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PubMed1999

The removal of human breast cancer cells from hematopoietic CD34+ stem cells by dielectrophoretic field-flow-fractionation.

Dielectrophoretic field-flow-fractionation (DEP-FFF) was used to purge human breast cancer MDA-435 cells from hematopoietic CD34+ stem cells. An array of interdigitated microelectrodes lining the bottom surface of a thin chamber was used to generate dielectrophoretic forces that levitated the cell mixture in a fluid flow profile. CD34+ stem cells were levitated higher, were carried faster by the fluid flow, and exited the separation chamber earlier than the cancer cells. Using on-line flow cytometry, efficient separation of the cell mixture was observed in less than 12 min, and CD34+ stem cell fractions with a purity >99.2% were obtained. The method of DEP-FFF is potentially applicable to many biomedical cell separation problems, including microfluidic-scale diagnosis and preparative-scale purification of cell subpopulations.

Bone Marrow Purging↗

PubMedDate not supplied

Stem cell biology and the cellular pathways of carcinogenesis.

Tissues in the body are maintained by somatic stem cells. This has been demonstrated both in organs with high cell turnover rate, such as the bone marrow, colon and skin, and in organs with low cell turnover rate, such as the brain. To maintain homeostasis in the body it is important to keep tight control over stem cell fate. Stem cells are under strict control from both intrinsic and extrinsic factors and loss of this control has been postulated to be a key step in the carcinogenic process. There is increasing evidence that cancer initiation results from accumulative oncogenic mutations (intrinsic loss of control) in long-lived stem cells or their immediate progenitor, followed by modification of the surrounding microenvironment (loss of extrinsic control). Decades ago, studies on teratocarcinoma led to the hypothesis that a small subset of self-renewing cancer stem cells with differentiation potential exists within tumors. These studies showed that teratocarcinomas contain undifferentiated embryonic carcinoma cells that are able to give rise to differentiated cells which belong to all three germ layers. More recent studies have confirmed cancer stem cells in such diverse cancers as leukemia, brain and breast cancer. It is, however, unclear whether cancer stem cells originate from resident stem cells or whether they arise as a result of an acquired gain of self-renewal capacity in tissue progenitor cells or even more differentiated cells. The characterization of a cancer stem cell profile within diverse cancer types may open up new avenues for cancer treatment. In this review we discuss the concept of cancer stem cells and focus on examples where these cells have been identified.

Animals↗

PubMed1998

The Rationale for Performing Autologous Peripheral Blood Stem Cell Transplants in Community Cancer Centers.

There is debate over whether or not the technology of peripheral blood stem cell (PBSC) support of high-dose chemotherapy (HDC) should be disseminated to practicing oncologists or continue to be administered only in academic referral centers. High-dose therapy with stem cell support is now the standard of care for selected patients with lymphoma, multiple myeloma and possibly breast cancer. Such therapies, delivered in a clinical trials setting, need to be more widely available to eligible patients. This manuscript presents the rationale for performing HDC with PBSC support in community cancer centers. The availability of PBSC has made the delivery of well-established HDC regimens safe and effective in an outpatient setting. Delivery of such therapy where the patient lives has many economic and social advantages to the patient compared to referral to a transplant center. In addition, more patients can be treated more cost effectively if such therapy is administered locally where the patient lives. From the scientific point of view, improved access to HDC in the community should increase accrual to clinical trials, allowing the generation of outcome data more rapidly.

Journal Article↗

PubMed1997

Restoration of T and NK cell function in GM-CSF mobilized stem cell products from breast cancer patients by monocyte depletion.

Rapid immune reconstitution is observed following autologous peripheral blood stem cell transplantation (PSCT) as compared to autologous bone marrow transplantation (ABMT), although it is depressed compared to that observed in normal individuals. The immune dysfunction occurs despite the restoration of normal lymphoid cell numbers and may be associated with the immunologic characteristics of the infused peripheral blood stem cell (PSC) product. We report herein that the in vitro T cell proliferation and NK activity in PSC products of breast cancer patients are significantly increased following the removal of CD14+ monocytes (33 +/- 2% of the PSC product) by carbonyl iron magnetic cell isolation (CI). In vitro expansion of PSC cells cultured for 7-21 days in the presence of interleukin-2 (IL-2) is also significantly increased by depletion of the phagocytic cells. The PHA and IL-2 mitogenic responses, as well as NK activity of the expanded cells, was also significantly increased by the depletion of the phagocytes. In summary, the depletion of phagocytic monocytes from PSC products restores the proliferative and functional properties of T and NK lymphocytes and may facilitate adoptive cellular therapy, as well as rapid immunologic reconstitution post-PSCT.

Breast Neoplasms↗

PubMed2002

High-dose chemotherapy and stem cell support for breast cancer: where are we now?

