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PubMed1997

[Intensive chemotherapy with autologous stem cell transplantation in ovarian cancers: analysis of 67 patients treated at the Paoli-Calmettes Institute and a review of the literature].

Despite important initial chemosensitivity, advanced ovarian cancer has a bad prognosis with a median survival of 20 to 30 months. These results might be better with intensive chemotherapy. We analysed 67 patients treated by intensive chemotherapy with autologous stem cell transplantation for advanced ovarian cancer at Institute Paoli-Calmettes between 1980 and 1994. Population was divided in two groups: salvage group (n = 30) for initial chemotherapy-refractory patients and consolidation group (n = 37) for sensitive patients. Several successive conditioning regimens were used, all based on alkylating agents. Principal toxicities were severe aplasia and mucositis. Four patients died from toxicity related to infection during strong immunosuppression. In salvage group, 9 out of 21 evaluable patients responded (43%), but duration of responses was short (median range of 5 months) and 2-year overall survival rate was 8% after transplantation. In consolidation group, 19 patients are alive and 15 are without disease progression with a median follow-up of 42 months (17, 161) after diagnosis. Five-year disease-free survival rate is 28% (median range of 35 months) and 5-year overall survival rate is 48% (median range of 41 months). Intensification does not seem to be long term beneficial for initial chemotherapy refractory patients, despite objective responses rate better than classical treatment. On the other hand, results seem better than conventional treatments in case of chemosensitive disease and should be confirmed prospectively in larger cohort of patients. Moreover, other research directions are open like intensification supported by hematopoietic growth-factors and peripheral stem cells, definition of best conditioning regimen, use of taxanes, and intensification in first line chemotherapy after initial surgery.

Adult↗
PubMedDate not supplied

[High-dose chemotherapy and stem-cell in patients with breast cancer].

BACKGROUND: The treatment of breast cancer patients with high-dose chemotherapy and stem-cell support is still highly controversial. The elucidation of its clinical benefit awaits the maturation of on-going clinical trials. METHODS: Patients with chemotherapy-sensitive metastatic or locally advanced disease and patients with stage II/III disease and at least four positive axillary lymph nodes in the initial surgical specimen were eligible for transplantation. RESULTS: Fifty-five women underwent transplantation between 1994 and 2000. For the 19 women with metastatic disease, the median time to progression was seven month and survival 28 months. Only two patients are progression-free, at 48 and 77 months, both with supraclavicular and/or cervical lymph node-only disease. For the 36 women with stage II/III disease, the median time to progression and survival were both 65 months -19 are alive, 18 disease-free. Among the subgroup of 23 patients with 10 or more positive axillary nodes, the five-year event-free survival was 57%. CONCLUSION: The clinical benefit of stem-cell transplantation for metastatic breast cancer is limited since the time to progression and survival after transplantation is similar to those reported in patients with newly diagnosed metastases and treated with conventional-dose chemotherapy. However, in patients with high-risk stage II/III disease the time to progression is longer than that reported for similar patients treated with conventional systemic treatment. These results are similar to previous reports in the literature.

Adult↗
PubMed2000

[Cost of antibiotic therapy in neutropenic patients undergoing peripheral blood stem cell transplantation for breast cancer].

The increase in pharmaceutical costs, especially for expensive procedures such as bone marrow transplants, has led to the study of the economic impact of febrile neutropenia in peripheral blood stem cell transplantation (PBSCT). We analyzed 89 consecutive patients with breast cancer who underwent PBSCT. All patients developed febrile neutropenia and were administered an empirical intravenous regimen based on the combination of piperacillin-tazobactam and amikacin. We analyzed the direct costs of this treatment and grouped them into drug acquisition cost, administration costs (cost of the additional material), and preparation costs (time employed for the preparation and administration of the drug). We found that the overall cost was $1,110, 65% of which corresponded to the initial therapy and the rest (35%) to the use of additional antibiotics. This higher cost was especially related to the use of vancomycin or teicoplanin (50%). The acquisition costs accounted for 90% of the overall treatment costs. Thirty-six patients (40%) did not need additional antibiotics and the cost in this group was less ($663). We concluded that knowledge of the costs of pharmacological therapy for infection in PBSCT is indispensable for the appropriate development of treatment units, especially in terms of optimizing resources and comparing different therapeutic or prophylactic approaches.

