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PubMed1999

Acute quadriplegic myopathy following autologous peripheral blood stem cell transplantation for breast cancer.

Autologous peripheral blood stem cell transplantation (APSCT) is increasingly used in the treatment of breast cancer. We report a patient who experienced septic shock, and after treatment with antibiotics, high-dose corticosteroids and mechanical ventilation due to respiratory insufficiency, developed quadriplegia. Electroneurophysiological examination, as well as a muscle biopsy, showed a typical picture of acute quadriplegic myopathy with loss of thick filament proteins. This is, to the best of our knowledge, the first reported case of this complication following APSCT.

Acute Disease↗
PubMed2000

Epithelial stem cell repertoire in the gut: clues to the origin of cell lineages, proliferative units and cancer.

Gastrointestinal stem cells are shown to be pluripotential and to give rise to all cell lineages in the epithelium. After damage, gut stem cells produce reparative cell lineages that produce a wide range of peptides with important actions on cell proliferation and migration, and promote regeneration and healing. Increase in stem cell number is considered to induce crypt fission, and lead to increases in the number of crypts, even in the adult; it is also the mode of spread of mutated clones in the colorectal mucosa. Stem cell repertoire is defined by both intrinsic programming of the stem cell itself, but signalling from the mesenchyme is also vitally important for defining both stem cell progeny and proliferation. Carcinogenesis in the colon occurs through sequential mutations, possibly occurring in a single cell. A case is made for this being the stem cell, but recent studies indicate that several stem cells may need to be so involved, since early lesions appear to be polyclonal in derivation.

Animals↗
PubMed1998

Allogeneic cell-mediated immunotherapy for breast cancer after autologous stem cell transplantation: a clinical pilot study.

Allogeneic cell therapy (allo-CT) is emerging as an effective treatment for patients relapsing after allogeneic bone marrow transplantation (BMT), indicating that tumor cells resisting chemoradiotherapy may still respond to immunocompetent allogeneic lymphocytes. We investigated possible graft-versus-tumor (GVT) effects in six patients with metastatic breast cancer that would be comparable to the graft-versus-leukemia (GVL) phenomenon occurring after allogeneic BMT in hematologic malignancies. The patients were cytoreduced with high-dose chemotherapy and autologous stem cell transplantation (ASCT), and were treated ambulatory with allo-CT consisting of adoptive transfer of HLA-matched donor peripheral blood lymphocytes (PBL) activated in vivo with human recombinant interleukin-2 (rIL-2). If no graft-versus-host disease (GVHD) developed, allo-CT was augmented with infusion of donor PBL, preactivated in vitro with rIL-2. Treatment was well tolerated, with low therapy-related toxicity in all patients. Two patients developed signs and symptoms compatible with GVHD grade I-II, one of whom shows no evidence of disease at more than 34 months out. In the remaining patients, progression-free survival following allo-CT ranged between 7 and 13 months. Allogeneic cell-mediated, cytokine-activated immunotherapy might be utilized for induction of GVT in metastatic breast cancer. A search for techniques to boost chimerism without severe GVHD is indicated.

Adult↗
PubMed2000

Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer.

Prostate stem cell antigen (PSCA) is a recently defined homologue of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA mRNA is expressed in the basal cells of normal prostate and in more than 80% of prostate cancers. The purpose of the present study was to examine PSCA protein expression in clinical specimens of human prostate cancer. Five monoclonal antibodies were raised against a PSCA-GST fusion protein and screened for their ability to recognize PSCA on the cell surface of human prostate cancer cells. Immunohistochemical analysis of PSCA expression was performed on paraffin-embedded sections from 25 normal tissues, 112 primary prostate cancers and nine prostate cancers metastatic to bone. The level of PSCA expression in prostate tumors was quantified and compared with expression in adjacent normal glands. The antibodies detect PSCA expression on the cell surface of normal and malignant prostate cells and distinguish three extracellular epitopes on PSCA. Prostate and transitional epithelium reacted strongly with PSCA. PSCA staining was also seen in placental trophoblasts, renal collecting ducts and neuroendocrine cells in the stomach and colon. All other normal tissues tested were negative. PSCA protein expression was identified in 105/112 (94%) primary prostate tumors and 9/9 (100%) bone metastases. The level of PSCA expression increased with higher Gleason score (P=0.016), higher tumor stage (P=0.010) and progression to androgen-independence (P=0. 021). Intense, homogeneous staining was seen in all nine bone metastases. PSCA is a cell surface protein with limited expression in extraprostatic normal tissues. PSCA expression correlates with tumor stage, grade and androgen independence and may have prognostic utility. Because expression on the surface of prostate cancer cells increases with tumor progression, PSCA may be a useful molecular target in advanced prostate cancer.

