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PubMed1998

Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells.

Bcl-2 and a Bcl-2-binding protein BAG-1 function in protection from apoptosis induced by a variety of stimuli. Deregulated expression of Bcl-2 leads to inhibition of apoptosis and is correlated with development of various cancers. Here, we provide evidence that prolonged cell survival introduced by overproduction of Bcl-2 or BAG-1 strongly enhances peritoneal dissemination of human gastric cancer MKN74 cells. Gene transfer-mediated overexpression of Bcl-2 or BAG-1 led to prolonged cell survival of MKN74 cells against serum-starved apoptosis and anoikis. When the viable transfectants were inoculated into the intraperitoneal cavity of BALB/c nude mice, the Bcl-2-expressing MKN74 cells and the BAG-1-expressing MKN74 cells exhibited strongly enhanced peritoneal dissemination in BALB/c nude mice and whole disseminated tumor weights were increased by 4-fold and 3.3-fold, respectively, compared with the control transfectants. The enhanced peritoneal dissemination of MKN74-Bcl-2 and MKN74-BAG-1 transfectants correlated well with resistance to cell death induced by serum-starvation and anoikis. However, the overexpression of Bcl-2 or BAG-1 caused no significant difference among the transfectants in cell growth rates, either in vitro or in vivo. Taken together, these studies demonstrate that resistance to apoptosis is a crucial factor for development of peritoneal dissemination of human gastric cancer cells.

Adenocarcinoma↗

PubMed1996

Defective antigen processing associated with familial disseminated mycobacteriosis.

To gain insights into a possible immune defect predisposing to disseminated mycobacteria infection, we studied three of six surviving children with disseminated Mycobacterium avium complex infection, who had no recognized form of immunodeficiency. We used mycobacteria isolated from the patients and diphtheria, tetanus and pertussis vaccine (DTP) to study antigen-specific T lymphocyte responses. We observed that interferon-gamma (IFN-gamma) production by T cells in response to antigens (both mycobacteria and DTP) in these patients with disseminated infection was greatly impaired. This defect did not seem to be the result of T cell unresponsiveness, as phytohaemagglutinin (PHA) stimulation was able to induce high levels of IFN-gamma comparable to those seen in control patients with localized infection. Further experiments showed that peripheral blood mononuclear cells (PBMC) from patients with disseminated infection were able to present influenza haemagglutinin (HA) peptides to specific T cell clones. However, this ability was lost when the whole HA protein was used as source of antigen. Taken together, these observations support the notion that the primary immune defect in these patients with disseminated mycobacterial infection rests in the antigen-processing functions of their antigen-presenting cells (APC). These findings may provide clues to the wider problem of susceptibility to mycobacteria and other intracellular pathogens and have implications in designing therapy for these patients.

Antigen Presentation↗

PubMed2003

Antigenic profiles of disseminated breast tumour cells and microenvironment in bone marrow.

AIMS: Thirty per cent of breast cancer patients with axillary lymph node negative at primary surgery will relapse within 10 years. This may be caused by disseminated tumour cells from the primary tumour. This study report the phenotypic profiles of disseminated tumour cells and microenvironmental characteristics in bone marrow of breast cancer. METHODS: We detected the biologic markers on the disseminated tumour cells with immunocytochemical staining, analysed the immunological changes through flow-cytometry, and investigated the u- PA activity in the plasma of bone marrow. RESULTS: With the immunocytochemical staining of EMA and CK19, we detected micrometastasis in thirty out of 72 (41.67%) breast cancer patients. Compared with the primary tumours, disseminated tumour cells expressed low protein cyclin D1, P53, Ki-67, EGFR, and high protein P21. The percentage of memory CD4+ T cells was significantly higher in the micrometastasis-positive group than in the micrometastasis-negative group. Tumour size and axillary lymph node status were found to be significantly correlated with the u- PA activity level. CONCLUSIONS: Immunophenotypic profiles of disseminated tumour cells could be measured by immunocytochemical staining and microenvironment can be analysed by flow cytometry.

Adult↗

PubMed2001

Detection of craniospinal dissemination of intracranial germ cell tumours based on serum and cerebrospinal fluid levels of tumour markers.