Amikacin↗
PubMed1998

Randomized study of filgrastim versus molgramostim after peripheral stem cell transplant in breast cancer.

BACKGROUND AND OBJECTIVE: The aim of this study was to compare the efficacy and toxicity of Filgrastrim (granulocyte colony-stimulating factor-G-CSF) versus molgramostim (granulomonocyte colony-stimulating factor-GM-CSF) after autologous peripheral blood stem cell transplant (PBSCT) in patients with breast cancer. To the best of our knowledge no randomized studies comparing filgrastrim and molgramostim have been published. DESIGN AND METHODS: Forty-two patients with breast cancer were randomized to receive filgrastrim versus molgramostim subcutaneous at a dose of 5 mcgr/kg starting on day 6 after PBSCT. PBSC were collected in all patients after stimulation with filgrastrim and infused following conditioning with cyclophosphamide, cisplatin and carmustine (n = 25) or cyclophosphamide, carboplatin and thiotepa (n = 17). RESULTS: The median days to reach > 0.5 x 10(9)/L granulocytes was similar for patients receiving filgrastrim (10.5 +/- 0.8 days) and molgramostim (10.2 +/- 0.9 days). No significant differences were observed in time taken to reach 20 x 10(9)/L platelets 10.8 +/- 2.2 vs 12 +/- 2.9 for filgrastrim and molgramostim, respectively, but in time to reach 50 x 10(9)/L was slightly lower in the filgrastrim arm (15.1 +/- 2.9 vs 18.9 +/- 8.4, p = 0.03). Nevertheless there were no differences in the number of platelets transfused. Time of discharge was two days earlier in the filgrastrim arm (15 +/- 4.2 vs 17.4 +/- 4.7, p = 0.04). Finally, the incidence of adverse side effects attributable to the cytokines (filgrastrim or molgramostim) was equivalent and only present in 19% of the patients. INTERPRETATION AND CONCLUSIONS: This randomized study shows that filgrastrim and molgramostim yield quite similar toxicity and efficacy for early hematopoietic reconstitution after PBSCT in breast cancer patients.

Administration, Cutaneous↗
PubMed2006

Polyphenols prevent cell shedding from mouse mammary cancer spheroids and inhibit cancer cell invasion in confrontation cultures derived from embryonic stem cells.

The prognosis of cancer disease is worsened upon shedding of tumor cells from the primary tumor, which escape to the blood stream and form metastases at distant sites within the body. Inhibition of cell shedding from the primary tumor could therefore be exploited to avoid metastasis and delay the progression of the cancer disease. In the present study, we investigated the effects of the polyphenols resveratrol, baicalein, epicatechin, epigallocatechin and polyphenon 60 on cell shedding from multicellular tumor spheroids of the murine mammacarcinoma cell line 4T1, cell invasion into embryonic stem cell-derived tissues, generation of reactive oxygen species (ROS) and expression of matrix metalloproteinase 9 (MMP-9). With increasing tumor spheroid growth MMP-9 expression was upregulated and cells detached from tumor spheroids and formed subspheroids that displayed pronounced ROS generation. Upon incubation with polyphenols tumor growth was arrested and cell shedding was totally abolished. Polyphenol treatment decreased ROS generation and downregulated MMP-9 expression. Furthermore, polyphenols significantly inhibited invasion of tumor cells into embryonic stem cell-derived, vascularized tissues. Our data suggest, that polyphenols inhibit cell shedding and invasion by their anti-oxidative capacity and downregulation of MMP-9 expression.

Animals↗
PubMed2006

Glioblastoma-derived tumorospheres identify a population of tumor stem-like cells with angiogenic potential and enhanced multidrug resistance phenotype.

