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The original article to which this Retraction refers was published in Cancer (2002) 94(4 Suppl):1363-72.
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The aim of this study was to determine whether the detection of CTC in the apheresis product contribute significantly to treatment failure of patients with high-risk breast carcinoma treated with high-dose chemotherapy (HDC) and stem cell transplantation (SCT). Patients were with stage II and III adenocarcinoma of the breast with > or = 10 axillary lymph nodes affected after primary surgery (> or = 10 N+) who had received HDC with SCT. We analyzed retrospectively the presence of CTC as assessed by immunocytochemistry (ICC) in the apheresis products obtained after standard adjuvant chemotherapy. We compared the clinical outcome of patients who received HDC and SCT with or without CTC-positive apheresis. One hundred and twenty-seven apheresis products samples were obtained from 51 patients. Fourteen (27.4%) of these samples were CTC positive. After a median follow-up of 4.6 years, 20 patients have relapsed, 14 died from progression of their disease and 30 patients remain alive and free of progression. For the whole group of patients the 5 year probabilities of DFS and OS were 60% (IC 95%, 47-75%) and 71% (IC 95%, 55-83%), respectively. However, the 5 year probabilities of DFS were 23% (IC 95%, 0-46) and 75% (IC 95%, 60-89) for patients with CTC positive and negative, respectively. The 5 year probabilities of OS were 42% (IC 95%, 15-68) and 83% (IC 95%, 70-95) for patients with CTC positive and negative, respectively. Both univariate and multivariate analysis showed that the presence of CTC in the apheresis product was the only prognostic factor associated with a higher incidence of clinically overt disease relapse (P = 0.002) and shorter survival (P = 0.003). The presence of cytokeratin-positive metastatic cells in the apheresis product increases the risk of relapse after HDC and SCT in patients with stage II and III adenocarcinoma of the breast with > or = 10 N+.
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This report reviews clinical experience with high-dose chemotherapy with stem-cell support in breast cancer and attempts to integrate clinical and molecular biological observations into a model of drug resistance. Despite the remarkable initial chemosensitivity of breast cancer, the majority of patients with advanced breast cancer die of their disease. In trials to date, high-dose chemotherapy has not been able to overcome primary drug resistance and patients with disease progression during induction therapy benefit little from further high-dose therapy. On the other hand, high-dose chemotherapy produces improved objective response rates compared with standard-dose chemotherapy due to converting some partial responses achieved by standard-dose induction therapy to complete response. This suggests that high-dose chemotherapy may overcome partial clinical drug resistance and may result in a more complete elimination of chemosensitive cells. Whether increased complete response rates will translate into higher cure rates and increased overall survival remains to be unequivocally demonstrated. There are multiple clinical patterns of drug failure including continued growth during chemotherapy, partial response followed by a period of stable disease, initial complete response with subsequent recurrence within a few months or after several years. Different mechanisms of drug resistance may operate at different stages of the disease and predispose patients to different clinical patterns of failure. A model of clonal progression of cancer is proposed that could explain several intriguing features of clinical drug resistance. We hypothesize that drug-sensitivity is an acquired characteristic of neoplastic cells and that a 'physiological drug-resistant' state may precede drug sensitivity at early stages of neoplastic transformation. Some recurrences may, in this context, represent progression of physiologically drug-resistant clones to sensitivity and subsequently to 'pathologic resistance' to chemotherapy. Optimal therapy to delay or prevent recurrence may differ depending on the stage and biology of the tumor and may include combinations of cytotoxic drugs and chemopreventive agents to arrest progression of early physiologically drug-resistant neoplastic stem cells.
Self-renewal pathways crucial for maintaining stem cells are deregulated in cancer, raising the spectre that cancer therapies targeting such pathways might also ablate normal stem cells. As Yilmaz et al. (2006) report in a recent Nature paper, this may not be the case for the tumor suppressor protein Pten, which drives the self-renewal of normal hematopoietic stem cells and the formation of leukemia cells through different mechanisms.
