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PubMed2001

Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts.

Prostate stem-cell antigen (PSCA) is a cell-surface antigen expressed in normal prostate and overexpressed in prostate cancer tissues. PSCA expression is detected in over 80% of patients with local disease, and elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence, including high expression in bone metastases. We evaluated the therapeutic efficacy of anti-PSCA mAbs in human prostate cancer xenograft mouse models by using the androgen-dependent LAPC-9 xenograft and the androgen-independent recombinant cell line PC3-PSCA. Two different anti-PSCA mAbs, 1G8 (IgG1kappa) and 3C5 (IgG2akappa), inhibited formation of s.c. and orthotopic xenograft tumors in a dose-dependent manner. Furthermore, administration of anti-PSCA mAbs led to retardation of established orthotopic tumor growth and inhibition of metastasis to distant sites, resulting in a significant prolongation in the survival of tumor-bearing mice. These studies suggest PSCA as an attractive target for immunotherapy and demonstrate the therapeutic potential of anti-PSCA mAbs for the treatment of local and metastatic prostate cancer.

Animals↗

PubMed2000

Outcomes of high-dose chemotherapy and autologous stem cell transplant in isolated locally recurrent breast cancer: a multicenter evaluation.

To determine the outcomes of women with isolated loco-regional recurrence (LRR) of breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) following conventional therapy, we conducted a retrospective review of 58 patients from five institutions treated between 1990 and 1998. Forty-five patients (78%) had > or = 2 poor prognostic factors (PPF) (defined as disease-free interval preceding LRR < or = 2 years, hormone receptor negative/refractory disease, and incomplete resection). At median follow-up of 14.2 (0.5-72) months, 36 patients (62%) developed progressive disease. Disease progression usually occurred at local (27 patients) vs distant (nine patients) sites. Median time to disease progression following ASCT was 6.1 (1.3-31.4) months. At last follow-up, 23 patients (40%) had expired (all due to disease progression), and 13 (22%) were alive with, and 22 (38%) without progressive disease. By Kaplan-Meier analysis, the estimated median PFS and OS was 20.3 and 29.2 months, respectively. In a multivariate model, complete remission at time of HDCT and estrogen-receptor positive disease were predictive of significantly longer PFS and OS. The survival of this cohort was similar to previous reports of those treated with conventional therapy alone, and to those with distant metastases treated with HDCT. Frequent progression locally, suggests that strategies to improve local disease control are needed.

Adult↗

PubMed1994

Outcome of children with brain stem gliomas after treatment with 7800 cGy of hyperfractionated radiotherapy. A Childrens Cancer Group Phase I/II Trial.

BACKGROUND: Brain stem gliomas remain the childhood brain tumors most resistant to treatment. Treatments with hyperfractionated radiotherapy at doses as high as 7560 cGy have been fairly well tolerated. This study was undertaken to determine the toxicity and possible efficacy of hyperfractionated radiotherapy in children with brain stem gliomas using 100 cGy of radiation twice daily, to a total dose of 7800 cGy. METHODS: Sixty-six children (mean age at diagnosis, 7.5 years) with diffuse intrinsic brain stem gliomas were treated. Patients were evaluated for potential toxicity of treatment, progression-free survival, survival, and response to treatment. RESULTS: Objective response to treatment was documented in 20 of 58 (34%) evaluable patients, with 8 (14%) patients having a greater than 50% reduction in tumor size. Overall survival was 35% plus or minus 6% at 1 year and 11% plus or minus 6% at 3 years. Intralesional cystic/necrotic radiographic changes developed in nine patients 6 weeks after radiation, and three of these patients subsequently improved without antitumor intervention. Six of 14 autopsied patients had evidence of probable radiation-induced intralesional necrotic damage, and in 1, necrosis may have played a role in death. Thirty-three of 66 patients were treated with steroids for prolonged periods. CONCLUSIONS: The results of this treatment regimen demonstrate that hyperfractionated radiotherapy, as delivered in this study to a total dose of 7800 cGy, is relatively well tolerated, but may result in prolonged steroid-use dependency and possible radiation-associated damage. Objective responses to treatment were seen in 34% of patients, but these results were not better than those seen at lower doses of hyperfractionated radiotherapy. There is no evidence that radiation to 7800 cGy results in improved survival for patients with diffuse intrinsic brain stem gliomas.