We investigated in vitro the properties of selected populations of cancer stem-like cells defined as tumorospheres that were obtained from human glioblastoma. We also assessed their potential and capability of differentiating into mature cells of the central nervous system. In vivo, their tumorigenicity was confirmed after transplantation into the brain of non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice. The angiogenic potential of tumorospheres and glioblastoma-derived cells grown as adherent cells was revealed by evaluating the release of angiogenic factors such as vascular endothelial growth factor and CXCL12 by ELISA, as well as by rat aortic ring assay. The proliferative response of tumorospheres in the presence of CXCL12 was observed for the first time. Multidrug resistance-associated proteins 1 and 3 as well as other molecules conferring multidrug resistance were higher when compared with primary adherent cells derived from the same tumor. Finally, we obtained cells from the tumor developing after grafting that clearly expressed the putative neural stem cell marker CD133 as shown by FACS analysis and also nestin and CXCR4. The cells' positivity for glial fibrillary acidic protein was very low. Moreover these cells preserved their angiogenic potential. We conclude that human glioblastoma could contain tumor cell subsets with angiogenic and chemoresistance properties and that this chemoresistance potential is highly preserved by immature cells whereas the angiogenic potential is, to a higher extent, a property of mature cells. A better understanding of the features of these cell subsets may favor the development of more specifically targeted therapies.

AC133 Antigen↗
PubMedDate not supplied

Telomerase as a target for cancer immunotherapy.

Telomerase is the ribonucleoprotein that enables cancer and stem cells to maintain their telomeres, resulting in unlimited proliferative potential. The catalytic component of telomerase in humans, hTERT, is upregulated in nearly 90% of all cancers, making it the most widely expressed marker of malignancy. With the exception of germ cells and stem cells, hTERT is undetectable in somatic human tissues. Together, these properties make telomerase a leading candidate for cancer therapy. Various therapies have been tested in tissue culture and in mouse models utilizing genetic, pharmacological, and immunological approaches. The purpose of this review is to critically examine the role of hTERT in cancer immunotherapy by providing a comparison of the current experiments and a proposal for an innovative method utilizing DNA vaccination.

CD4-Positive T-Lymphocytes↗
PubMed2006

Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies.

In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for tissue regeneration and cancer therapies. We describe new procedures for derivation and maturation of these stem cells into the tissue-specific cell progenitors. The localization of the adult stem cells and their niches, as well as their implication in the tissue repair after injuries and during cancer progression, are also described. The emphasis is on the interactions among certain developmental signaling factors, such as hormones, epidermal growth factor, hedgehog, Wnt/beta-catenin, and Notch. These factors and their pathways are involved in the stringent regulation of the self-renewal and/or differentiation of adult stem cells. Novel strategies for the treatment of both diverse degenerating disorders, by cell replacement, and some metastatic cancer types, by molecular targeting multiple tumorigenic signaling elements in cancer progenitor cells, are also illustrated.

Animals↗
PubMed1990

[Autologous hematopoietic stem cell transplantation--application to recurrent breast cancer].

High-dose chemotherapy with autologous hematopoietic stem cell transplantation (HD-CT with AHSCT) has been studying to overcome drug resistance and to obtain higher antitumor efficacy on hematological malignancies and solid tumors. The annual rate of transplants is increasing steadily. This method has boon now performed safely owing to the development of researches about hematopoietic growth factors and stem cells. It was demonstrated that the administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) and granulocyte Macrophage colony stimulating factor (rhGM-CSF) could shortened the duration of leukopenia. Autologous peripheral stem cell transplantation has the advantage for the earlier bone marrow reconstitution and the unnecessary of purging. Recently, it was found that rhG-CSF and rhGM-CSF could increase the number of peripheral blood stem cells, so further studies are expected. For recurrent breast cancers resistant to conventional chemotherapy, response rates of 60-80% may be achieved using HD-CT with AHSCT, but the duration of response is generally short. So, trials consisted of induction conventional chemotherapy followed by HD-CT with AHSCT in the earlier course of the illness have conducted to obtain higher complete response (CR) rate and survival rate. Although the observed duration is short, higher CR rate has been achieved in several clinical studies. There are still remaining with many problems to be settled, HD-CT with AHSCT may have the potentiality to cure not only recurrent breast cancer but also another malignancies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

[Therapeutic intensification and autotransplantation of hematopoietic stem cells in metastatic breast cancers].

The first studies on intensive chemotherapy for metastatic breast cancer conducted in the 80s were disappointing. Despite good response rates, the duration of remission was short and long-term survivals exceptional. Nevertheless, these phase I and II trials helped to develop a better understanding of the potential indications of this new therapeutic approach and apprehend its technical aspects. Over the last 5 years, considerable progress has been made in grafting techniques and hematopoietic support greatly improving the safety of the method. Notwithstanding the financial considerations involved, it must be noted that the efficacy autologous stem cell support, in terms of recurrence-free overall survival, has not yet been demonstrated although the (controversial) results of two randomized controlled trials have recently been published. In France, the PEGASE programs for the study of autologous stem cell support in breast cancer have been developed in an attempt to elucidate the question.

