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PubMed2005

High-dose etoposide, thiotepa, and dose-adjusted carboplatin (TVCa) with autologous hematopoietic stem cell rescue as treatment of relapsed or refractory germ cell cancer.

A phase I/II trial with high-dose etoposide, thiotepa, and dose-adjusted carboplatin (TVCa) with autologous hematopoietic stem cell rescue (AHSCT) as treatment for patients with relapsed or refractory germ cell cancer was investigated. The phase I portion involved a dose escalation schema for carboplatin and thiotepa while keeping the dose of etoposide constant. The intended carboplatin dose was adjusted for renal function based on the glomerular filtration rate. The phase II portion of the trial evaluated the efficacy, feasibility, and safety of tandem TVCa with AHSCT. Twenty-four patients with relapsed or refractory germ cell cancer were treated in this phase I/II trial. Nine of 24 (38%) achieved a complete response. With a median follow up of 71 months (range,1-108 months), all 9 of 24 (38%) are alive and continuously disease-free. There were 2 (7%) treatment-related deaths. The median time to an absolute granulocyte count greater than 0.5 x 10/L was 11 days (range, 9-20 days) on phase I and 10 days (range, 9-13 days) on phase II therapy. The median time to a platelet count greater than 20 x 10/L was 15 days (range, 12-40 days) on phase I and 14 days (range, 13-27 days) on phase II therapy. Nonhematologic toxicity was mild to moderate. A significant correlation was seen between intended carboplatin dose and actual AUC. TVCa high-dose chemotherapy is active and well tolerated in patients with relapsed or refractory germ cell cancer.

Adult↗

PubMed1984

Variations in committed stem cells (CFU-GM and CFU-TL) in the peripheral blood of cancer patients treated by sequential combination chemotherapy for breast cancer.

The present work compared the blood variations in some committed stem cells (CSC), and corresponding differentiated WBC during the first three courses of a 6-day sequential chemotherapy given to 16 breast cancer patients for 28 days each. The granulomonocytic and lymphocytic colony-forming unit levels in blood were significantly lowered in cancer patients before treatment. These CSC appeared to have cyclic variations following each course of chemotherapy. In granulomonocytic colony-forming units, a nadir was observed by Day 15, followed by a sharp rebound above the initial values by Days 22 to 24, which was not affected in magnitude by the continuation of treatment. In lymphocytic colony-forming units, the Day 1 level increased with the continuation of chemotherapy. The initial decrease was less marked, but by Day 15 a minimal level was also observed, followed by a progressive increase to reach a maximum by Day 28. Leukocytes and granulocytes reached a nadir by Days 16 to 17 and recovered by Day 25. The cyclic evolution of monocytes was less apparent as was that of lymphocytes; however, there was less restoration of monocytes and lymphocytes than of granulocytes at the end of the resting period. This study showed: (a) an apparent relationship between the level of CSC in blood, and subsequent variations in the corresponding mature cells of the same lineage; and (b) a weak interval of time between the nadir and peaks of CSC and the corresponding mature cells, which was more evident in the granulocytic lineage. These observations seemed to be of physiological importance, but the possible prediction value of peripheral granulomonocytic colony-forming unit peak magnitude following treatment remains to be established.

Adult↗

PubMed2003

High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer.

BACKGROUND: The use of high-dose adjuvant chemotherapy for high-risk primary breast cancer is controversial. We studied its efficacy in patients with 4 to 9 or 10 or more tumor-positive axillary lymph nodes. METHODS: Patients younger than 56 years of age who had undergone surgery for breast cancer and who had no distant metastases were eligible if they had at least four tumor-positive axillary lymph nodes. Patients in the conventional-dose group received fluorouracil, epirubicin, and cyclophosphamide (FEC) every three weeks for five courses, followed by radiotherapy and tamoxifen. The high-dose treatment was identical, except that high-dose chemotherapy (6 g of cyclophosphamide per square meter of body-surface area, 480 mg of thiotepa per square meter, and 1600 mg of carboplatin per square meter) with autologous peripheral-blood hematopoietic progenitor-cell transplantation replaced the fifth course of FEC. RESULTS: Of the 885 patients, 442 were assigned to the high-dose group and 443 to the conventional-dose group. After a median follow-up of 57 months, the actuarial 5-year relapse-free survival rates were 59 percent in the conventional-dose group and 65 percent in the high-dose group (hazard ratio for relapse in the high-dose group, 0.83; 95 percent confidence interval, 0.66 to 1.03; P=0.09). In the group with 10 or more positive nodes, the relapse-free survival rates were 51 percent in the conventional-dose group and 61 percent in the high-dose group (P=0.05 by the log-rank test; hazard ratio for relapse, 0.71; 95 percent confidence interval, 0.50 to 1.00). CONCLUSIONS: High-dose alkylating therapy improves relapse-free survival among patients with stage II or III breast cancer and 10 or more positive axillary lymph nodes. This benefit may be confined to patients with HER-2/neu-negative tumors.