The active metabolite of vitamin D 1,25-dihydroxycholecalciferol is a hormone-like agent that regulates cell differentiation and proliferation. Various vitamin D derivatives have been shown to induce differentiation in neoplastic cells. The prerequisite for any hormone action is the presence of its receptor. We studied the expression of vitamin D receptor in human lung cancer cell lines and in primary lung cancer tissue. Employing the polymerase chain reaction, 10 out of 11 cell lines stemming from small-cell lung cancer and 15 out of 15 cell lines stemming from non-small-cell lung cancer demonstrated vitamin D receptor expression. An immunohistochemical analysis, using a specific monoclonal antibody, demonstrated vitamin D receptor protein expression in 31 out of 117 (26%) primary small-cell lung cancer cases tested. Positive cells exhibited a nuclear reaction pattern. Twenty-one out of 37 primary non-small-cell lung cancer cases, particularly adenocarcinomas (9/14) and squamous-cell carcinomas (10/15), exhibited vitamin D receptor. Results indicate that a subset of lung cancer cases may be susceptible to the differentiating effects of vitamin D analogues.
This article summarizes the various current uses of cytokines, and bone marrow and peripheral blood stem cell transplantation for cancer treatment. Interferons, interleukin-2 and hematopoietic growth factors are extensively used for the treatment of hematopoietic as well as nonhematopoietic malignancies, either as the main therapeutic agents or as an adjuvant. Research on gene therapy using cytokines is in progress. Stem cell transplantation is also discussed in the context of gene therapy of cancer. Gene therapy is expected to become a future modality in cancer treatment.
As previously shown, the stem cell marker nestin is expressed in nascent blood vessels in transgenic nestin-driven green fluorescent protein (ND-GFP) nude mice. This mouse model was recently utilized to evaluate angiogenesis in primary tumors in an orthotopic model of pancreatic cancer. In the present study, nascent angiogenesis of pancreatic cancer liver metastasis in the ND-GFP transgenic nude mice after splenic injection of low-passage xPA-1 human pancreatic cancer cells expressing red fluorescent protein (RFP) was visualized by dual-color fluorescence imaging. ND-GFP was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing liver metastasis. Immunohistochemical staining showed that CD31 co-localized in ND-GFP-expressing nascent blood vessels. The density of nascent blood vessels in the tumor was readily quantitated. Gemcitabine significantly decreased the mean nascent blood vessel density in the pancreatic liver metastases. In conclusion, the dual-color model of the ND-GFP nude mouse with RFP-expressing pancreatic cancer liver metastases, enabled the simultaneous visualization and quantitation of nascent angiogenesis and its response to angiogenesis inhibitors. This model will be useful for understanding the mechanism of angiogenesis of pancreatic cancer liver metastasis and for the discovery of effective new inhibitors of this process.
Preclinical studies have demonstrated the rapid and efficient mobilization of hematopoietic peripheral blood stem cells (PBSC) in a mouse model using the combination of paclitaxel with recombinant human granulocyte colony-stimulating factor (rhG-CSF). On the basis of these results, a clinical trial was initiated using rhG-CSF with paclitaxel for PBSC mobilization in high-risk breast cancer patients. The mobilized PBSC were evaluated for CD34(+) cell number, mononuclear cell content, and clonogenic potential. One-hundred and seventeen breast cancer patients received paclitaxel (300 mg/m(2)) administered as a 24-h continuous intravenous infusion. Forty-eight hours after completing paclitaxel, rhG-CSF (5 microg/kg) was initiated and continued until completion of PBSC collection. Leukapheresis was initiated once the white blood cell count reached 1.0 x 10(9)/L. Each collection was evaluated for the numbers of mononuclear cells (MNC) and CD34(+) cells. Clonogenic potential was enumerated using colony-forming units-granulocyte-macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E). Patients receiving paclitaxel with rhG-CSF mobilized a large number of mononuclear cells/apheresis (mean, 3.7 x 10(8); range, 3.3-4.1) and CD34(+) cells/apheresis (mean, 7.2 x 10(6); range, 6.1-8.4). The average number of leukophereses needed was 1.8 (mean, range 1.6-2.0). Colony growth was normal with 178.9 x 10(5) and 214.8 x 10(5) colonies counted in CFU-GM and BFU-E assays, respectively. Patients engrafted platelets and neutrophils on day 10 following transplantation. In conclusion, PBSC mobilization with paclitaxel and rhG-CSF results in a large number of mononuclear cells and CD34(+) cells with normal clonogenic potential. The cells engraft normally following high-dose chemotherapy and autologous stem cell transplantation in high-risk breast cancer patients. These results demonstrate that paclitaxel with rhG-CSF is an efficient mobilizing agent in high-risk breast cancer patients.