Adolescent↗

PubMed2003

High-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous stem cell transplantation in patients with advanced breast cancer: a retrospective evaluation.

This study was conducted to evaluate the efficacy of high-dose thiotepa, melphalan and carboplatin (TMCb) regimen in 27 patients undergoing autologous stem cell transplantation (ASCT) for metastatic breast cancer. A total of 27 patients with stage IV breast cancer underwent ASCT following thiotepa (500 mg/m(2)), melphalan (100 mg/m(2)) and carboplatin (1200-1350 mg/m(2)). Of 27 patients, 17 had refractory relapse, eight had responding relapse, and two had no evidence of disease (NED) at the time of transplant. In all, 11 patients had only bone disease, nine had bone plus visceral disease, three had only visceral disease, and two had locoregional recurrent disease. The median time from diagnosis to transplant was 1081 days (range 180-2341). Staging for evaluation of response was performed 4-6 months after transplantation. Five patients were not evaluable (NE) for response because of NED at transplant (n=2) or early death due to transplant-related complications (n=3) (two of viral pneumonia and one of regimen-related toxicity) occurring at a median of 4 days (range 11-46) post-transplant. One of the two patients who was NED at the time of transplant is still NED on day 760 post-transplant. Seven of 15 refractory (47%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft-tissue disease with at least improvement in bone lesions. Of 27 patients (37%),(10) are alive and progression-free, a median of 582 days (range 410-1380) after treatment, 6/17 (35%) with refractory disease and 4/10 (40%) with responsive disease. The probability of progression-free survival (PFS) for all patients was 0.50. The probabilities of PFS at 2 years for patients with refractory (n=17) and responsive (n=10) disease were 0.42 and 0.60, respectively. PFS at 2 years for the 14 patients who were NED or achieved CR/PR(*) following-HDC was 0.67. PFS at 2 years for patients who did not achieve CR/PR(*) following-DHC was 0.33. These preliminary data suggest that high-dose TMCb followed by autologous stem cell transplantation is an effective regimen for patients with advanced breast cancer and may be comparable to some previously used regimens.

Adult↗

PubMed1996

High-dose cyclophosphamide, carboplatin, and etoposide with autologous stem cell rescue in patients with breast cancer.

This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy.

Adult↗

PubMed1989

High-dose consolidation therapy with autologous stem cell rescue in stage IV breast cancer.

We designed a phase II study to determine whether induction chemotherapy (CT) consisting of leucovorin, vincristine, methotrexate, doxorubicin, and cyclophosphamide (LOMAC) followed by high-dose intensification chemotherapy (ICT) with cyclophosphamide, thiotepa, and autologous stem cell rescue (ASCR) could increase the complete response (CR) rate and survival in women with stage IV breast cancer. Twenty-nine women were enrolled on study; 16 patients had received prior adjuvant chemotherapy and no patient had received chemotherapy for stage IV disease. Two patients were found to be ineligible and excluded from further analysis. Of the 27 patients treated, four (15%) obtained a CR and 15 (56%) a partial response (PR) after LOMAC induction, for an overall response rate of 70%. Of the 22 patients treated with ICT, 12 patients had a CR, and nine were in PR after induction and converted to CR after ICT. The toxicities included nausea/vomiting, mucositis, diarrhea, dermatitis, alopecia, and infections secondary to neutropenia. The 1-year survival is 60%; the median has not yet been reached. The time to treatment failure for patients on study is 10 months. The treatment approach of ICT and ASCR following induction chemotherapy can lead to an improved CR rate in stage IV breast cancer. How this increased CR rate leads to a prolonged disease-free survival requires further follow-up.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Rebamipide inhibits gastric cancer growth by targeting survivin and Aurora-B.