Adult↗

PubMed2002

Patents and innovation in cancer therapeutics: lessons from CellPro.

This article discusses the interaction between intellectual property and cancer treatment. CellPro developed a stem cell separation technology based on research at the Fred Hutchinson Cancer Center. A patent with broad claims to bone marrow stem cell antibodies had been awarded to Johns Hopkins University and licensed to Baxter Healthcare under the 1980 Bayh-Dole Act to promote commercial use of inventions from federally funded research. CellPro got FDA approval more than two years before Baxter but lost patent infringement litigation. NIH elected not to compel Hopkins to license its patents to CellPro. CellPro went out of business, selling its technology to its competitor. Decisions at both firms and university licensing offices, and policies at the Patent and Trademark Office, NIH, and the courts influenced the outcome.

Biomedical Research↗

PubMed2001

Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review.

Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Disease status (no. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Fifteen (52%) received both transplants. Treatment-related mortality was 10%. Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Three seminoma patients remain progression-free. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). The median PFS and OS for the whole group are 4 and 14 months, respectively. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. New treatment modalities are needed for the latter group.

Adolescent↗

PubMed1998

A randomized trial of two doses of cyclophosphamide with etoposide and G-CSF for mobilization of peripheral blood stem cells in 318 patients with stage II-III breast cancer.

The purpose of this study was to develop a less toxic outpatient chemotherapy regimen for mobilizing peripheral blood stem cells (PBSC). Three hundred eighteen patients with newly diagnosed stage II-III breast cancer who had received conventional dose adjuvant chemotherapy were randomized to receive intermediate-dose cyclophosphamide (2 g/m2), etoposide (600 mg/m2), and granulocyte colony-stimulating factor (G-CSF) 6 micrograms/kg/day (ID-Cy, n = 162) or high-dose cyclophosphamide (4 g/m2) and the same doses of etoposide and G-CSF (HD-Cy, n = 156) followed by collection of PBSC. Three hundred seventeen of 318 patients had apheresis performed, and 315 received high-dose chemotherapy (HDC) followed by PBSC support. The median numbers of CD34+ cells collected in a median of two apheresis following ID-Cy and HD-Cy were 19.9 and 22.2 x 10(6)/kg, respectively (p = 0.04). The fractions of patients achieving CD34+ cell doses > or = 2.5 or > or = 5.0 x 10(6)/kg were not different between the two regimens. More patients receiving HD-Cy had grade 3-4 nausea (p = 0.001), vomiting (p = 0.03), and mucositis (p = 0.04). The fractions of patients having a neutrophil nadir < 0.5 x 10(9)/L following ID-Cy and HD-Cy were 0.83 and 0.95, respectively (p = < 0.001). The fractions of patients having a platelet nadir < 25 x 10(9)/L following ID-Cy and HD-Cy were 0.13 and 0.51, respectively (p = < 0.001). More patients in the HD-Cy group received platelet (p < 0.001) and red blood cell (p < 0.001) transfusions and were admitted to the hospital more frequently (p = 0.03) than patients receiving ID-Cy. Three hundred fifteen patients received HDC followed by infusion of PBSC. There were no significant differences in the incidence of transplant-related death or early survival between patients receiving ID-Cy or HD-Cy followed by HDC. It was concluded that a regimen of Cy 2 g/m2 with etoposide and G-CSF was effective for mobilization of PBSC with low morbidity and resource utilization in patients with limited prior chemotherapy exposure.