Nineteen intracranial germ cell tumours treated during the past 11 years were evaluated retrospectively. The tumours were classified into three groups according to the level of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (HCG) in serum and cerebrospinal fluid, and the optimal treatment for each group was determined. Group A consisted of patients with normal titres of AFP and HCG, group B of patients with relatively high titres (< 10 times normal), and group C comprised patients with higher titres ( 10 times normal levels). In group A, an appropriate field and dose of irradiation was necessary to prevent craniospinal dissemination. In group B, none of four patients who underwent total or subtotal resection of the tumour had craniospinal disseminatio n or tumour recurrence, whereas dissemination occurred in four further patients, including two who had received radiochemotherapy only, and two who had undergone partial resection of the tumour. While patients in group C had dissemination at the time of initial diagnosis, most patients in group B developed dissemination more than 10 months after initial treatment, suggesting that the type of treatment received as first line therapy is important in patients in this group. The prognosis of patients in group C, however, was unaffected by the priority given to either surgery, radiation or chemotherapy as first line treatment. Craniospinal dissemination can be prevented in patients with germ cell tumours who have a relative increase in levels of AFP and HCG by aggressive removal of the tumours as first line therapy, regardless of the type of adjuvant therapy given.

Adolescent↗

PubMed2002

Multiresistant clones of Salmonella enterica: The importance of dissemination.

Increasing anitmicrobial resistance among foodborne pathogens has prompted calls for the reduction of anitmicrobial use in livestock to prevent future emergence or resistance. In the case of Salmonella enterica, clonal dissemination may play a more critical role in regional changes in antimicrobial resistance in Salmonellae than antimicrobial selection pressure. Multi-resistant Salmonella Typhimurium definitive type 104 (mr-DT104) emerged from an unknown location and was disseminated globally during the 1980s and 1990s. Other clones of Salmonella Typhimurium and non-Typhimurium Salmonellae have demonstrated an ability to disseminate widely. The clonal epidemiology of mr-DT104 is in contrast with that of Campylobacter jejuni, in which antimicrobial resistance is polyclonal and seems to develop in response to local antimicrobial pressures. The epidemiology of mr-DT104 is more similar to that of methicillin resistant Staphylococcus aureus, which is also characterized by international transmission of a few clonal subtypes. Control measures for multiresistant disseminated clones of Salmonellae must focus on the interruption of dissemination in order to be effective.

Animals↗

PubMed2005

Detection of disseminated tumor cells in peripheral blood.

Metastases are the major cause of cancer-related deaths in patients with solid epithelial malignancies, such as breast, colorectal and prostate carcinomas. Hematogenous spreading of tumor cells from a primary tumor can be considered as a crucial step in the metastasis cascade leading eventually to the formation of clinically manifest metastases. Consequently, as shown in recent studies, the detection of disseminated tumor cells in peripheral blood might be of clinical relevance with respect to individual patient prognosis and staging or monitoring of therapy. However, the rarity of disseminated tumor cells in peripheral blood renders the application of sensitive techniques mandatory for their detection. The emergence of highly sophisticated reverse transciptase-polymerase chain reaction (RT-PCR) assays, combining a preanalytical enrichment step with the assessment of multiple molecular tumor markers expressed in disseminated tumor cells, provides a powerful tool in detecting disseminated tumor cells with high sensitivity and specificity. This review will discuss currently used tumor markers as well as experimental means to enhance the sensitivity and specificity of RT-PCR assays to detect disseminated tumor cells in the peripheral blood of patients with breast, colorectal, and prostate cancers, and their clinical relevance assessed in recent studies.

Animals↗

PubMed2006

Yersinia pseudotuberculosis disseminates directly from a replicating bacterial pool in the intestine.

Dissemination of Yersinia pseudotuberculosis within mice after oral inoculation was analyzed. Y. pseudotuberculosis translocated to organs such as the liver and spleen shortly after oral inoculation, but was quickly cleared. In contrast, a second temporally distinct bacterial translocation event resulted in successful hepatosplenic replication of the bacteria. Replicating pools of bacteria could be established in these organs in mouse mutants that lacked Peyer's patches. These animals frequently had sterile mesenteric lymph nodes, a finding consistent with translocation taking place independently of regional lymph node colonization. In further contradiction to accepted models for dissemination of enteropathogens, clonal analysis revealed that bacteria causing disease in the spleen and liver of C57BL/6J mice were derived from populations located outside the intestinal lymph nodes. Replication of bacteria in the intestine before translocation appeared critical for dissemination, as transient selective suppression by streptomycin of bacterial growth in the intestine delayed dissemination of Y. pseudotuberculosis. These results collectively indicate that hepatosplenic colonization appears intimately connected with the ability of Y. pseudotuberculosis to successfully establish replication in the intestinal lumen and does not result from ordered spread leading from the intestine to regional lymph nodes before dissemination.