Rebamipide accelerates healing of gastric ulcers and gastritis but its actions on gastric cancer are not known. Survivin, an anti-apoptosis protein, is overexpressed in stem, progenitor, and cancer cells. In gastric cancer, increased and sustained survivin expression provides survival advantage and facilitates tumor progression and resistance to anti-cancer drugs. Aurora-B kinase is essential for chromosome alignment and mitosis progression but surprisingly its role in gastric cancer has not been explored. We examined in human gastric cancer AGS cells: (1) survivin expression, (2) localization of survivin and Aurora-B, (3) cell proliferation, and (4) effects of specific survivin siRNA and/or rebamipide (free radical scavenging drug) on survivin and Aurora-B expression and cell proliferation. Survivin and Aurora-B are strongly expressed in human AGS gastric cancer cells and co-localize during mitosis. Survivin siRNA significantly reduces AGS cell viability. Rebamipide significantly downregulates in AGS cell survivin expression, its association with Aurora-B and cell proliferation. Rebamipide-induced downregulation of survivin is at the transcription level and does not involve ubiquitin-proteasome pathway.

Alanine↗

PubMed2005

The adult Drosophila posterior midgut is maintained by pluripotent stem cells.

Vertebrate and invertebrate digestive systems show extensive similarities in their development, cellular makeup and genetic control. The Drosophila midgut is typical: enterocytes make up the majority of the intestinal epithelial monolayer, but are interspersed with hormone-producing enteroendocrine cells. Human (and mouse) intestinal cells are continuously replenished by stem cells, the misregulation of which may underlie some common digestive diseases and cancer. In contrast, stem cells have not been described in the intestines of flies, and Drosophila intestinal cells have been thought to be relatively stable. Here we use lineage labelling to show that adult Drosophila posterior midgut cells are continuously replenished by a distinctive population of intestinal stem cells (ISCs). As in vertebrates, ISCs are multipotent, and Notch signalling is required to produce an appropriate fraction of enteroendocrine cells. Notch is also required for the differentiation of ISC daughter cells, a role that has not been addressed in vertebrates. Unlike previously characterized stem cells, which reside in niches containing a specific partner stromal cell, ISCs adjoin only the basement membrane, differentiated enterocytes and their most recent daughters. The identification of Drosophila intestinal stem cells with striking similarities to their vertebrate counterparts will facilitate the genetic analysis of normal and abnormal intestinal function.

Aging↗

PubMed2005

Clinical features of bone metastases resulting from thyroid cancer: a review of 28 patients over a 20-year period.

Bone is the second most frequent site of metastasis resulting from thyroid cancer. Many studies have investigated clinical features and prognostic factors of distant metastases stemming from thyroid cancer in Western countries. The purpose of this study was to review clinical characteristics of Korean patients with bone metastasis originating from thyroid cancer. Between January 1985 and August 2004, 28 patients with thyroid cancer were diagnosed with bone metastases at the Yonsei Severance Hospital in Seoul, Korea. Their clinical characteristics were analyzed retrospectively. Incidence of bone metastasis from follicular thyroid cancer was 6.8% (9 of 132 patients), and 0.4% (13 of 3,154 patients) from papillary thyroid cancer, with an odds ratio of 17.67 (95% confidence interval; 7.41-42). Twelve patients had no symptoms of bone metastasis. Overall mean number of metastasis sites was 2.6 +/- 1.9, and 12 patients had a solitary bone metastasis. Survival rates between the synchronous and metachronous metastasis groups were not significantly different, and the number of metastasis sites did not affect survival. However, the survival of patients that underwent curative treatment was longer than those with palliation (P = 0.0317). In Korea, the overall incidence of bone metastasis resulting from thyroid cancer was less than our expectation. Many patients were asymptomatic, and had a tendency of undergoing less aggressive or palliative treatment, even though the long-term survival of distant metastasis resulting from thyroid cancer with active treatment is relatively good. Further studies of the prognostic factors and effectiveness of various treatments of these patients are needed to enhance survival.

Adenocarcinoma, Follicular↗

PubMed1989

Multifactorial hamster respiratory carcinogenesis with interdependent effects of cannula-induced mucosal wounding, saline, ferric oxide, benzo[a]pyrene and N-methyl-N-nitrosourea.

