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At least 991 records · Page 55Linked to original sources
PubMed1998

[High-dose chemotherapy with autologous peripheral blood stem cell transfusion in the treatment of advanced testis cancer].

Four patients with advanced testis cancer were treated by high-dose chemotherapy supporting by autologous peripheral blood stem cell transplantation. High-dose chemotherapy (carboplatin 250 mg/m2 or nedaplatin 200 mg/m2, etoposide 1,500 mg/m2, ifosphamide 7.5 g/m2 was given and peripheral blood stem cell transfusion was performed 72 hours after the last dose of chemotherapy. High-dose chemotherapy. was given followed by 1 or 2 cycles of pre high-dose therapy consisting of cisplatin 100 mg/m2 or carboplatin 500 mg/m2, etoposide 450 mg/m2, ifosphamide 6 g/m2. All 4 patients were evaluable. Three patients obtained a complete response and one showed a partial response. The partial responder was given RPLND. The RPLND specimen showed necrotic tissue.

Adult↗
PubMed1999

Thymic hyperplasia after high-dose chemotherapy and autologous stem cell transplantation: incidence and significance in patients with breast cancer.

OBJECTIVE: The purpose of this study was to determine the incidence and clinical significance of thymic hyperplasia after high-dose chemotherapy and autologous stem cell transplantation for treatment of metastatic or high-risk primary (with at least four positive lymph nodes) breast cancer. MATERIALS AND METHODS: We retrospectively reviewed clinical records and CT scans of 102 breast cancer patients treated with high-dose chemotherapy and autologous stem cell transplantation. Patients were 26-63 years old (mean, 46 years). The length and width of the thymus gland were measured on serial CT scans obtained before and after treatment. Moderate thymic hyperplasia was recorded if a focal or diffuse increase was seen in the oblong, triangular soft-tissue opacity conforming to the configuration of the normal gland within the anterior mediastinum after therapy. Minimal hyperplasia was recorded when a minimal increase was seen in soft-tissue attenuation conforming to the configuration of the normal bilobed thymus gland within the anterior mediastinum, but no discrete mass was visible. RESULTS: CT showed no thymic hyperplasia in 91 (89%) of the 102 patients. CT showed thymic hyperplasia in the other 11 patients (11%). Three patients (3%) had moderate hyperplasia, and eight patients (8%) had minimal hyperplasia. When comparing patients with and without hyperplasia, we found no difference in mean age or survival. CONCLUSION: Thymic hyperplasia is rare after high-dose chemotherapy and autologous stem cell transplantation in adult patients with metastatic or high-risk primary breast cancer. In this population, thymic hyperplasia does not appear to correlate with survival.

Adult↗
PubMed2006

Stem cells as a two edged sword--from regeneration to tumor formation.

Evidence has accumulated that quiescent stem cells or cells developmentally closely related to them distributed in various organs may be a cellular origin of cancer development. In support of this notion, stem cells (SC) are long-lived cells with distinctive properties of self-renewal and has the potential to proliferate extensively. Given these features, it's possible that they may become the subject of consecutive accumulated mutations that are crucial for initiation of cancer. Therefore, mutations that occur in normal stem cells might lead to their malignant transformation and tumor initiation. Furthermore, many biological features of normal and cancer SC such as the physiological trafficking of normal and metastasis of cancer stem cells involve similar molecular mechanisms, and we discuss these similarities here.

Animals↗
PubMed2004

Genomic profiling of viable and proliferative micrometastatic cells from early-stage breast cancer patients.

PURPOSE: Metastases in distant organs are the major cause of death for cancer patients, and bone marrow is a prominent homing organ for early disseminated cancer cells. However, it remains still unclear which of these cells evolve into overt metastases. We therefore established a new approach based on the analysis of viable and proliferating cancer cells by single-cell comparative genomic hybridization. EXPERIMENTAL DESIGN: The bone marrow of early-stage breast tumor patients (pN(0)M(0)) was screened for tumor cells by immunostaining. By applying special short-term culturing, we selected for viable and proliferative tumor cells. The short-term culturing allowed us to evaluate the proliferative potential of micrometastatic cells, which we had previously shown to represent an independent prognostic marker. We assessed genomic changes in single disseminated cancer cells by single-cell comparative genomic hybridization. RESULTS: We found that these viable disseminated cancer cells already had a plethora of copy number changes in their genome. All of these cells showed chromosomal copy number changes with a substantial intercellular heterogeneity and differences to the matching primary tumors. CONCLUSIONS: The established experimental strategy might pave the way for the identification of metastatic stem cells in cancer patients. Our preliminary results support the new concept that early disseminated cancer cells evolve independently from their primary tumor.