To date, there is no definitive evidence that high-dose chemotherapy and haematopoietic stem cell support offers a survival advantage over conventional-dose chemotherapy for metastatic or high-risk primary breast cancer. Studies of metastatic disease discussed in this review have an adequate duration of follow-up given the short natural history of metastatic breast cancer. Thus, the results of these studies are unlikely to change with a longer observation period. On the other hand, studies of high-dose chemotherapy in the treatment of high-risk primary breast cancer need longer follow-up in light of the longer natural history of this type of disease. Results of unpublished studies and longer follow-up of available studies may still demonstrate a survival advantage for high-dose chemotherapy in patients with metastatic or high-risk primary breast cancer. We continue to encourage participation in innovative clinical studies.

Breast Neoplasms↗

PubMed1993

DNA stem line heterogeneity in esophageal cancer accurately identified by flow cytometric analysis.

BACKGROUND: This study was designed to evaluate the importance of DNA stem line heterogeneity in determining the malignant potential of esophageal cancer. METHODS: Flow cytometric analysis of intratumor heterogeneity of DNA contents was performed on step-sectioned slices of 57 resected esophageal carcinomas. RESULTS: DNA stem line heterogeneity, as assessed by DNA content measurements, was present in 25 (44%) tumors; 6 (11%) were a combination of diploid and aneuploid DNA pattern, and 19 (33%) had two or more aneuploid peaks with different DNA contents (multiploid). Of the remaining 32 homogeneous tumors, 4 showed only a diploid DNA pattern in all samples examined, whereas 28 tumors had only the aneuploid pattern. Tumors with the heterogeneous DNA pattern had a significantly higher frequency of lymph node metastasis than did those with the homogeneous DNA pattern (P < 0.05). CONCLUSIONS: For evaluation of the highly malignant potential of esophageal carcinoma by nuclear DNA contents, it is important to identify accurately intratumoral heterogeneity. Because different DNA stem lines were evident in different areas of the lesion, evaluation of multiple specimens from a wide area of each lesion is needed to determine with accuracy the degree of intratumor DNA stem line heterogeneity.

Adult↗

PubMed2005

Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation.

BACKGROUND: The prognosis of advanced pancreatic cancer is extremely poor and therefore a novel treatment strategy is desired. The authors thus started a prospective study of allogeneic reduced-intensity hematopoietic stem cell transplantation (RIST) for patients with advanced pancreatic cancer to evaluate the feasibility and efficacy of this approach for such patients. METHODS: Only patients with pathologically proven pancreatic cancer that was locally advanced or metastatic and not amenable to curative resection were included. The conditioning regimen consisted of gemcitabine, fludarabine, and busulfan. RESULTS: In the first stage of this study, the authors treated seven patients. Treatment-related mortality before day 100 was observed in one patient. The median survival after RIST was 229 days. An objective response on computed tomographic scan was observed in two patients and another had a tumor marker response. Marked tumor shrinkage was observed in one of the remaining patients after donor lymphocyte infusion. These antitumor effects appeared after the effect of the conditioning regimen had disappeared. In addition, some of these responses were associated with an increase in the serum anticarcinoembryonic antigen antibody level. CONCLUSIONS: Pancreatic cancer appeared to be sensitive to a graft-versus-tumor effect; therefore, a larger clinical study with a refined strategy is warranted.

Adult↗

PubMed1995

[High-dose chemotherapy in breast cancer. Promising results in combination with stem cell support].

Thirty-three women with breast cancer have undergone high dose chemotherapy with autologous stem cell support at Huddinge Hospital. Twenty-eight patients had stage IV disease while five patients had disease stage II or III with involvement of > 10 axillary lymph nodes. Patients who received peripheral stem cells had a shorter duration of neutropenia than patients who received autologous bone marrow (p < 0.001). The transplant related mortality was 3 per cent. The calculated progression free survival was 39 per cent at 24 months after high dose therapy in women with stage IV chemosensitive breast cancer. Patients who got a complete remission after standard dose chemotherapy had a better survival rate than patients who got a partial remission. All women with refractory disease progressed within five months from therapy. Four out of five patients with disease stage II or III are progression free with the longest follow-up time of 46 months. High dose chemotherapy with stem cell support can be given with acceptable toxicity. The follow-up time is short but the results are promising, in particular for women who obtain a complete remission before the high dose therapy starts.

Adult↗

PubMed2005

Pilot study of a home-based aerobic exercise program for sedentary cancer survivors treated with hematopoietic stem cell transplantation.