Antineoplastic Agents↗
PubMed1995

[High-dose chemotherapy (HDCT) with peripheral blood stem cell transplantation (PBSCT) in ovarian cancer patients with poor prognosis].

Platinum is a key drug in ovarian cancer chemotherapy. Through combination with peripheral blood stem cell transplantation (PBCST), up to three times the usual carboplatin dose (1,200 mg/m2) may be given. If granulocyte colony stimulating factor (G-CSF) is added to the PBSCH harvest and apheresis is performed twice when the leukocyte count exceeds 10,000/microliters 14 days before and after the platinum-based chemotherapy, the necessary hematopoietic stem cell collection for bone marrow reconstitution can be done. This treatment proves most effective when the initial treatment is under way and it is used as a consolidation therapy for minimum residual disease very similar to PCR or for PCR itself. Forthcoming investigation should determine what impact this therapeutic approach will have on longer survival, or whether it will contribute to treatment of an ovarian cancer with a poor prognosis, for example, when the residual tumor measures more than 2 cm in diameter. Moreover, what results can be expected if one uses effective ip chemotherapy with the standard dose in conjunction with the PBSCT-HDCT combination? Especially, if one can contact the residual tumor in the intraperitoneal cavity most likely to have a recurrence with a drug at an extremely high concentration, enabling a massive dose to the intraperitoneal cavity comparable to the standard dosage by vas internal administration with equivalent blood concentration, distant metastases may also be prevented.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

High-dose chemotherapy with autologous stem cell support for breast cancer.

Breast cancer is a major public health issue, expected to affect one out of nine women over a lifetime. High-dose chemotherapy with autologous stem cell support is a current approach to the management of metastatic breast cancer and high-risk primary breast cancer. This review considers the effectiveness of this modality in the treatment of breast cancer in an effort to define its role in overall patient management. Current research directions, including technical advances aimed at reducing toxicity, are discussed. Finally, controversies regarding the role of third-party payers in the investigational process are considered.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

[Chemotherapy with autologous stem cell support for breast cancer].

The importance of dose intensity in breast cancer chemotherapy has been stressed in recent years with clear correlations demonstrated between dose intensity and clinical outcome of the patients in both therapeutic and adjuvant settings. In addition to various and intense supportive care, autologous stem cell support (ASCS) has been used over the past 15 years in order to overcome myelotoxicity of cancer chemotherapy. ASCS was initially practiced in the form of bone marrow transplantation, and more recently peripheral stem cell transplantation has been combined in addition to administration of G-CSF. Our pilot study in patients with recurrent/advanced breast cancer showed a higher response rate and a higher survival rate as compared to conventional chemotherapy, and there have been some long-term disease-free survivors with probable cures among complete responders with ASCS-supported chemotherapy. In adjuvant settings for patients with a high risk for recurrence who had been given a high-dose, the ASCS-supported regimen showed a higher disease-free survival rate as compared to those who were treated with conventional adjuvant therapy. Whether these apparently better results in our pilot studies hold true generally remains to be seen with well-scheduled randomized clinical trials.

Antineoplastic Agents↗
PubMed2005

Intrahepatic cholangiocarcinoma arising in cirrhotic liver frequently expressed p63-positive basal/stem-cell phenotype.

In general, intrahepatic cholangiocarcinoma (ICC) is not related to liver cirrhosis. However, a few cases have been reported in which ICC was accompanied by severe liver fibrosis. Some researchers have proposed that hepatocellular and cholangiocellular (HC-CC) carcinoma, an intermediate mixed phenotype possibly arising in cirrhotic liver, might originate from hepatic precursor cells. In the liver, hepatocytes and cholangiocytes form the epithelial element, but stromal and mesenchymal elements may be produced by hepatic stem cells. Based on these aspects, not only HC-CC, but also other combinations of cellular phenotypes, would cover all the cancers with stem cell features. In this study, which aimed at determining the characteristics of the ICC phenotype, we used immunohistochemistry to examine the expression of basal/stem-cell markers, i.e., p63 in ICC with and without liver cirrhosis, as well as the expressions of cytokeratin (CK) 34 beta E12, specific for the basal-cell marker, and c-kit, specific for the stem-cell marker. Aberrant p63 was frequently expressed in ICC arising in cirrhotic liver. This result suggests that ICC cancer cells originate from hepatic precursor cells with a hidden multi-differentiation potential.