Adult↗
PubMed1993

Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group.

Children's Cancer Group Protocol CCG-9882 was designed to determine the effectiveness of hyperfractionated radiation for the treatment of children and young adults with brain stem gliomas. The study opened for the accrual of patients on September 21, 1988, and was closed on June 30, 1991. The first 54 children in the study were treated with irradiation doses of 100 cGy given twice daily to a total dosage of 7200 cGy. The next 66 children were treated with a similar daily regimens to a total of 7800 cGy. Tumors were diagnosed by clinical and radiographic criteria. Decisions about the need for surgery were left to the discretion of the treating neurosurgeon; tissue diagnosis did not alter the therapy in patients with diffuse infiltrating tumors. We reviewed the neuroradiology and neurosurgery reports as well as the pathological specimens of children entered on the study. By magnetic resonance (MR) imaging criteria, tumors involved the majority of the brain stem in 76% of cases; only three patients had tumors localized to the midbrain or medulla. Operations were performed on 56 of 120 patients (47%). Cerebrospinal fluid shunts were inserted in 27 (23%) of the children; insertion of a shunt was the only operation in 11, and a shunt was inserted in conjunction with a tumor operation in 16. Tumor operations were performed in 45 (38%) of the patients; 24 had stereotactic biopsies, and 21 had craniotomies. Of the 21 patients who had craniotomies, only biopsies were performed in 11; partial tumor resections were performed in 5 patients and subtotal resection in 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

Liver stem cells: implications for hepatocarcinogenesis.

Numerous studies point to the fact that liver tumors are derived from single cells (monoclonal), but the important question is, which cell? Stem cell biology and cancer are inextricably linked. In continually renewing tissues such as the intestinal mucosa and epidermis, in which a steady flux of cells occurs from the stem cell zone to the terminally differentiated cells that are imminently to be lost, it is widely accepted that cancer is a disease of stem cells, as these are the only cells that persist in the tissue for a sufficient length of time to acquire the requisite number of genetic changes for neoplastic development. In the liver the identity of the founder cells for the two major primary tumors, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC), is more problematic. The reason for this is that no such obvious unidirectional flux occurs in the liver, though it is held that the centrilobular hepatocytes may be more differentiated (polyploid) and closer to cell senescence than those cells closest to the portal areas. Moreover the existence of bipotential hepatic progenitor cells (HPCs), along with hepatocytes endowed with longevity and long-term repopulating potential suggests there may be more than one type of carcinogen target cell. Irrespective of which target cell is involved, cell proliferation at the time of carcinogen exposure is pivotal for "fixation" of the genotoxic injury into a heritable form. Taking this view, any proliferative cell in the liver can be susceptible to neoplastic transformation. Thus, hepatocytes are implicated in many instances of HCC, direct injury to the biliary epithelium implicates cholangiocytes in some cases of CC, whereas HPC/oval cell activation accompanies very many instances of liver damage irrespective of etiology, making such cells very likely carcinogen targets. Of course, we must qualify this assertion by stating that many carcinogens are both cytotoxic and cytostatic, and that HPC proliferation may be merely a bystander effect of this toxicity. An indepth discussion of causes of cancer in the liver are beyond the scope of this review, but infectious agents (e.g., hepatitis B and C viruses) play a major role, not just in transactivating or otherwise disrupting cellular proto-oncogenes (hepatitis B virus [HBV]), but in also causing chronic inflammation (hepatitis C virus [HCV] and HBV). Sustained epithelial proliferation in a milieu rich in inflammatory cells, growth factors, and DNA-damaging agents (reactive oxygen and nitrogen species produced to fight infection), will lead to permanent genetic changes in proliferating cells. The upregulation of the transcription factor nuclear factor kappaB (NF-kappaB) in transformed hepatocytes, through the paracrine action of tumor necrosis factor-alpha from neighboring endothelia and inflammatory cells, may be critical for tumor progression given the mitogenic and anti-apoptotic properties of proteins encoded by many of NF-kappaB's target genes.