The carcinogenic response induced in the respiratory tract of Syrian golden hamsters by repeated intratracheal instillations of benzo[a]pyrene (BP) adsorbed to ferric oxide (Fe2O3) particles suspended in saline, is shown to result from the interactions of these factors and cannula-induced tracheal wounding. Previous acute studies of intratracheal cannulation (ITC) versus intralaryngeal cannulation (ILC) showed that tracheal cell proliferation increased significantly in ITC-induced mucosal wounds. Only mild increases in intrapulmonary cell proliferation were produced by Fe2O3-saline given by ILC or ITC (Keenan et al., Cancer Res., 49: 1521-1527, 1989). The present chronic studies included the following variables: a single instillation by ILC of N-methyl-N-nitrosourea (MNU) at 5 weeks of age; 15 weekly treatments (beginning at 7 weeks of age) by ILC or ITC alone, or with instillations of saline, or Fe2O3-saline, or BP-Fe2O3-saline; and appropriate controls. Repeated ITC-induced tracheal wounds caused persistent tracheal epithelial hyperplasia, metaplasia and/or atrophy and submucosal fibroplasia during the observation period of 22 to 78 weeks of age (the time of terminal sacrifice). Tracheal cancers (in situ or invasive carcinomas) were seen only in those hamsters which had received repeated ITC and one or both carcinogens. The cancer latency was shortest and the incidence of tracheal (50%) and main-stem bronchial (21%) cancers highest in hamsters given MNU and repeated ITC with BP-Fe2O3-saline. Hamsters given carcinogens by ILC (which induced laryngeal but not tracheal wounds) developed proliferative lesions and cancers of the larynx but no tracheobronchial cancers. These data show the singular importance of repeated ITC-induced intratracheal wounding as an enhancing factor in this respiratory carcinogenesis model. The findings suggest that the mechanism of tumor enhancement involves not only changes in target epithelial cell proliferation, but also alterations in normal epithelial-mesenchymal interactions during tracheal regeneration from repeated chronic submucosal inflammation and mesenchymal repair. In the present experimental model, a single dose of MNU at 5 weeks of age, repeated instilled doses of BP, and tracheal mucosal wounding were each found to be important determinants of the carcinogenic response. Additional effects were observed for instilled Fe2O3 particles, and possibly saline. Interplay of all these factors, as well as of genetic, nutritional, and infectious factors, are considered in relation to risk assessment and prevention.

Animals↗

PubMed2002

Reconstitution of naïve T cells and type 1 function after autologous peripheral stem cell transplantation: impact on the relapse of original cancer.

BACKGROUND: Phenotypic and functional reconstitution of T cells after peripheral blood stem cell transplantation (PBSCT) and its influence on posttransplant immune status is important in terms of immune surveillance and relapse of original cancer. We investigated the relationship between the dominant immune reconstitution pathway and the immune surveillance. We also tested the cytokine bias acquired by T cells after transplantation and its possible influence on relapse of original malignancy. METHODS: Immunophenotyping of naïve and memory T cells was performed by flow cytometry on patients who underwent PBSCT for various cancers. Cytokine production by peripheral memory helper (CD4) and cytotoxic (CD8) T cells was investigated at various pretransplant and posttransplant time points with fluorescein isothiocyanate-based intracellular cytokine assay after short-term in vitro mitogenic stimulation (phorbol myristate acetate + ionomycin). Data on T-cell subsets and polarized cytokines gamma-interferon (Ifn) and interleukin 4 produced by memory T cells were compared with that of healthy controls. RESULTS: The reconstitution of naïve T cells and gamma-Ifn-producing memory cells was significantly lower in patients who experienced relapse of original cancer within 1 year of PBSCT compared to those who showed no signs of relapse even after 2 years and compared to normal subjects. The results indicate that efficient reconstitution of naïve T cells and type 1 function of memory T cells are important in maintaining T-cell repertoire diversity after PBSCT. It also confers appropriate levels of immune surveillance against diverse neoantigens that evolve from residual tumor burden. The data reveal that chemotherapy-induced thymic injuries may impair regeneration of naïve cells that result in a naivopenic state in a susceptible host. CONCLUSIONS: The study highlights the importance of naïve T-cell reconstitution and points towards cell replacement strategies for improving immune surveillance after PBSCT.