Animals↗

PubMed2002

Discontinuation of secondary prophylaxis against disseminated Mycobacterium avium complex infection and toxoplasmic encephalitis.

We retrospectively studied outcomes for patients infected with human immunodeficiency virus who received highly active antiretroviral therapy (HAART) and had stopped receiving secondary prophylaxis against toxoplasmic encephalitis (TE) or disseminated Mycobacterium avium complex (MAC) infection. Nineteen patients had a history of TE, and 26 had a history of disseminated MAC infection. The median duration of secondary prophylaxis was 27 months, and the median duration of HAART before discontinuation of secondary prophylaxis was 22 months. Median CD4(+) cell counts at the time of cessation of secondary prophylaxis against TE or disseminated MAC infection were 404 and 105 cells/mm(3), respectively. Plasma virus load was undetectable in 68% of the patients who had a history of TE and in 31% of patients who had a history of disseminated MAC infection. Patients were followed up for a median of 29 months after discontinuation of secondary prophylaxis; no relapses occurred in patients with a history of TE, and 3 relapses occurred in patients with a history of disseminated MAC infection (incidence, 4 relapses per 100 person-years).

AIDS-Related Opportunistic Infections↗

PubMed1999

Development of novel cationic liposomes for efficient gene transfer into peritoneal disseminated tumor.

A novel series of cationic lipids has been found, by in vivo screening, to be effective for gene transfer into peritoneal disseminated tumor. O,O'-Ditetradecanoyl-N-(alpha-trimethylammonioacetyl)diethan olamine chloride (DC-6-14), having dimyristyl acid, has shown the highest transfection activity in vitro, provided that 10% fetal bovine serum is present. To enhance the transfection efficiency of DC-6-14, we added dioleoylphosphatidylethanolamine (DOPE) and/or cholesterol (Chol) as helper lipids in various ratios. Cationic liposomes containing DC-6-14, DOPE, and Chol in molar ratios of 1:0.75:0.75 and 1:1:0.8 maintained efficient transfection activity under serum-containing conditions in HRA, mEIIL, and ES-2 cell lines in vitro, as determined by luciferase assay. With our novel liposomes, transfection efficiencies were higher in cells proliferating faster than in cells proliferating slower, depending on mitotic activity as represented by labeling index. In the mEIIL peritoneal disseminated tumor model, cancer cells were specifically transfected with the lacZ gene. Gene transfer was observed by X-Gal staining not only in floating cancer cells in the ascites, but also in the peritoneal disseminated cancer tissue. The percentage of LacZ-positive cells was about 1%, which was significantly higher than with commercially available Lipofectin (0.38%), LipofectACE (0.62%), or LipofectAMINE (0.23%). In the mEIIL peritoneal disseminated tumor-nude mouse model, herpes simplex thymidine kinase gene (HSV tk) transfer with our novel liposomes, followed by ganciclovir (GCV) treatment, resulted in significantly longer survival compared with control mice (p < 0.05, Cox-Mantel). These results suggest that these liposomes show promise as tools in gene therapy for patients with intraperitoneal disseminated cancer.

Animals↗

PubMed2001

Urokinase-like plasminogen activator receptor expression on disseminated breast cancer cells.

Disseminated tumor cells are detected frequently in bone marrow, peripheral blood, and cytokine-mobilized peripheral blood cell products of women undergoing high-dose therapy for breast cancer. Several attempts were made to purge autografts from contaminating cancer cells; however, the biological and clinical impact of these contaminations has not been clarified so far. Expression of distinct phenotypes is a surrogate marker for metastatic behavior of cancer cells. The expression of the urokinase-like plasminogen activator receptor seems to be a factor of high importance. It is not expressed by normal mammary tissue. Disseminated cancer cells from marrow, blood, and stem cell products have been investigated by double-stain technique for urokinase-like plasminogen activator receptor (uPA-R) expressing cytokeratin-positive cells. uPA-R(+)/CK(+) cells could be found in all qualities of samples; however, significantly less in G-CSF-mobilized peripheral blood stem cells compared to samples of other provenance (p = 0.02). It can be concluded that epithelial cells of malignant phenotype occur in blood, marrow, and autografts of breast cancer patients. Populations of disseminated tumor cells are phenotypically heterogeneous. Reduced uPA-R expression on cancer cells from leukapheresis samples might suggest a less aggressive nature of these cells compared to disseminated cells found in bone marrow. Furthermore, the data suggest that the phenotype of tumor cell contamination in leukapheresis products differs significantly from those of disseminated cancer cells in bone marrow or blood.