Adult↗

PubMed1998

Tales from the human crypt--intestinal stem cell repertoire and the origins of human cancer.

A generally accepted model for the origin of human cancer is that tumours arising from the gut-lining epithelium--the adenomas and carcinomas--are of clonal origin, i.e., they are derived from a single 'abnormal' cell. Recent work has shed considerable light on these matters and suggests that this model may be erroneous and that at least some adenomas are of multiclonal origin. These findings have basic implications for more generalized models of tumourigenesis and for researchers examining the potential clinical value of gene therapy.

Adenoma↗

PubMed1998

Efficacy and toxicity of sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer.

Patients with high-risk breast cancer may benefit from dose-escalated chemotherapy. We studied toxicity and therapeutic efficacy of sequential high-dose therapy consisting of two cycles of ifosfamide 12,000 mg/m2, carboplatin 900 mg/m2, and epirubicin 180 mg/m2 (ICE) with peripheral blood stem cell support. Ninety-one patients with advanced breast cancer were included. Fifty-one patients with stage II/III disease and 10 or more tumor-positive axillary lymph nodes received high-dose therapy as adjuvant treatment; the remaining 40 patients were treated for metastatic disease. Peripheral blood stem cells were collected following granulocyte colony-stimulating factor-supported induction chemotherapy. In 68 patients, induction chemotherapy included two cycles of ifosfamide 7,500 mg/m2 and epirubicin 120 mg/m2, while 23 patients received one cycle of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 135 mg/m2, ifosfamide 6,000 mg/m2, and epirubicin 90 mg/m2. One hundred ninety-two cycles of ICE were supported with a median of 3.5 x 10(6) CD34+ cells/kg body weight (range, 1.7 to 38 x 10(6) CD34+ cells/kg body weight), which resulted in rapid hematologic reconstitution with recovery times, for a median neutrophil count of 0.5 x 10(9)/L of 13 days (range, 6 to 20 days) and for a median platelet count greater than 20 x 10(9)L of 9 days (range, 5 to 24 days). Seven patients received only one cycle of ICE because of progressive disease (in two patients with metastatic disease), central nervous system toxicity (one patient), cardiac toxicity (one patient), severe enterocolitis (one patient), development of human leukocyte antigen antibodies (one patient), and wish to withdraw from the study (one patient). Seventeen patients with metastatic disease received an additional high-dose cycle consisting of the non-cross-resistant agents thiotepa 600 mg/m2, etoposide 1,500 mg/m2, and paclitaxel 165 mg/m2. In patients treated adjuvantly, the probability of disease-free survival was 64% at 47 months, which compares favorably with results of conventional treatment protocols, with a 47% event-free probability at the same time period. The probability of progression-free survival in patients with metastatic disease was 18% at 44 months. In conclusion, sequential high-dose therapy with peripheral blood stem cell support in patients with high-risk breast cancer can be administered safely and offers a potential benefit in the adjuvant setting.

Adult↗

PubMed1997

High-dose chemotherapy and stem-cell rescue in the treatment of high-risk breast cancer: prognostic indicators of progression-free and overall survival.