We report a pilot study of a home-based aerobic exercise program in a group of 17 adult hematopoietic stem cell transplant (HSCT) recipients. Participants had received no cancer treatment for at least 6 months and reported leisure time physical activity less than 20 min per day and fewer than three times a week during the previous month. Following baseline assessments of aerobic fitness, fatigue symptoms, and quality of life, participants were placed on home-based aerobic exercise programs consisting of 20-40 min of activity in the target heart rate zone (40-60% predicted heart rate reserve) delivered in three to five sessions per week for 12 weeks. Subjects were supplied with electronic heart rate monitors and we encouraged program adherence using weekly telephone contacts and exercise diaries. In all, 32 of the 42 qualified candidates consented (acceptance=76%). Of these, 17 kept appointments for baseline assessments, four did not complete the study (attrition=46%), and no exercise-related adverse events were reported. Scores on measures of aerobic fitness, fatigue severity, and physical well-being improved (signed ranks test; P<0.05) during program participation. Our findings suggest that individually prescribed, home-based aerobic exercise is an acceptable, safe, and potentially effective intervention for improving physical functioning and fatigue in sedentary HSCT recipients.

Adult↗

PubMed2004

Enhanced stem cell survival in familial adenomatous polyposis.

Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.

Adenomatous Polyposis Coli↗

PubMed1983

Tumor stem cell assay for detecting metastases of human lung cancer.

We applied a tumor stem cell assay using an enriched double-layered soft agar system for the detection of metastatic sites of lung cancer. Lung cancer colonies grew from 7 of 10 effusions cytologically positive for tumor cells and 7 of 10 bone marrow aspirates cytologically and histologically positive for tumor cells. Twenty-six of 29 bone marrow aspirates cytologically and histologically negative for tumor cells showed no colony growth. However, the remaining three bone marrow aspirates, which were obtained from patients with small cell lung cancer, formed colonies in soft agar. These results indicate that the tumor stem cell assay is useful for detecting metastatic sites of lung cancer.

Bone Marrow↗

PubMed1997

Recovery of leukocyte function after super-high-dose chemotherapy with peripheral blood stem cell transplantation in testicular cancer patients.

Leukocyte functions (superoxide production and phagocytosis) were evaluated in patients with testicular cancer who had undergone super-high-dose chemotherapy (SHDT) with peripheral blood stem cell transplantation (PBSCT). In 5 patients with advanced or relapsed testicular cancer who received 8 cycles of SHDT with PBSCT, we measured superoxide production activity by phorbol myristate acetate (PMA) stimulation, as well as phagocytic activity using latex particles before and after PBSCT. The median time to reach a leukocyte count of > or = 1,000/microl was 9 days after PBSCT. Superoxide production activity was significantly decreased on day 7 compared with the pre-chemotherapy level. However, it recovered by day 12 and sustained such a level thereafter. Phagocytic activity was within the normal range on day 7 but declined slightly on days 12 and 21 compared with the pre-chemotherapy level. Our results indicate that leukocyte function and leukocyte count recover promptly following PBSCT and that PBSCT is a safe and convenient adjunctive therapy after SHDT for patients with advanced testicular cancer.

Adult↗

PubMed2007

The decatenation checkpoint.

The decatenation checkpoint delays entry into mitosis until the chromosomes have been disentangled. Deficiency in or bypass of the decatenation checkpoint can cause chromosome breakage and nondisjunction during mitosis, which results in aneuploidy and chromosome rearrangements in the daughter cells. A deficiency in the decatenation checkpoint has been reported in lung and bladder cancer cell lines and may contribute to the accumulation of chromosome aberrations that commonly occur during tumour progression. A checkpoint deficiency has also been documented in cultured stem and progenitor cells, and cancer stem cells are likely to be derived from stem and progenitor cells that lack an effective decatenation checkpoint. An inefficient decatenation checkpoint is likely to be a source of the chromosome aberrations that are common features of most tumours, but an inefficient decatenation checkpoint in cancer stem cells could also provide a potential target for chemotherapy.

Cell Line, Tumor↗

PubMed2000

Elevation of plasma prolactin in patients undergoing autologous blood stem-cell transplantation for breast cancer: is its modulation a step toward posttransplant immunotherapy?

Prolactin is a suspected promotor of breast cancer cell growth, and it shares pleiotropic immunoregulatory properties. We studied plasma prolactin and its drug-induced modulation in 20 women with breast cancer undergoing high-dose chemotherapy and autologous blood stem-cell transplantation. Plasma prolactin levels were serially assayed before and during conditioning and within and beyond 30 days after transplant. Before transplant, prolactin plasma levels were in the age-adjusted range of normal women. During conditioning and within 30 days after transplant, prolactin levels increased in all patients (p < 0.0001), but remained in the normal range. Antiemetic drugs such as metoclopramide and phenothiazines, known to enhance pituitary prolactin secretion, further elevated prolactin plasma levels (p < 0.00001). Patients remaining in continuous complete remission after transplant (median follow-up, 3 years) disclosed higher prolactin levels compared with those obtaining only partial remission or ensuing early relapse. Prolactin levels are regularly elevated during conditioning and within 30 days after autologous transplantation for breast cancer. Further elevations of prolactin plasma levels are induced by metoclopramide and other antiemetic drugs. Elevated plasma prolactin had no adverse effect on disease-free survival after transplant. We propose to investigate further the upregulation of prolactin after transplant aiming to induce a posttransplant consolidative immune reaction.