Blood Cells↗

PubMed1996

New trends in the drug therapy of localized and disseminated Mycobacterium avium complex infection.

Recent advances in the drug therapy of localized and disseminated infection with Mycobacterium avium complex (MAC) are reviewed. MAC infection is the most commonly reported bacterial infection in patients with AIDS, and the frequency of this infection in patients negative for the human immunodeficiency virus (HIV) is increasing. The main portals of entry for MAC are the gastrointestinal and respiratory tracts. Localized MAC infection is more common in HIV-negative than HIV-infected patients. The symptoms of disseminated MAC disease are those typical of advanced HIV disease. The most reliable diagnosis is provided by blood cultures; radiometric culturing techniques are favored. The overall treatment of MAC infection has improved greatly with the introduction of new agents during the past 15 years; survival time has been extended. Clarithromycin and azithromycin have proven effective against both localized and disseminated MAC infection. Clarithromycin is the cornerstone of therapy for disseminated infection. Ciprofloxacin has been successfully used to treat disseminated infection as part of a four-drug regimen including rifampin, ethambutol, and clofazimine. Rifabutin has substantial efficacy when combined with other agents. Liposomal aminoglycosides, such as amikacin, and interferon gamma have shown some initial promise. Rifabutin is currently recommended for the prevention of MAC disease in HIV-infected patients. Clarithromycin and azithromycin have also shown efficacy for prophylaxis, and fluoroquinolones may play a preventive role as well. New drug therapies are improving the outlook for persons infected with MAC.

AIDS-Related Opportunistic Infections↗

PubMed1994

Disseminated growth of Hodgkin's-derived cell lines L540 and L540cy in immune-deficient SCID mice.

Local tumor growth has been reported after subcutaneous and intraperitoneal injection of Hodgkin's disease (HD) derived cell lines into different immunodeficient mouse strains. An animal model with disseminated growth of tumor cells would be useful for studying the in vivo biology of HD cells as well as for preclinical testing of new therapeutic regimens. For this purpose the HD-derived cell lines L540, L540cy, L428, and KM-H2 were injected intravenously into SCID mice. In contrast to L428 and KM-H2, widespread neoplasia occurred after a period of four to six weeks following injection of L540 and the subline L540cy. Lymph nodes were found to be the preferred site of tumor growth. CD30 surface antigen expression on Hodgkin cells and the karyotype of the tumor cells were preserved in the animal host. Thus, to a large extent, the SCID mouse model mimics the dissemination pattern of Hodgkin's disease in man. To evaluate the role of adhesion molecule expression in the dissemination of HD-derived cell lines, CD44 and members of the immunoglobulin, integrin, selectin, and Fc receptor families were quantified by flow cytometry. CD30 expression was also measured. Although CD44 expression has been correlated with dissemination in non-Hodgkin's lymphoma (NHL), this was not the case in the Hodgkin's SCID mouse model. CD44 was not expressed on the disseminating cell lines L540 and L540cy but was expressed in the nondisseminating lines L428 and KM-H2.

Animals↗

PubMedDate not supplied

Disseminated fusarial infection in the immunocompromised host.

A report of the species Fusarium proliferatum causing systemic infection in a child with acute lymphoblastic leukemia is presented, with a review of the clinical and laboratory features relating to outcome in disseminated fusarial infections. Thirteen cases of disseminated infection due to Fusarium species have been reported, all but one of which were fatal. Hematologic malignancy is the commonest underlying illness. The frequent occurrence of multiple skin lesions, orbitofacial involvement, and fungemia is in contrast to the otherwise similar disseminated aspergillosis or mucormycosis. Fungemia in disseminated fusariosis may reflect a capacity for invasion of intravascular catheters by Fusarium species. Fusarium isolates from disseminated infections are variably sensitive to amphotericin B, ketoconazole, and miconazole and uniformly resistant to 5-fluorocytosine. The correlation between antifungal susceptibility status and clinical outcome is poor, reflecting problems in susceptibility testing, marginally effective chemotherapy, and serious impairment of host defenses. Attention to early diagnosis and the care of indwelling prosthetic devices may enhance survival until more effective chemotherapy is available.