PURPOSE: To examine the predictive value of tumor- and treatment-specific prognostic indicators of relapse-free survival (RFS) and overall survival (OS) in patients with high-risk breast cancer (HRBC) treated with high-dose chemotherapy (HDCT) and stem-cell rescue. PATIENTS AND METHODS: Between June 1989 and September 1994, 114 patients with HRBC (stage II with > or = 10 axillary lymph nodes involved, stage IIIA, and stage IIIB inflammatory carcinoma) received adjuvant chemotherapy followed by HDCT with etoposide, cyclophosphamide, and either doxorubicin (CAVP) or cisplatin (CCVP). Variables analyzed included stage, tumor size, number of axillary nodes involved, grade and receptor status, and types of adjuvant chemotherapy and radiation therapy and HDCT. RESULTS: With a median follow-up time of 46 months (range, 23 to 93), Kaplan-Meier estimates of 3.5-year OS for stage II, IIIA, and IIIB HRBC are 82% (95% confidence interval [CI], 67% to 97%), 79% (95% CI, 67% to 91%), and 72% (95% CI, 53% to 91%); RFS estimates are 71% (95% CI, 56% to 85%), 57% (95% CI, 43% to 72%), and 50% (95% CI, 29% to 71%) irrespective of the HDCT regimen. In univariate analysis, the risk of relapse was lower for patients with progesterone receptor (PR)-positive tumors (risk ratio [RR], 0.43; 95% CI, 0.22 to 0.81; P = .01) and higher for patients with inflammatory carcinoma (RR, 2.20; 95% CI, 1.02 to 4.76; P = .05). OS was better for patients with PR (RR, 0.16; 95% CI, 0.05 to 0.55; P = .003) and estrogen receptor (ER)-positive tumors (RR, 0.42; 95% CI, 0.17 to 1.02; P = .05); OS was worse for patients with high-grade primary tumors (RR, 4.08; 95% CI, 1.21-13.7; P = .02). In multivariate analysis, PR positivity was associated with improved RFS (P = .01) and OS (P = .001). CONCLUSION: HDCT in selected patients with HRBC is safe and warrants further evaluation. Patients with receptor-negative, high-grade, or inflammatory tumors require improvement in their therapeutic options. Better assessment of the role of HDCT awaits completion of ongoing randomized trials.

Adult↗

PubMed1998

[The role of high-dose chemotherapy with hemopoietic stem cell transplantation in the treatment of breast cancer with unfavorable prognosis].

High-dose chemotherapy using transplantation of hemopoietic precursor cells offers much advantage for treatment of prognostically unfavorable cancers of the breast. Both experimental and clinical evidence points to a potential of raising antitumor effect by increased dosage of chemical drugs. Clinical studies using high-dose chemotherapy for treating patients with stage II-III tumors or with greater than or equal to 10 positive axillary lymph nodes, and locally-advanced and disseminated tumor established a relative rise in overall and recurrence-free survival, as compared with standard treatment. Hazardous cytopenia and related complications can be significantly reduced when hemopoietic precursor cells are transplanted from peripheral blood.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2000

[Peripheral blood stem cell harvest in patients with limited stage small-cell lung cancer].

Chemotherapy plus granulocyte colony-stimulating factor (G-CSF) induced mobilization of peripheral blood stem cells (PBSC) was performed in patients with limited stage small-cell lung cancer. Chemotherapy consisted of cisplatin/etoposide or cisplatin/adriamycin/etoposide. The amounts of CD34 positive cells and granulocyte-macrophage colony forming units (CFU-GM) collected during 2-3 courses of apheresis were 3.1 +/- 2.9 x 10(6)/kg (n = 10) and 3.1 +/- 1.5 x 10(5)/kg (n = 8), respectively. Adequate amounts of PBSC were also harvested even in patients treated with concurrent chemoradiotherapy. Eight patients were successfully treated with high-dose chemotherapy consisting of ifosfamide, carboplatin and etoposide with PBSC transfusion. The patients'-bone marrow reconstruction was rapid and no treatment-related death was observed.

Adult↗

PubMed2000

Efficacy and hematologic toxicity of salvage chemotherapy following stem cell-supported high-dose chemotherapy in women with recurrent ovarian cancer.

OBJECTIVE: The objective of this study was to determine the efficacy and hematologic toxicity of salvage chemotherapy in patients with recurrent ovarian cancer following high-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT). METHODS: A retrospective analysis of 19 Massachusetts General Hospital case records of women with relapsed ovarian cancer following PBSCT was conducted. RESULTS: Between February 1996 and September 1998, 24 women with ovarian cancer were treated with PBSCT. Nine patients were treated with an upfront PBSCT regimen to consolidate first-line chemotherapy and 15 patients were treated with PBSCT after a median of two lines (range: 1-3) of prior chemotherapy. Sixteen patients presented with relapsed disease at a median of 230 days post-PBSCT and 3 patients had persistent disease through high-dose chemotherapy. Each of these 19 patients has been treated with salvage chemotherapy following PBSCT. Patients received one of six different first-line salvage chemotherapy regimens. Sixteen of nineteen patients are alive a median of 383 days (range: 156-868) after relapse following PBSCT. Three patients died of progressive disease at a median of 284 days (range: 224-648) after post-PBSCT relapse. Six patients achieved a complete response, four patients had a partial response, three patients had stable disease, and six patients had progressive disease in response to first-line salvage chemotherapy. Seven patients experienced grade III/IV neutropenia, and three patients experienced grade III/IV thrombocytopenia. CONCLUSIONS: We conclude that in a patient population selected for chemotherapy sensitive and low-volume disease prior to PBSCT, patients with recurrent tumor appear to respond to salvage chemotherapy, and associated hematologic toxicity is acceptable and manageable.