Antibodies, Monoclonal↗
PubMed2001

Engraftment syndrome in breast cancer patients after stem cell transplantation is associated with poor long-term survival.

An autoaggression graft-versus-host (GVHD)-like syndrome or engraftment syndrome (ES) presenting with skin rash, fever, and other clinical findings can accompany the early phase of engraftment after autologous peripheral blood stem cell (PBSC)/bone marrow (BM) transplantation. Because ES was suggested to be analogous to GVHD, we have investigated whether ES was associated with any graft-versus-tumor effect that would affect disease progression and survival in breast cancer patients. Eighty-five consecutive patients who received BM/PBSC transplantation for breast cancer (stages II-IV) between July 1991 and July 1997 with minimum 2-year follow-up were studied. Median follow-up time was 892 days (range, 106-2913 days). Thirty-three patients (39%) developed ES. The incidence of relapse/progressive disease for the whole cohort was 61% and was similar in patients who developed ES compared with those who did not. However, there was an increased rate of mortality observed among the patients who had developed ES versus those who had not, although it was statistically not significant, (52% versus 31%, respectively; log rank, P = .08). Increased mortality rates due to disease progression were seen in all patients with ES regardless of their disease stage. In relapsed patients, median survival time after transplantation was 586 days for those with ES versus 847 days for those without ES, and the mortality rate was 85% (17/20) versus 51% (16/31) (P = .008) for those with or without ES, respectively. Visceral (lung, liver, brain, adrenal) or multiple-site relapses were observed in 85% of patients with ES versus 52% without ES (P = .01). In conclusion, whereas there was no effect of ES on relapse rate, a surprisingly significant increase in disease-related mortality rates among relapsed breast cancer patients with ES was found. Thus, patients with ES should be considered for close follow-up and further therapy posttransplantation.

Adult↗
PubMed2006

Is repetitive wounding and bone marrow-derived stem cell mediated-repair an etiology of lung cancer development and dissemination?

The prevailing view of lung cancer is multi-step progression of normal cells into cancer cells through gain of function oncogenes coupled with loss of tumor suppressor genes. This progression of genetic damage ultimately results in the hallmarks of cancer. This theory has strong support from studies finding genetic damage in early stage preneoplastic lesions in lung epithelial cells from current or former smokers. This paper discusses an alternate theory that lung cancer is a bone marrow stem cell derived disease. Chronic cigarette smoking results in lung inflammation and epithelial damage that activates a chronic wound repair program. Recent studies have demonstrated that ability of bone marrow derived stem cells to respond to epithelial wounding and contribute to epithelial repair. The identification of cancer stem cells that are distinct from the bulk tumor cells through their ability of self-renewal may suggest that such cells are important in the development of lung cancer. The evidence supporting the hypothesis along with its implications are discussed. Confirmation of the hypothesis would suggest that the transition time from a normal cell to overt cancer cell may be much shorter than that based on the multi-step cancer progression model. Additionally, if wounding in other organs is a beacon that attracts bone marrow derived tumor cells, efforts to ameliorate areas of epithelial injury and compensatory wounding may block bone marrow derived tumor cell homing, aberrant repair, and metastasis. Finally, a bone marrow derived lung cancer stem cell would require stem cell poisons for cure.

Bone Marrow Cells↗
PubMed1985

Inflammation initiates cancer by depleting stem cells.

According to the theory presented herewith, neoplasia results solely from stem cell depletion. Besides serving as tissue progenitors, stem cells are postulated to secrete a vital substance 'A' necessary for proper tissue function. Carcinogens interfere with 'A' production mainly by destroying stem cells and since the latter are not replenished, less 'A' is produced. In order to repair the deficiency, the organism grows a special organ, the neoplasm, dedicated to produce a substitute, denominated here as substance 'B'. Since carcinogens continue depleting stem cells, the neoplasm has to grow more and more in order to keep up with the demand, until reaching a stage of decompensation when the harm inflicted by it is greater than its benefit. Any stem cell depleting substance or process e.g. ablation, chemotherapy and inflammation, is regarded here as a carcinogen. Even animal tumor viruses are postulated here to exert their harm mainly by depleting stem cells. Protracted inflammation e.g. ulcerative colitis or cystic mastopathy, hits stem cells and is followed therefore by neoplasia. Age specific incidence rates of such pathologies resemble precursor-successor curves of tracer kinetics. The precursor inflammation hits young adults, while its successive neoplasia is more prevalent in older individuals. Although most age specific curves of adult cancers are unimodal, at least five are bimodal, resembling precursor-successor curves. These are: Hodgkin's disease, seminoma, nasopharyngeal and retroperitoneal tumors and cancer of bone and joints. It is suggested here that these age specific curves are mixtures of two pathologies, an inflammatory, which is prevalent in young persons, followed by neoplasia.