Child↗

PubMed1995

Preventing disseminated Mycobacterium avium complex disease in patients infected with human immunodeficiency virus.

Disseminated Mycobacterium avium complex (MAC) infection is an important late-stage complication of infection with the human immunodeficiency virus. Since MAC is widely dispersed in the environment, the source of infection for patients with disseminated MAC generally cannot be determined. Therefore, specific recommendations for avoiding exposure are not supported at this time. Routine screening of stools and sputum to detect MAC colonization as a means of targeting prophylaxis for disseminated disease is also not recommended at present. Two randomized, placebo-controlled trials have demonstrated that prophylactic use of rifabutin in persons with low CD4 lymphocyte counts results in a 50% decrease in MAC bacteremia as well as a reduction in some signs, symptoms, and laboratory abnormalities associated with MAC disease. Thus a prophylactic daily dose of rifabutin (300 mg) should be considered for adults who have had a previous AIDS-defining opportunistic illness and who have a CD4 lymphocyte count of < 75/microL. Many experts would consider prophylaxis appropriate only when the CD4 lymphocyte count is < 50/microL, particularly when there has not been a previous AIDS-defining opportunistic infection. Clinicians should be aware of drug interactions and potential adverse effects associated with the use of rifabutin. Preliminary reports of randomized, placebo-controlled trials suggest that chemoprophylaxis with clarithromycin is also effective in the prevention of disseminated MAC disease, and evaluation of other agents is under way. Prophylaxis for disseminated MAC infection in children has not been evaluated but is presumed to be as effective as that in adults. Decisions regarding initiation of MAC chemoprophylaxis should be individualized.

AIDS-Related Opportunistic Infections↗

PubMed2006

System-wide adoption of health promotion practices by schools: evaluation of a telephone and mail-based dissemination strategy in Australia.

Schools can potentially benefit from system-wide approaches to the dissemination of health promotion practices. This intervention study undertaken in the Hunter Region of NSW, Australia, used a pre-post design to assess whether a phone and mail intervention dissemination strategy was associated with an increase in the proportion of 218 primary schools undertaking eight health promotion practices. Health promotion practices addressed the prevention of harm associated with five agreed health issues-smoking, nutrition, playground safety, asthma and infectious diseases. The study also assessed acceptability of the dissemination strategy to schools, cost and whether intervention schools' characteristics were associated with uptake of health promotion practices. Compared to baseline a significant improvement in prevalence was observed at both 1 and 2 year follow-up for seven of the eight health promotion practices addressed. The greatest improvement occurred in the first year of the project. There was a greater uptake of the practice of providing information regarding passive smoking in urban schools. The dissemination strategy was found to have a cost per adopted practice of 121 Australian dollars and to be acceptable to the large majority (>90%) of schools. The results suggest that the dissemination strategy may represent a relatively low cost method of enhancing health promotion practices in schools and of monitoring such practices. Further research addressing the methodological issues of this study is needed to confirm these findings.

Australia↗

PubMed1996

Disseminated Mycobacterium avium complex infection in AIDS: immunopathogenic significance of an activated tumor necrosis factor system and depressed serum levels of 1,25 dihydroxyvitamin D.

Disseminated Mycobacterium avium complex (MAC) infection is associated with considerable morbidity and mortality in patients with AIDS. Because both tumor necrosis factor-alpha (TNF-alpha) and 1,25-dihydroxyvitamin D3 (1,25D) may be involved in the normal control of MAC infection, these parameters were studied in AIDS patients with disseminated MAC infection. Of 53 AIDS patients studied, 24 had no clinical events, 11 had disseminated MAC infection, and 18 had other clinical events. Patients with disseminated MAC infection had significantly higher serum levels of both TNF-alpha and soluble TNF receptors compared with other AIDS patients; almost half of the MAC-infected patients had TNF bioactivity in serum. MAC-infected patients also had severely decreased serum 1,25D levels compared with all other AIDS patients. The activation of the TNF system was significantly correlated with the degree of 1,25D deficiency. These findings may reflect interaction between vitamin D and the TNF system in the pathophysiology of disseminated MAC infection in AIDS.