Adult↗

PubMed2004

Microsatellite instability predicts poor short-term survival in patients with advanced breast cancer after high-dose chemotherapy and autologous stem-cell transplantation.

PURPOSE: The purpose is to define molecular prognostic factors in patients with advanced breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). EXPERIMENTAL DESIGN: Thirty-nine patients with breast cancer and extensive lymph node (level III) and/or systemic metastases from a prospective single-center study of sequential HDCT/ASCT were studied. Microsatellite analysis was performed after laser microdissection using 15 markers selected for sensitive detection of microsatellite instability (MSI) in breast cancer. Exons 5-9 of the P53 gene were directly sequenced. Expression of P53, HER-2/neu, and the mismatch repair proteins hMSH2 and hMLH1 was evaluated by immunohistochemistry. RESULTS: MSI of at least three markers was detected in 13 of 39 patients (33%) and was predominantly found at tetranucleotide markers. All MSI-positive tumors showed normal expression of hMSH2 and hMLH1. Complete sequence analysis of exons 5-9 of the P53 gene was successful in 34 cases; 18% (n = 6) revealed a mutation. Overexpression of HER-2/neu and P53 was observed in 7 (22%) and 12 (46%) of 26 evaluated cases, respectively. The presence of MSI strongly correlated with shorter overall survival (OS; P = 0.0004) and progression-free survival (PFS; P = 0.02). None of the other investigated clinical or molecular factors correlated with OS in univariate analyses, with the exception of menopausal status and previous adjuvant chemotherapy. Testing various multivariate Cox regression models, MSI remained a highly significant, independent, and adverse risk factor for OS. CONCLUSIONS: MSI is frequent in advanced breast cancer and could be an indicator of chemotherapy resistance and poor prognosis in breast cancer patients treated with HDCT/ASCT.

Adult↗

PubMed2004

A prostate stem cell antigen-derived peptide immunogenic in HLA-A24- prostate cancer patients.

BACKGROUND: We attempted to identify prostate stem cell antigen (PSCA)-derived peptides immunogenic in HLA-A24+ prostate cancer patients. METHODS: Peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with each of three different PSCA-derived peptides, which were prepared based on the HLA-A24 binding motif, and their peptide-specific and HLA-A24-restricted anti-tumor responses were examined. Plasma levels of immunoglobulin G (IgG) against PSCA peptides were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Among three PSCA peptides, the PSCA 76-84 peptide most effectively induced peptide-specific cytotoxic T lymphocytes (CTLs) from PBMCs of HLA-A24+ prostate cancer patients. Cytotoxicity was dependent on peptide-specific and CD8+ T cells. The PSCA 76-84 peptide-stimulated PBMCs showed a significant level of cytotoxicity against prostate cancer cells in an HLA-A24-restricted manner. IgG reactive to the PSCA 76-84 peptide was detected in half of patients. CONCLUSIONS: The PSCA 76-84 peptide should be considered for use in clinical trials of immunotherapy for HLA-A24+ patients.

Antigens, Neoplasm↗

PubMed2006

Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation.

Immunotherapies using cancer-testis (CT) antigens as targets represent a potentially useful treatment in patients with multiple myeloma (MM) who commonly show recurrent disease following chemotherapy. We analyzed the expression of 11 CT antigens in bone marrow samples from patients with MM (n=55) and healthy donors (n=32) using reverse transcriptase-polymerase chain reaction (RT-PCR). CT antigens were frequently expressed in MM with 56% (MAGEC2), 55% (MAGEA3), 35% (SSX1), 20% (SSX4, SSX5), 16% (SSX2), 15% (BAGE), 7% (NY-ESO-1), and 6% (ADAM2, LIPI) expressing the given antigen. Importantly, CT antigens were not expressed in healthy bone marrow. Analyzing patients with MM (n=66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT). Antibody responses against NY-ESO-1 correlated with NY-ESO-1-specific CD4+ and CD8+ T-cell responses against peptide NY-ESO-1(51-62) and CD4+ responses against NY-ESO-1(121-140) in 1 of these patients. These allogeneic immune responses were not detectable in pretransplantation samples and in the patients' stem cell donors, indicating that CT antigens might indeed represent natural targets for graft-versus-myeloma effects. Immune responses induced by alloSCT could be boosted by active CT antigen-specific immunotherapy, which might help to achieve long-lasting remissions in patients with MM.