Adult↗

PubMed2003

Development of reduced-intensity hematopoietic stem cell transplantation in the National Cancer Center Hospital, Japan.

Reduced-intensity hematopoietic stem cell transplantation (RIST) is a new approach of stem cell transplantation, which has shown promising features as reported in multiple phase I and II studies. Elderly patients, who are not eligible for conventional myeloablative hematopoietic stem cell transplantation (HSCT), are now treatable with RIST. It has also reduced regimen-related toxicity and provided better prognosis in short-term follow-up than that of conventional HSCT. Favorable results have been reported particularly in hematological malignancies, such as chronic myelocytic leukemia and malignant lymphoma. Among solid tumors, metastatic renal cell carcinoma was found to respond well to RIST. Clinical studies are currently being conducted to evaluate the efficacy of RIST in other types of solid tumors. However, the mechanism of graft-versus-host disease and graft-versus-tumor remains unclear. More knowledge on the mechanism is crucial to enhance antitumor effect and to further improve the prognosis.

Adult↗

PubMed2005

Tumour stem cells and drug resistance.

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

ATP-Binding Cassette Transporters↗

PubMed2002

[Preoperative high-dose chemotherapy with peripheral blood stem cell support in breast cancer: report of 3 cases].

OBJECTIVE: To investigate the possibility and short-term effect of high dose chemotherapy with peripheral blood stem cell support in the preoperative therapy of breast cancer, and-its influence on the following operation and would healing. METHODS: Three patients with T(3)N(1)M(0) (III(a)), T(4)N(1)M(0) (III(b)), T(4)N(1)M(1) (IV) of breast cancer were diagnosed histopathologically. After receiving HDC/APBSCT, the 3 patients were operated on. HDC/APBSCT process included 2 cycles of FEC induction chemotherapy; PBSC mobilization, APBSC collection and cryopreservation and PBSC infusion; and high-dose chemotherapy, APBSC infusion and supportive therapy. The therapy consisted of CTX2.5 g/m(2), VP-16 600 mg/m(2), and cerboplatin 600 mg/m(2) delivered on day 1, APBSC infusion 48 h later, rhG-CSF (150 microg, BID) was administered 4 h after infusion of APBSC until WBC was higher than 10 x 10(9)/L. During HDC/APBSCT, the patients were protected in the air laminar flow room with supportive therapy of antibiotics, anti-virus and anti-fungus drugs. They left the air laminar flow room after their WBC was greater than 2 x 10(9)/L. Case 1 was treated by radical mastectomy, Case 2 by improved radical mastectomy, Case 3 by improved radical mastectomy and transplantation of skin for the large area. RESULTS: Rapid recovery of bone marrow function was observed in all 3 patients. Operation was performed 4 weeks after HDC/PBSCT in Cases 1, 2 and 33 days in Case 3. No influence was seen on operative procedure and would healing, especially in Case 3 with a large area of skin transplantation. Two patients with stage III(a) and III(b) have been alive since the treatment for 30 months and the other with stage IV died of brain metastasis 16 months later. CONCLUSIONS: HDC/APBSCT as a preoperative therapy for breast cancer has no influence on the coming surgery and would healing, even on skin transplantation for a large area. It has a practical response in stage III(a) and III(b), but it is still controversial in stage IV. This method as a salvage therapy for patients with breast cancer of intemuediate or stage.

Adult↗

PubMed2007

Neuropsychological and psychiatric functioning pre- and posthematopoietic stem cell transplantation in adult cancer patients: a preliminary study.

The current study characterizes cognitive and psychiatric status in hematopoietic stem cell transplantation (HSCT) patients shortly before and after transplant. Thirty adult patients were assessed prospectively 1-2 weeks before transplantation and 100 days posttransplantation on neuropsychological and psychiatric measures. Before transplant, participants showed mild impairments on several neuropsychological measures, with the poorest performances occurring on learning and attention. Psychiatric functioning was significantly elevated compared with normative data. Significant improvements, however, were observed on neuropsychological measures by 100 days after transplant. Depression and anxiety scores also improved. Candidates for HSCT experienced mild diffuse cognitive dysfunction and psychiatric morbidity before the procedure, but these symptoms significantly improved by 3 months following their transplant in this small sample. Education about these possible pretransplant sequelae and the potential for rebound may be helpful to patients and families as they prepare for this treatment and the recovery period.

Adult↗