Animals↗
PubMed2002

Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics.

A long-standing intriguing hypothesis in cancer biology is that adult stem cells avoid mutations from DNA replication errors by a unique pattern of chromosome segregation. At each asymmetric cell division, adult stem cells have been postulated to selectively retain a set of chromosomes that contain old template DNA strands (i.e., "immortal DNA strands"). Using cultured cells that cycle with asymmetric cell kinetics, we confirmed both the existence of immortal DNA strands and the cosegregation of chromosomes that bear them. Our findings also lead us to propose a role for immortal DNA strands in tissue aging as well as cancer.

Adult↗
PubMed2006

Medical applications of macrocyclic polyamines.

Macrocyclic polyamines comprise a special group of heterocycles that bind different guests. Over the past decade, medical interest has focused on macrocyclic polyamines owning to their chemical and biological properties. The discovery and development of the bicyclam AMD3100 highlighted the clinical potential of such compounds in AIDS, cancer and stem-cell mobilization. Many macrocyclic polyamines and their transition metal complexes had the cytotoxic activities to tumors through binding DNA, cleaving DNA, crosslinking DNA, or depleting the endogenous ATP levels of the tumor cells. Furthermore, macrocyclic polyamines also could be labeled with metal ionic radii and have applications in cancer radioimmunotherapy and in vivo magnetic resonance imaging (MRI). The current rational design, and medical applications of macrocyclic polyamines will be reviewed in this manuscript.

Animals↗
PubMed2001

c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny.

BACKGROUND: The epidermis is maintained throughout adult life by pluripotential stem cells that give rise, via daughter cells of restricted self-renewal capacity and high differentiation probability (transit-amplifying cells), to interfollicular epidermis, hair follicles, and sebaceous glands. In vivo, transit-amplifying cells are actively cycling, whereas stem cells divide infrequently. Experiments with cultured human keratinocytes suggest that c-Myc promotes epidermal-stem cell differentiation. However, Myc is a potent oncogene that suppresses differentiation and causes reversible neoplasia when expressed in the differentiating epidermal layers of transgenic mice. To investigate the effects of c-Myc on the stem cell compartment in vivo, we targetted c-MycER to the basal layer of transgenic mouse epidermis. RESULTS: The activation of c-Myc by the application of 4-hydroxy-tamoxifen caused progressive and irreversible changes in adult epidermis. Proliferation was stimulated, but interfollicular keratinocytes still underwent normal terminal differentiation. Hair follicles were abnormal, and sebaceous differentiation was stimulated at the expense of hair differentiation. The activation of c-Myc by a single application of 4-hydroxy-tamoxifen was as effective as continuous treatment in stimulating proliferation and sebocyte differentiation, and the c-Myc-induced phenotype continued to develop even after the grafting of treated skin to an untreated recipient. CONCLUSIONS: We propose that transient activation of c-Myc drives keratinocytes from the stem to the transit-amplifying compartment and thereby stimulates proliferation and differentiation along the epidermal and sebaceous lineages. The ability, demonstrated here for the first time, to manipulate exit from the stem cell compartment in vivo will facilitate further investigations of the relationship between stem cells and cancer.

Animals↗
PubMed2001

Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma.

Serial analysis of gene expression (SAGE) can be used to quantify gene expression in human tissues. Comparison of gene expression levels in neoplastic tissues with those seen in nonneoplastic tissues can, in turn, identify novel tumor markers. Such markers are urgently needed for highly lethal cancers like pancreatic adenocarcinoma, which typically presents at an incurable, advanced stage. The results of SAGE analyses of a large number of neoplastic and nonneoplastic tissues are now available online, facilitating the rapid identification of novel tumor markers. We searched an online SAGE database to identify genes preferentially expressed in pancreatic cancers as compared with normal tissues. SAGE libraries derived from pancreatic adenocarcinomas were compared with SAGE libraries derived from nonneoplastic tissues. Three promising tags were identified. Two of these tags corresponded to genes (lipocalin and trefoil factor 2) previously shown to be overexpressed in pancreatic carcinoma, whereas the third tag corresponded to prostate stem cell antigen (PSCA), a recently discovered gene thought to be largely restricted to prostatic basal cells and prostatic adenocarcinomas. PSCA was expressed in four of the six pancreatic cancer SAGE libraries, but not in the libraries derived from normal pancreatic ductal cells. We confirmed the overexpression of the PSCA mRNA transcript in 14 of 19 pancreatic cancer cell lines by reverse transcription-PCR, and using immunohistochemistry, we demonstrated PSCA protein overexpression in 36 of 60 (60%) primary pancreatic adenocarcinomas. In 59 of 60 cases, the adjacent nonneoplastic pancreas did not label for PSCA. PSCA is a novel tumor marker for pancreatic carcinoma that has potential diagnostic and therapeutic implications. These results establish the validity of analyses of SAGE databases to identify novel tumor markers.