Antibodies, Neoplasm↗

PubMed2006

Stem cells and Helicobacter-induced gastric cancer: where do we stand at the end of 2006.

The process of carcinogenesis, which may well extend over decades, provides an excellent opportunity for early detection and intervention to prevent development of gastric cancer. Evidence supporting a causal association between such tumour and Helicobacter infection has been demonstrated by epidemiological data, ecologic studies and, in experimental animal models. Lately, an increasing amount of evidences point out to bone marrow stem cells (BMSC) as target of neoplastic transformation. The term BMSC includes a heterogenous group of cells that both in vivo and in vitro studies, have shown to have plasticity, with their ability to acquire features of mesoderm, ectoderm and endoderm. In the gastric setting, a recent experiment in C57BL/6 mice has permitted to show that BMSC are the cell of origin of Helicobacter-induced gastric cancer. Based on these results, a model for epithelial cancer by which chronic inflammation leads to tissue injury and with time, to tissue stem cell failure, has been proposed. This phenomenon would induce the recruitment and engraftment of BMSC into the tissue stem cell niche. During differentiation, BMSC fail to regulate growth programme appropriately and progress through stages of metaplasia and dysplasia. Due to several reasons, in humans, data are conflicting. Further studies may shed light on the molecular bases of gastric lesions, leading to the development of preventive strategies.

Animals↗

PubMed2000

A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle.

Multi-cycle high-dose chemotherapy with autologous stem cell support (HDC-ASCS) may improve the results obtained with single-cycle HDC-ASCS in metastatic breast cancer (MBC). However, the tolerability and efficacy of additional cycles of HDC-ASCS in patients selected using standard eligibility criteria for single cycle HDC-ASCS is uncertain. Twenty-nine patients with MBC and a CR or PR to induction chemotherapy were selected by standard institutional eligibility criteria for single-cycle HDC-ASCS. Cycle 1 HDC-ASCS (cyclophosphamide 6 g/m2; mitoxantrone 70 mg/m2; carboplatin 800 mg/m2) was followed by a planned second cycle (etoposide 1.6 g/m2; thiotepa 800 mg/m2; carboplatin 800 mg/m2 modulated by tamoxifen 120 mg/m2/day x 5 days) with a median interval of 3.2 months. CR rate was 20% after induction chemotherapy and 33% and 54% after HDC cycles I and II, respectively. Sixteen patients (55%) failed to complete HDC cycle II within 200 days because of disease progression, toxicity, inadequate stem cell collection, insurance denials or patient choice. Median progression-free survival (PFS) for all 29 patients entered is 301 days from date of HDC cycle I and actuarial PFS at 2 years is 35%. For the 13 patients who received the two cycles of HDC-ASCS, actuarial PFS at 2 years was 54% (P = NS compared to those receiving only one cycle). These data show that a second cycle of full-dose intensity HDC-ASCS may increase the proportion of patients with MBC that achieve CR and may increase PFS. However, a large proportion of patients that complete HDC-ASCS cycle I may fail to proceed to cycle II in a timely fashion. Bone Marrow Transplantation (2000) 25, 519-524.

Adult↗

PubMed2002

The impact of induction duration and the number of high-dose cycles on the long-term survival of women with metastatic breast cancer treated with high-dose chemotherapy with stem cell rescue: an analysis of sequential phase I/II trials from the Dana-Farber/Beth Israel STAMP program.