AIDS-Related Opportunistic Infections↗

PubMed2000

Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E. coli overgrowth are reduced by ornithine alpha-ketoglutarate administration.

The efficacy of ornithine alpha-ketoglutarate (OKG) in preventing bacterial translocation and dissemination, metabolic disorders and changes in mucosal enzyme activities was assessed in a model of bacterial translocation in rats. Antibiotic decontamination was performed 4 d before intragastric inoculation with an Escherichia coli strain (10(10) bacteria/kg body). Two days later, the rats were given either a lipopolysaccharide (LPS) 0127:B8 or a saline injection and were deprived of food for 24 h. Enteral nutrition, [Osmolite, 880 kJ/(kg. d)] supplemented with either OKG (LPS + OKG) or glycine (Saline + Gly or LPS + Gly), was then given for 2 d. Urinary total nitrogen losses and 3-methylhistidine excretion were determined daily. On killing at d 3, bacterial translocation to the mesenteric lymph nodes (MLN) and dissemination to the spleen and liver were evaluated, jejunal mucosa enzyme activities were assayed and tissue free amino acids in muscles were measured. Endotoxin induced translocation from the gut lumen to the MLN in all groups, whereas dissemination occurred only in LPS-treated rats. OKG significantly reduced dissemination of the bacteria in the spleen. 3-Methylhistidine excretion was greater in the LPS + Gly group (+25%, P: < 0.05) than in either the LPS + OKG or Saline + Gly group. The group fed the OKG-enriched diet had higher muscular glutamine, ornithine and arginine concentrations than did the Gly-supplemented groups (P: < 0.05). Intestinal sucrase and aminopeptidase activities were higher in the LPS + OKG group than in the LPS + Gly group (-30%, P: < 0.05). OKG supplementation limits bacterial dissemination and metabolic changes after injury in rats and thus may be useful in the prevention of gut-derived sepsis in critically ill patients.

Animals↗

PubMed2006

Dissemination of adjuvant multiagent chemotherapy and tamoxifen for breast cancer in the United States using estrogen receptor information: 1975-1999.

BACKGROUND: Clinical trials have shown tamoxifen to be effective only in women with estrogen receptor (ER)-positive tumors. In a previous model, trends in the utilization of adjuvant therapy were modeled only as a function of age and stage of the disease and not ER status. In this paper, we integrate this previous estimate on the use of adjuvant systemic therapy for breast cancer in the United States with information on ER status from the Patterns of Care (POC) data to estimate the dissemination of adjuvant therapy for women with different ER-status tumors. We also summarize efficacy of adjuvant systemic therapy reported in the overviews of early breast cancer clinical trials. These two inputs, dissemination and efficacy, are key pieces for models that investigate the effect of breast cancer adjuvant therapy on the decline of U.S. breast cancer mortality. METHODS: The adjustments to the previous models are calculated using the POC data on 7116 women with breast cancer diagnosed from 1987 to 1991 and in 1995 who were randomly selected from the Surveillance, and Epidemiology, and End Results (SEER) program registries. The POC data provide more accurate information on treatment and clinical variables (e.g., ER status) than the SEER data because medical records are reabstracted and further verified with treating physicians. RESULTS: Use of multiagent chemotherapy is higher for younger women (<50 years) and for women whose tumors were shown to be ER negative or borderline. The use of tamoxifen is higher among older women and women with ER-positive tumors. After 1980 the combined use of multiagent chemotherapy and tamoxifen for women diagnosed with breast cancer at ages 69 or younger increased more for women whose tumors were ER status positive or unknown than ER status negative. Older women (>69 years) seem to receive almost exclusively tamoxifen irrespective of ER status, except for a small percentage of those with more advanced stages (II- and II+/IIIA) who also receive multiagent chemotherapy. DISCUSSION: The estimated dissemination trends by ER status, based on modeling the POC data, reveal that treatment strategies with demonstrated efficacy in clinical trials have been adopted into practice. The dissemination and efficacy are the two factors necessary to input into models to determine the population impact of these therapies on U.S. breast cancer mortality. The largest decline in mortality would be expected for younger women (<60 years) with ER-positive tumors or whose tumors are of unknown status because of the largest efficacy and dissemination of adjuvant therapy in this group.

Aged↗