Adenocarcinoma↗
PubMed1997

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer.

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.

Adult↗
PubMed2000

The addition of topotecan to carboplatin and paclitaxel as first-line therapy for advanced ovarian cancer; is it possible only with peripheral blood stem cell support?

A phase I study was performed in order to evaluate the tolerability of the combination of fixed doses of carboplatin and paclitaxel and escalated doses of topotecan as first line chemotherapy for advanced epithelial ovarian cancer. Three stage III and one stage IV patients entered the study. The dose limiting toxicity (neutropenia and thrombocytopenia) was reached at the first dose level: paclitaxel 175 mg/m2 on day 1, carboplatin AUC 5 on day I and topotecan 0.5 mg/m2 daily from day 1 to day 3. We conclude that it is not possible to add topotecan to standard regimens of carboplatin and paclitaxel without bone marrow support.

Adult↗
PubMed1996

Immunocytochemical detection of breast cancer cells in marrow and peripheral blood of patients undergoing high dose chemotherapy with autologous stem cell support.

Detection of small numbers of breast cancer cells is important in staging the disease and can be helpful in assessing the efficacy of purging regimens prior to autologous stem cell infusion. Immunohistochemical methods are potentially useful and broadly applicable for this purpose since they are simple to perform, sensitive, and may be quite specific. We have used a combination of four monoclonal antibodies [260F9, 520C9, 317G5 (Baxter Corp); BrE-3 (Dr. R. Ceriani)] against tumor cell surface glycoproteins in a sensitive immunocytochemical assay to identify breast tumor cells in bone marrow and peripheral blood. Immunostained cytospin preparations were fixed prior to staining to preserve cytological details of immunopositive cells. After immunostaining, slides were counterstained with hematoxylin to confirm the identify of labeled cells. In cytocentrifuge experiments in which small numbers of CAMA human breast tumor cells were added to bone marrow mononuclear cells, a linear relationship between the number of tumor cells added and the number of tumor cells detected was obtained over a broad range of tumor cell concentrations. The probability of detecting tumor cells was dependent on the number of cytocentrifuge slides examined. When ten slides (5 million cells) were examined, the probability of detecting tumor at a concentration of 4 tumor cells per million bone marrow mononuclear cells was 98%. In clinical specimens, tumor cells were detected in marrow aspirates from 73 of 240 (30%) patients undergoing autologous transplantation, including 70 (37%) of 190 patients with clinical stage IV disease, 0 of 7 patients with clinical stage III disease, and 3 of 43 (7%) patients with clinical stage II disease. Seventy-three of 657 peripheral blood specimens from 26 of 155 patients (17%) contained breast cancer cells with counts ranging from 1 to 97 tumor cells per million leukocytes. Tumor cells were most frequently found in the blood of patients with stage IV disease [21 of 107 (20%)] but were also found in a substantial number [5 of 44 (11%)] of patients with stage II disease. Positive selection of CD34-positive hematopoietic progenitor cells as well as negative purging methods such as incubation with 4-hydroxyperoxy-cyclophosphamide (4-HC) were evaluated with respect to tumor cell depletion. Selection of CD34-positive progenitor cells from bone marrow or peripheral blood resulted in log reduction of 1 to > 4 tumor cells reinfused at autologous transplantation. A lesser log reduction (up to 1) was demonstrated following 4-HC purging. We conclude that properly performed and controlled immunocytochemical staining of bone marrow and peripheral blood cytospins is a sensitive and simple way to detect and quantitate breast cancer cells in hematopoietic specimens harvested for autotransplantation and that CD34-positive progenitor cell selection results in significant reduction in the number of breast cancer cells reinfused with marrow or peripheral blood stem cells.