Although high-dose chemotherapy (HDC) with stem cell rescue for the treatment of women with metastatic breast cancer (MBC) is currently a controversial strategy, we report the long-term outcomes of women undergoing high-dose therapy for MBC over the past 12 years while participating in a sequence of research studies transitioning between a single to a double intensification approach. Univariate and multivariate analyses provide a framework to understand the prognostic factors important for event-free and overall survival. Between May 1988 and April 1998, we enrolled 188 women with MBC into 3 trials of previously reported sequential transplantation strategies. Trial I (long induction/single transplantation) accepted 62 women in partial or complete response to an unspecified induction therapy and treated them with high-dose CTCb (cyclophosphamide, thiotepa, and carboplatin) supported by marrow or peripheral blood progenitor cells (PBPC). Trial II (long induction/double transplantation) accepted 68 women in partial or complete response to an unspecified induction therapy, and mobilized stem cells with 2 cycles of AF (doxorubicin and 5-fluorouracil) with granulocyte colony-stimulating factor (G-CSF). These women then received 1 cycle of high-dose single-agent melphalan followed 3 to 5 weeks later by CTCb, each with marrow or PBPC support. Trial III (short induction/double transplantation) enrolled 58 women prior to chemotherapy treatment for metastatic disease. Induction/mobilization consisted of 2 cycles given 14 days apart of doxorubicin and G-CSF. In contrast to trials I and II, patients with stable disease or better response to induction were eligible to proceed ahead with 2 cycles of HDC, 1 being CTCb and the other being dose escalated paclitaxel together with high-dose melphalan (TxM). These 2 HDC regimens were administered 5 weeks apart. TxM was given first in 32 patients and CTCb was given first in 26 patients. The median follow-up periods for trials I, II, and III were 98, 62, and 39 months from the initiation of induction chemotherapy and 92, 55, and 36 months from last high-dose therapy, respectively. The patient characteristics upon entry into these trials were similar. Important differences were that only those patients achieving a partial response or better to induction therapy were enrolled and analyzed for trials I and II, but all patients were analyzed on an intent-to-treat basis for trial III, including those who did not receive intensification. The median event-free survival (EFS) times from induction chemotherapy were 13, 19, and 27 months for trials I, II, and III, respectively (III versus I + II, P = .0004; III versus I, P = .0005; III versus II, P = .005; II versus I, P = .25). The median overall survival (OS) times from induction chemotherapy were 30, 29, and 57 months for trials I, II, and III, respectively (III versus I + II, P = .002; III versus I, P = .003; III versus II, P = .009; II versus I, P = .47). By multivariate Cox regression, participation in the short induction/double transplantation trial III and having no prior adjuvant chemotherapy remained favorable prognostic factors for both EFS and OS. The presence of visceral disease shortened EFS, and hormone sensitivity was of borderline significance. No substantive differences in the characteristics of the patient populations between the 3 trials appeared to interact with outcomes. In conclusion, we found that single transplantation in responding patients after long induction achieves a small cohort of long-term survivors, similar to the results reported by other transplantation centers. Adding a cycle of single-agent high-dose melphalan in this context delayed median time to relapse but did not affect long-term EFS or OS. The double transplantation approach using CTCb and TxM early in the course of treatment was associated with the best EFS and overall survival and was safe, feasible, and tolerable. Treatment duration was only 14 weeks, and this treatment option eliminated lengthy induction chemotherapy. Although selection biases may have in part contributed to this effect, a randomized comparison of standard therapy versus short induction/double transplantation is warranted.

Adult↗

PubMed1998

Power-frequency fields and cancer.

There is a widespread public perception that exposure to "EMF" is linked to cancer. This concern stems largely from a few epidemiological studies that appear to show an association between cancer and residence near power lines. However, the epidemiological evidence for such a link falls far short of that needed to conclude that a causal relationship exists, and examination of the biophysics leads to the conclusion that biological effects are implausible at the field strengths encountered in environmental settings. In a case such as this, where the epidemiological evidence for a link between an agent and a disease is weak to nonexistent and the effect is biophysically and/or biochemically implausible, laboratory evidence becomes critical for risk evaluation. The mechanisms of carcinogenesis are sufficiently well established that laboratory studies can be used to assess whether an agent has carcinogenic potential. There are approximately 100 published reports that have looked for evidence that power-frequency fields have genotoxic or epigenetic activity. These studies have found no replicated evidence that power-frequency fields have the potential to either cause or contribute to cancer. Of the few studies that have shown some evidence for carcinogenic activity, most have used exposure conditions with little relevance to real world exposure, none have been replicated, and many have failed direct attempts at replication. In conjunction with the epidemiology and biophysics, this leads to the conclusion that a causal association between power-frequency fields and cancer is not only unproven, but rather unlikely.

Animals↗