BACKGROUND: The optimum dose of granulocyte colony-stimulating factor (G-CSF) for peripheral blood stem cell (PBSC) mobilization after disease-oriented, conventional-dose chemotherapy remains unknown. METHODS: A multicenter dose-finding study of glycosylated G-CSF (lenograstim) for the mobilization of PBSCs following adjuvant CAF chemotherapy (cyclophosphamide, doxorubicin and 5-fluorouracil) was performed in 38 patients with postoperative breast cancer. Each 10, ten and eight patients were sequentially allocated to one of the three dose groups (2, 5 and 10 micrograms/kg, respectively) of lenograstim. Lenograstim was administered subcutaneously (s.c.) daily from day 8 to the day of the last apheresis and CD34+ cells and colony-forming units-granulocyte macrophage (CFU-GMs) in peripheral blood were measured serially. Additionally, 10 patients who received adjuvant CAF chemotherapy alone also participated in the study, as a control. RESULTS: Lenograstim was well tolerated up to 10 micrograms/kg, except for one patient given 10 micrograms/kg who developed transient grade 3 hepatic enzyme elevation. The peak levels of CD34+ cells and CFU-GMs in peripheral blood showed dose-response relationships. The median peak CD34+ cells for the 0, 2, 5 and 10 micrograms/kg dose groups were 5.4, 34.3, 55.0 and 127.6 cells/microliter, respectively, and those of CFU-GMs for the 0, 2, 5 and 10 micrograms/kg dose groups were 0.01, 0.33, 1.32 and 3.30 CFU-GMs/microliter, respectively. CONCLUSIONS: Considering the previous reports suggesting that a pre-apheresis number of 40-50 CD34+ cells/microliter in peripheral blood is highly predictive for achievement of more than 2.5 x 10(6) CD34+ cells/kg in a standard apheresis procedure of 10 litres, the optimum dose of lenograstim for PBSC mobilization following CAF chemotherapy in patients with postoperative breast cancer is 5 micrograms/kg/day s.c.
Precise quantification of oral complications in cancer patients receiving bone marrow and stem cell transplantation is essential when testing new treatment strategies for mucositis. Using 133 adult transplant patients, the authors evaluated the 20 item oral mucositis index (OMI), adapted from the 34 item OMI, to facilitate use by nondental health professionals. The OMI-20 consists of nine items measuring erythema, nine measuring ulceration, one measuring atrophy, and one measuring edema; all are scored from 0 = none to 3 = severe and summed for a total possible score of 0-60. The two sets of nine items measuring erythema and ulceration can also be summed separately to produce subscale scores ranging from 0 to 27. Results demonstrated internal consistency, test-retest, and inter-rater reliability, and strong evidence of construct validity. Provided that clinical examiners have appropriate training and experience, the OMI-20 can be used as a reliable, valid, and quantifiable measure of mucositis in clinical research.
In contrast to the haematopoietic system in which each cell type is subject to constant turnover, thus endowing this system with the permanent ability to reconstitute itself, the nervous system has long been known as an organ devoid of spontaneous cellular reconstitution. Yet the discovery that certain regions of the mammalian central nervous system do sustain neurogenesis throughout life, together with the fact that cells can be isolated from the adult brain that generate neurons in vitro, has led to the idea that the nervous tissue harbours neural stem cells. The term "neural stem cell" has now become associated with enormous expectations for curing diseases of the nervous system. Yet many of the biological fundamentals of neural stem cells need to be revealed before these expectations can be properly judged or even fulfilled. This begins with the question of whether the neural stem cell corresponds to a real entity or rather represents an in vitro dedifferentiation phenomenon. In this chapter we attempt to give an overview of our current knowledge of the biology of the presumable adult neural stem cell. This is followed by a comparative assessment of the possibilities of using adult neural stem cells and embryonic stem cells for therapeutic approaches in the context of neurodegenerative diseases. Finally, we will look at the "evil side" of stemness by discussing the evidence that brain cancers may originate from cells with stem cell-like properties.