Antibodies, Monoclonal↗
PubMed2001

Measuring telomerase activity for the early detection of cancer.

Telomeres are the terminal portions of chromosomes and consist of the repeated nucleotide sequence TTAGGG. Chromosomes lose a small amount of telomeric deoxyribonucleic acid (DNA) after each cell replication. A hypothetical function of telomeric DNA is to allow for a finite number of cell divisions without loss of functional genes. A second proposed function of telomeric DNA is to prevent undesirable interactions between chromosomal ends and cellular repair enzymes. In cells that maintain a proliferative capacity, such as stem cells and cancer cells, telomere length is maintained by the reverse transcriptase, telomerase. Virtually every major human malignancy has been evaluated for telomerase activity and approximately 80% to 90% have demonstrated the presence of telomerase. In this article we review the current assays available for telomerase detection and discuss their relative strengths and limitations.

Enzyme-Linked Immunosorbent Assay↗
PubMed1999

[Combination of high-dose chemotherapy with autologous hematopoietic stem cell transplantation for recurrent and high-risk breast cancer: a pilot study].

OBJECTIVE: To evaluate the therapeutic effectiveness and safety of combined high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (AHSCT) for recurrent and high-risk breast cancer. METHODS: Thirteen patients with recurrent or high-risk breast cancer underwent HDC with AHSCT. Seven cases had relapsed metastasis who had failed in the previous chemotherapy. Two cases had stage IV disease who had received palliative excision. Four cases had stage II or III breast cancer with over 10 positive axillary lymph nodes who had received radical surgical resection. Four cases received autologous bone marrow transplantation, and six received autologous peripheral blood stem cell transplantation. The consolidation regimen was Thiotepa 500 (250-604) mg/m2, Cyclophosphamide 4.9 (3.3-6.0) g/m2. Eight cases were also given Carboplatin 800 (400-800) mg/m2, and two received Etoposide 830 (800-830) mg/m2 instead of Thiotepa in the consolidation regimen. Twelve cases underwent endocrinotherapy after HDC with AHSCT, six operated cases underwent radiotherapy in the area of chest wall and regional lymph nodes after HDC with AHSCT. RESULTS: After a median follow-up of 8(1-47) months, four cases achieved complete remission (CR) and 3 achieved partial remission (PR) in the 7 cases with relapsed metastasis after induction of chemotherapy, PR patients achieved CR after HDC with AHSCT. The disease free survival (DFS) was 1-31 months in these 7 cases. One of two stage IV cases achieved CR and the other had progressive disease (PD) after induction chemotherapy, but the PD patient achieved PR after HDC with AHSCT, they underwent local radiotherapy after HDC with AHSCT and DFS was 5 and 22 months, respectively. The DFS was from 1-47 months in 4 cases with stage II or III disease. CONCLUSION: HDC with AHSCT is a highly potential therapeutic means for recurrent and high-risk breast cancer paitents.

Adult↗
PubMed1994

High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow: a role for peripheral blood progenitor transplant.

This retrospective analysis was done to determine the response rate and survival of women with metastatic breast cancer with bone marrow involvement treated with high-dose cyclophosphamide and thiotepa and peripheral progenitor cell rescue. Eligibility criteria included histologically-documented metastatic breast cancer and either stable disease, a partial response or a complete response to conventional dose chemotherapy. Due to bone marrow involvement, all patients received peripheral progenitor cell reinfusion. Purging of the stem cell product was not performed. Cyclophosphamide (CY) 7.5 gm/m2 total dose and thiotepa 675 mg/m2 total dose was used as the intensification regimen. Of 27 treated patients, 4 (14%) died of treatment-related toxicity. Three patients were in complete remission after induction chemotherapy and remained so after high-dose chemotherapy. Three patients converted from a partial response after induction to a complete response after transplant. This yielded a complete remission rate of 21%. Five of these six patients continue in CR at 5, 6, 11, 14, and 26 months post-transplant. Eight patients (29%) are alive with stable disease post transplant. Ten patients developed disease progression. Six patients died shortly after disease progression; however, four patients are alive with disease at 18, 26, 33, and 53 months post-transplant. The median time to treatment failure is 12 months. In women with metastatic breast cancer with bone marrow involvement, durable responses after high-dose chemotherapy are possible utilizing peripheral blood progenitor support rather than marrow purging.

Adult↗