To trace infused cells, three patients with colorectal, three with renal, and one with breast carcinoma were treated with Indium-111 (111-In)-oxinate-labeled lymphocytes. Four patients received the DLI IA, all after radio-frequency ablation (RFA) of liver metastases. Three patients with other metastases received 111-In DLI intravenously (IV). One of them had RFA before SCT. RESULTS: Localization of the IA 111-In DLI activity on scintigrams homed to the liver. After IA injection, the liver to sternum ratio of radioactivity was higher compared with IV injection. Cells (CD3+, 19+, and 56+) of donor origin in biopsies of liver metastasis in two patients treated with IA injection increased to 80% to 100%. Two of four patients treated using the IA DLI showed stable size and number of liver metastases for 5 and 21 months, respectively. Both are alive 18 and 34 months after SCT. Two of three patients receiving DLI IV are doing well, with a stable metastatic disease or still without metastases 21 and 20 months after cell infusions (26 and 34 months after SCT), respectively. Three patients died because of progressive disease. CONCLUSION: When infused by way of the HA, 111-In-labeled lymphocytes home to the liver and its metastases. The liver metastasis infiltrating cells of donor origin increased. DLI by way of the HA combined with RFA may be used to treat liver metastases after SCT.

Adult↗
PubMed2005

The disparate role of BMP in stem cell biology.

Stem cells share several characteristics of cancer cells including loss of contact inhibition and immortality. Therefore, stem cells represent an excellent model system in which to define the molecular mechanisms underlying cancer development and progression. Several signal transduction pathways including leukemia inhibitory factor, Wnt and FGF have been demonstrated to function in stem cell self-renewal and differentiation. However, more recently bone morphogenetic proteins (BMPs) have emerged as key regulators of stem cell fate commitment. Intriguingly, BMPs have disparate roles in regulating the biology of embryonic stem (ES) cells compared with neural crest stem cells (NCSCs). Furthermore, although BMPs block neural differentiation of ES cells from both mouse and human, they contribute to self-renewal specifically in mouse ES cells. These observations strongly suggest that combinations of extracellular factors regulate stem cells, and that crosstalk between intracellular signaling pathways precisely defines stem cell fate commitment. In this review, we focus on the role of BMP signaling in mouse and human ES cells compared with NCSCs. We then discuss how the molecular effectors of BMP signaling may contribute to cancer, and thus represent potential targets for therapeutic intervention.

Animals↗