Adult↗

PubMed1995

Patient with extensive small cell lung cancer given moderately dose-intensified chemotherapy and peripheral blood stem cell support.

Although recent progress in multi-drug chemotherapy has increased the median survival of patients with extensive Small cell lung cancer (SCLC) to 7 months, 2-year survivors are still exceptional. We describe a 40-year-old man with extensive SCLC involving the lungs and systemic nodes who was initially treated with 6 cycles of an alternating combination regimen consisting of cyclophosphamide, doxorubicin, vincristine, cisplatin and etoposide. After the second cycle of the regimen, Peripheral blood stem cells (PBSC) were harvested and frozen. The patient then received a moderately dose-intensified regimen consisting of cisplatin (80 mg/m2) and etoposide (500 mg/m2 X 3), followed by infusion of the thawed PBSC. Hematopoietic recovery was rapid, and the patient remained tumor free for 12 months until multiple tumor recurrence.

Adult↗

PubMedDate not supplied

High dose chemotherapy and stem cell support for poor risk and recurrent nonseminomatous germ cell cancer: initial experience with sequential therapy.

BACKGROUND: Approximately 20% of patients with germ cell tumours do not respond fully to standard therapy, or relapse after treatment. The prognosis of these patients is poor with conventional chemotherapy. Preliminary data suggest that they may have a higher durable response rate with high dose chemotherapy and peripheral blood stem cell support. AIMS: To treat a group of testicular cancer patients, either with relapsed disease or with poor prognostic features initially, with high dose chemotherapy and stem cell support, and evaluate their outcome. METHODS: Five patients with testicular cancer were treated with high dose chemotherapy and stem cell support. Of these, four underwent this treatment as salvage therapy and one patient with poor prognostic features was treated as primary treatment. RESULTS: At an average follow-up of 18 months, four patients remain free of disease while one patient has developed relapse. CONCLUSION: This report provides further support for high dose chemotherapy in this setting although randomised, controlled trials are essential to clarify its use.

Adult↗

PubMed2004

[High dose chemotherapy and stem cell transplant in patients with operable breast cancer and a poor prognosis; not indicated for the time being].

Early breast cancer with multiple tumour-positive axillary lymph glands is still characterised by a considerable mortality despite improvements in surgery, radiotherapy, chemotherapy and endocrine treatment. High-dose chemotherapy and bone-marrow support instead of the usual chemotherapy seemed to be a very promising approach back in the 1980s. Several phase-II studies supported this view and therefore phase-III studies were carried out. In a Cochrane review published at the start of 2003, a meta-analysis of several phase-III studies revealed that the results after high-dose chemotherapy were not significantly better than those after the usual treatment. Two large multicentre studies, one performed in the Netherlands and one in the USA, have recently been published. Neither of the two studies revealed survival differences, although one study demonstrated a significant benefit in actuarial 5-year relapse-free survival. Therefore, the routine clinical application of high-dose chemotherapy cannot be advocated yet.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Mobilization of peripheral blood progenitor cells (PBPC) in patients undergoing chemotherapy followed by autologous peripheral blood stem cell transplant (SCT) for high risk breast cancer (HRBC).