Aged↗
PubMed2002

Role of prostate stem cell antigen in prostate cancer research.

PURPOSE OF REVIEW: The identification of cell surface antigens is critical to the development of future prognostic and therapeutic modalities for the treatment of prostate cancer. Several prostate-specific proteins have been identified and are under investigation. This review reports on prostate stem cell antigen (PSCA), a protein with restricted expression that may have prognostic and therapeutic utility. RECENT FINDINGS: PSCA is a glycosylphosphatidylinositol-anchored cell-surface protein belonging to the Ly-6/Thy-1 family of cell surface antigens, and a murine homologue has been described. It is expressed in the normal human prostate and overexpressed in human prostate cancers. Its overexpression has been correlated with increased Gleason score, advanced stage and bone metastasis. PSCA is co-amplified with MYC, an independent predictor of progression and death. PSCA may therefore be a useful predictor of tumor biology and a useful target of immunotherapy against prostate cancer. Evidence suggests a potential role in strategies employing cytotoxic T cell lymphocytes. Anti-tumor activity has been demonstrated with monoclonal antibodies in tumor take and established tumor xenograft models. Conjugated antibody has recently been reported to have anti-tumor activity in preclinical models. SUMMARY: PSCA may serve as a tool in refining the prognosis of an individual cancer and may be a useful therapeutic target for immunotherapy. Future studies will be required to confirm its clinical utility as a prognostic factor. Future animal and clinical studies will be required to test various immunotherapy strategies for safety and efficacy. The study of PSCA regulation and expression may provide information on normal prostate development and prostate carcinogenesis.

Antigens, Neoplasm↗
PubMed1997

High-dose chemotherapy with autologous stem cell support for breast cancer.

High-dose chemotherapy is increasingly utilized for the treatment of metastatic and high-risk breast cancer. Autologous Blood and Marrow Transplant Registry data reveal that a single high-dose cycle of chemotherapy with stem cell support can produce high complete response rates, with 10% to 20% of patients disease-free at 5 years. For patients with locally advanced disease, pooled results estimate 63% without relapse at 3 years for stage II and III disease and 42% for inflammatory breast cancer. New strategies to improve on these results include the incorporation of newly identified active drugs into established regimens and the use of multiple high-dose cycles. Multicycle chemotherapy produces complete response rates ranging from 35% to 93% depending on the regimen. Additional strategies include the use of monoclonal antibodies, immunotherapy, and gene therapy for post-transplant consolidation. The strongest predictor of long-term disease-free survival in virtually all studies is a complete response prior to or following high-dose chemotherapy. Randomized studies are now in the process of being completed in Europe and the United States with reporting scheduled over the next several years.

Breast Neoplasms↗
PubMed1992

[High-dose adjuvant chemotherapy with peripheral blood stem cell transplantation for breast cancer with poor prognosis--a pilot study].

Three patients with breast cancer with poor prognosis were treated with high-dose chemotherapy (HD-CT) and peripheral blood stem cell transplantation (PBSCT) as adjuvant treatment. After radical mastectomy, the consolidation chemotherapy with Adriamycin 50 mg/m2, Cyclophosphamide 1,000 mg/m2, Vincristine 1.0 mg/m2 and Methotrexate 200 mg/m2 with Leucovorin rescue was started. Recombinant human granulocyte colony stimulating factor (rhG-CSF) was also added for early recovery from myelosuppression. This combination chemotherapy was given every 3 weeks for 3 courses, and after the 2nd and 3rd courses, peripheral blood stem cells (PBSC) were collected and cryopreserved. HD-CT with Cyclophosphamide 2,000 mg/m2/day, Thio-TEPA 200 mg/m2/day, and Etoposide 300 mg/m2/day, were administered for 3 consecutive days, and after 48 hours of last doses, frozen-thawed PBSC (6.4-8.9 x 10(4)/kg of CFU-GM) were administered. rhG-CSF was also added. HD-CT and PBSCT were well tolerated, recovery from myelosuppression of the HD-CT was very quick and no serious side effects were observed.

Antineoplastic Combined Chemotherapy Protocols↗