Adolescent↗
PubMed2002

Telomere dynamics, aneuploidy, stem cells, and cancer (review).

The real cause of genetic instability, which is the hall-mark of most cancers, is poorly understood. Specific gene mutations and acquired aneuploidy have been implicated as the root causes of genetic instability. Here we propose and cite evidence for the hypothesis that genetic instability of cancer cells is caused by telomere dynamics, erosion and/or amplification of the TTAGGG repeat sequences present at chromosomal termini. Since telomeres determine the domain of individual chromosomes within a nucleus and protect them from internal and external challenges, their erosion will destabilize the cell karyotype. Our hypothesis predicts that telomere dynamics provides the single unifying mechanism playing a major role in speciation, aging and cancer development. It was found that metastatic cancers of different histologic phenotypes, as well as mammalian taxa with active speciation and larger numbers of species exhibit amplification of their telomeric DNA as compared to non-metastatic counterpart cancers and taxa with only a limited number of species. The dynamic nature of this DNA can be found not only in the cancer cells but also in the peripheral lymphocytes of cancer patients. Human syndromes such as Down, Turner, Bloom, Werner, Fanconi, ataxia and many others, show aneuploidy and also are prone to develop various malignancies and premature aging. We have found that of all these syndromes have a reduced amount of telomeric DNA associated with specific mitotic catastrophes as compared to cells of age- and sex-matched normal individuals. From these and additional data generated by our group concerning speciation, aging and cancer karyotypes, we conclude that aneuploidy, which is responsible for birth defects, cancer initiation and is a major player in natural speciation, is a consequence of telomere dynamics. Because telomere reduction is linked to the aging process, which is a risk factor for cancer development in the human population, our hypothesis offers a unifying mechanism for the initiation of both hematologic and solid cancers, as well as for the origin of new species.

Aging↗
PubMed1996

Successful collection and transplantation of peripheral blood stem cells in cancer patients using large-volume leukaphereses.

It was the aim of our study to determine the collection efficiency and yield of CD34+ cells in 88 cancer patients (pts, 44 males/44 females) who underwent 154 large-volume leukaphereses (LV-LPs). The diagnoses were as follows: 18 patients had Non-Hodgkin's lymphoma, 9 Hodgkin's disease, 24 multiple myeloma, 6 acute leukemia, 27 breast cancer, and 4 patients had solid tumors of different types. During the course of LV-LPs, 20 liters (1) of blood were processed at a median flow-rate of 85 ml/min (CS 3000 Baxter) and 130 ml/min (COBE Spectra), respectively. Peripheral blood stem cells (PBSC) were collected following granulocyte colony-stimulating factor (G-CSF)-supported cytotoxic chemotherapy. A 31% and 21% mean decrease in the platelet and white blood count was noted at the end of the LV-LPs when compared with the pre-leukapheresis values. The aphereses were well tolerated without adverse effects. The level of circulating CD34+ cells was closely related to the number of CD34+ cells contained in the respective leukapheresis product (R = 0.89, P < 0.001). Compared with 270 patients who underwent 838 regular 10 1 LPs, the yield of CD34+ cells/kg was almost two-fold greater (4.84 +/- 0.63 x 10(6) [Mean +/- SEM] vs. 2.60 +/- 0.16 x 10(6), P < 0.001). The antigenic profile of CD34+ cells was assessed in 54 separate products collected on the occasion of 27 LV-LPs following the processing of 10 1 and 20 1, respectively. The intra-individual comparison included differentiation- as well as lineage-associated markers (CD38, Thy-1, c-kit, CD33, CD45RA). No difference in the subset composition was observed between the first and second product, arguing against a preferential release of particular CD34+ cell subsets during the procedure. As shown by molecular biological or immunocytochemical examination, the likelihood of harvesting malignant cells using large-volume aphereses was not increased in comparison with regular leukaphereses. Single harvests of > or = 2.5 x 10(6) CD34+ cells/kg could be obtained in 74% of the patients, compared with 52% in case of regular LPs. As the majority of patients were autografted with more than 2.5 x 10(6) CD34+ cells/kg following high-dose therapy, hematological recovery in general was rapid and not related to the type of apheresis product used. Considering patient comfort and savings in resource utilization, large-volume leukaphereses have become the standard procedure for PBSC collection in our center.

Adolescent↗
PubMed2001

Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus.