A 32-year-old woman who 1 year earlier underwent a right mastectomy for stage II breast cancer with the histology of invasive ductal carcinoma (scirrhus type) was admitted due to recurrent, metastatic breast cancer in January 1997. She presented multiple metastatic lesions in the skin, lymph nodes, bone, lungs, liver, and spleen, and her bone marrow was replaced almost entirely by tumor cells. The patient was sequentially treated with 5 courses of cyclophosphamide (CPA) and adriamycin (ADM) (CA); 2 courses of CPA, ADM, and 5-fluorouracil; 5 caurses of docetaxel hydrate; and 1 course of CA. After recovery of the normal bone marrow by standard-dose chemotherapies, peripheral blood stem cells (PBSC) were then collected after mobilization with G-CSF. The number of breast cancer cells in bone marrow and PBSC samples was determined by immunocytochemical staining with an anti-cytokeratin monoclonal antibody. The number of tumor cells in PBSC sample was within the level for non-metastatic breast cancer. Complete remission was obtained with high-dose chemotherapy consisting of CPA and Thio-TEPA, and supported by autologous PBSC transplantation.
We have recently treated 66 women with breast cancer with escalating doses of ifosfamide, carboplatin, and etoposide (ICE) followed by autologous stem cell rescue (ASCR). Patients received ifosfamide (6000-24,000 mg m-2), carboplatin (1200-2100 mg m-2), and etoposide (1800-3000 mg m-2) divided over 6 days with ASCR 48 h after completion of chemotherapy. Our patient population consisted of seven patients with stage II disease with eight or more positive nodes being treated in the adjuvant setting, 16 patients with a history of stage III or inflammatory breast cancer, and 43 patients with stage IV disease. Six patients were not evaluable for response due to early death from infection (three patients) and incomplete restaging (three patients). The overall response rate in patients with measurable metastatic disease was 50%. Of those patients with stage II disease, 85% remain alive and progression-free with a median follow-up of greater than one year. The two most frequent toxicities encountered were reversible elevations of liver function tests and mucositis/enteritis. The dose-limiting toxicities were central nervous system toxicity and nephrotoxicity.
BACKGROUND: ERBB2 overexpression predicts a worse outcome for patients receiving high-dose chemotherapy (HDC). Trastuzumab improves response rate and survival in ERBB2 overexpressing metastatic breast cancer patients (MBC). We investigated the feasibility of combining high-dose alkylating agents with autologous hematopoietic stem cell (AHSC) support and trastuzumab in ERBB2 overexpressing MBC. PATIENTS AND METHODS: Eleven consecutive patients with pre-treated ERBB2 overexpressing MBC were enrolled. HDC regimen consisted of a single course of cyclophosphamide 120 mg/kg + melphalan 140 mg/m2 (CyMEL, n =8), a single course of Thiotepa 600 mg/m2 (TTP, n = 1) or a sequential combination of Thiotepa 600 mg/m2 followed on day 21 by BCNU 600 mg/m2 (TTP-BCNU, n =2). Trastuzumab (4mg/kg) was started 24 h after AHSC infusion and then administered weekly (2 mg/kg). RESULTS: Median time to neutrophil and platelet recovery was 10 and 14.5 days, respectively. Three patients experienced febrile neutropenia and in 2 Herpes virus infections were documented. Five grade III/IV mucositis/oesophagitis were recorded. One patient experienced a reversible atrial arrhythmia on day 2 of trastuzumab, and another patients had a nonsymptomatic decrease in LVEF >10% on week 12 of trastuzumab. No toxic death was recorded. Median time to progression was 5 months (1 to 38 +). CONCLUSION: Combining alkylating agent-based HDC and trastuzumab appears to be feasible in ERBB2 overexpressing MBC and warrants further investigation in a larger cohort.