We have determined the effect of delayed addition of G-CSF after chemotherapy on PBPC mobilization in a group of 30 patients with high risk breast cancer (HRBC) undergoing standard chemotherapy followed by high-dose chemotherapy (HDCT) and autologous SCT. Patients received FAC chemotherapy every 21 days followed by G-CSF at doses of 5 microg/kg/day starting on day +15 (groups 1 and 2) or +8 (group 3) after chemotherapy. PBPC collections were performed daily starting after 4 doses of G-CSF and continued until more than 2.5 x 10(6) CD34+ cells had been collected. In group 1, steady-state BM progenitors were also harvested and used for SCT. Groups 2 and 3 received PBPC only. The median number of collections was three in each group. Significantly more PB CD34+ cells were collected in patients receiving G-CSF starting on day 8 vs day 15 (9.43 x 10(6)/kg and 6.2 x 10(6)/kg, respectively) (P < 0.05). After conditioning chemotherapy all harvested cells including BM and PBPC were reinfused. Neutrophil and platelet engraftment was significantly faster in patients transplanted with day 8 G-CSF-mobilized PBPC (P < 0.05) and was associated with lower transplant related morbidity as reflected by days of fever, antibiotics or hospitalization (P < 0.05). Both schedules of mobilization provided successful long-term engraftment with 1 year post-transplant counts above 80% of pretransplant values. In conclusion, we demonstrate that delayed addition of G-CSF results in successful mobilization and collection of PBPC with significant advantage of day 8 G-CSF vs day 15. PBPC collections can be scheduled on a fixed day instead of being guided by the PB counts which provides a practical advantage. Transplantation of such progenitors results in rapid short-term and long-term trilineage engraftment.

Adolescent↗

PubMed2001

Telomere length in breast cancer patients before and after chemotherapy with or without stem cell transplantation.

High-dose chemotherapy and peripheral blood stem cell transplantation (PBSCT) may accelerate telomere length loss in haematopoietic stem cells. As data including pre-and post-treatment samples are lacking, we studied leukocyte telomere length and telomerase activity before and after treatment in breast cancer patients randomized to receive 5 adjuvant courses FEC (5-FU, epirubicin and cyclophosphamide) (n = 17), or 4 x FEC followed by high-dose cyclophosphamide, thiotepa, carboplatin and autologous PBSCT (n = 16). Haemoglobin, MCV, leukocyte-and platelet numbers were assessed prior to (t(0)), 5 months after (t(1)) and 9 months after chemotherapy (t(2)); these parameters were decreased at t(1)and t(2)compared to t(0)(high-dose: all parameters; standard-dose: leukocytes and platelets), and all parameters were lower after high-dose than standard-dose treatment at t(1). Paired individual leukocyte samples of t(0)and t(1)showed telomere length change (determined by telomere restricted fragment (TRF) assay) ranging from +0.8 to -2.2 kb, with a decreased TRF length in 9 patients of both groups. Telomerase activity (determined by TRAP assay) was below detection limit in leukocyte samples of t(0)and t(1). Thus, standard-and high-dose chemotherapy negatively affect haematological reconstitution in this setting. In individual patients, telomere length can be remarkably changed following haematological proliferative stress after treatment.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer.

The cellular mechanisms underlying the increasing aggressiveness associated with ovarian cancer progression are poorly understood. Coupled with a lack of identification of specific markers that could aid early diagnoses, the disease becomes a major cause of cancer-related mortality in women. Here we present direct evidence that the aggressiveness of human ovarian cancer may be a result of transformation and dysfunction of stem cells in the ovary. A single tumorigenic clone was isolated among a mixed population of cells derived from the ascites of a patient with advanced ovarian cancer. During the course of the study, yet another clone underwent spontaneous transformation in culture, providing a model of disease progression. Both the transformed clones possess stem cell-like characteristics and differentiate to grow in an anchorage-independent manner in vitro as spheroids, although further maturation and tissue-specific differentiation was arrested. Significantly, tumors established from these clones in animal models are similar to those in the human disease in their histopathology and cell architecture. Furthermore, the tumorigenic clones, even on serial transplantation continue to establish tumors, thereby confirming their identity as tumor stem cells. These findings suggest that: (a) stem cell transformation can be the underlying cause of ovarian cancer and (b) continuing stochastic events of stem and progenitor cell transformation define the increasing aggression that is characteristically associated with the disease.

Clone Cells↗