During the past several decades, there has been a steady increase in the frequency of opportunistic invasive fungal infections (IFIs) in immunocompromised patients. However, there is substantial controversy concerning optimal diagnostic criteria for these IFIs. Therefore, members of the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group formed a consensus committee to develop standard definitions for IFIs for clinical research. On the basis of a review of literature and an international consensus, a set of research-oriented definitions for the IFIs most often seen and studied in immunocompromised patients with cancer is proposed. Three levels of probability are proposed: "proven," "probable," and "possible." The definitions are intended for use in the context of clinical and/or epidemiological research, not for clinical decision making.

Aspergillosis↗
PubMed2001

Clinical impacts of tumor cell contamination of hematopoietic stem cell products in metastatic breast cancer patients undergoing autologous peripheral blood stem cell transplantation: multicenter trial.

To determine whether the tumor cell contamination of peripheral blood stem cells influences clinical impacts on high-dose chemotherapy in patients with metastatic breast cancer, we analyzed carcinoembryonic antigen (CEA) mRNA in the apheresis products by nested RT-PCR (reverse transcriptase-polymerase chain reaction). A total of 38 metastatic breast cancer patients and ten normal healthy subjects as a negative control were included. Twenty out of 38 (51.3%) apheresis products from patients with metastatic breast cancer were positive for CEA mRNA. CEA mRNA was noted in 54.8% (17/31) of patients mobilized with chemotherapy plus G-CSF and 42.8% (3/7) of patients with G-CSF alone. There was no significant difference in age, estrogen receptor, menopausal status, mobilization method, disease free interval, or number of metastasis sites (1 vs > or = 2) between positive and negative groups. The presence of CEA mRNA in apheresis products did not influence the time to progression and overall survival in both groups. However, both the univariate and the multivariate analysis disclosed that the number of metastasis was associated with survival significantly. We suggest that the tumor cell contamination does not predict poor treatment outcome in patients with metastatic breast cancer.

Adult↗
PubMed1985

Mullerian inhibiting substance reduction of colony growth of human gynecologic cancers in a stem cell assay.

Mullerian Inhibiting Substance (MIS), a fetal testicular product that causes regression of the Mullerian duct in the male mammalian embryo, was evaluated for its antitumor effect on the premise that a substance active against this genital precursor in the fetus might also be active against tumors derived from these tissues. Increasingly pure fractions of biologically active MIS, prepared from newborn calf testes, were tested in the soft agar colony inhibition assay against single cell suspensions of fresh tumors derived in ascitic or solid form from patients with gynecologic malignancies. Twenty-eight tumor specimens placed in soft agar culture have provided sufficient growth to assess an MIS effect. Twenty-five of these 28 tumors showed significant colony inhibition after incubation with MIS. Increased antitumor response correlated with increased purification of MIS when the same tumor was treated with preparations of different purity. Samples obtained from the same patient at different times, from both ascites and solid tumor sources, produced nearly identical responses to MIS. MIS preparations, previously shown to be active in microcytotoxicity and colony inhibition assays against established human ovarian and endometrial carcinoma lines demonstrate consistent antitumor activity against fresh human gynecologic cancers removed at surgery.

Adenocarcinoma↗
PubMed2006

Mechanisms of disease: from stem cells to colorectal cancer.

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass beta-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.

Adenoma↗
PubMed2001

Bispecific single-chain antibodies as effective tools for eliminating epithelial cancer cells from human stem cell preparations by redirected cell cytotoxicity.

High-dose chemotherapy (HDC) with autologous bone marrow or peripheral stem cell transplantation is discussed as one option to treat the extensive stage of a variety of tumors. Effective methods to eliminate contaminating tumor cells from human bone marrow or stem cell grafts may improve the outcome of the patients. We investigated 3 recombinant bispecific single-chain antibodies (bscAbs) directed against 17-1A (EpCAM), c-erbB-2 (HER-2/neu) and LeY on the one and CD3 on the other binding site for their ability to induce lysis of epithelial tumor cells by retargeting autochthonous T lymphocytes present in bone marrow mononuclear cells (BMMC) and in peripheral stem cell mononuclear cells (PSMC). The bscAbs showed remarkable specific lysis of different epithelial tumor cell lines with BMMCs as well as with PSMCs as effector cells. Investigation of the alpha 17-1A-alpha CD3 bscAb revealed a significant correlation between the percentage of CD3(+) cells present in the BMMCs and the rate of lysis as well as the absence of detrimental effects on the viability of hematopoietic progenitor cells as determined by colony-forming unit assays (CFUs). Our results indicate that recombinant bispecific single-chain antibodies could be new tools for purging of human bone marrow and peripheral stem cell grafts from contaminating epithelial cancer cells for patients receiving autologous stem cell transplantation after HDC.

Antibodies, Bispecific↗
PubMed2002

Mammary cancer and epithelial stem cells: a problem or a solution?

The existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy?

Animals↗