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M Brown

Publications and source records attributed to M Brown.

At least 73 records · Page 4Linked to original sources
PubMed2001

Selective coactivation of estrogen-dependent transcription by CITED1 CBP/p300-binding protein.

CITED1, a CBP/p300-binding nuclear protein that does not bind directly to DNA, is a transcriptional coregulator. Here, we show evidence that CITED1 functions as a selective coactivator for estrogen-dependent transcription. When transfected, CITED1 enhanced transcriptional activation by the ligand-binding/AF2 domain of both estrogen receptor-alpha (ERalpha) and ERbeta in an estrogen-dependent manner, but it affected transcriptional activities of other nuclear receptors only marginally. CITED1 bound directly to ERalpha in an estrogen-dependent manner through its transactivating domain, and this binding activity was separable from its p300-binding activity. CITED1 was strongly expressed in nulliparous mouse mammary epithelial cells and, when expressed in ER-positive MCF-7 breast cancer cells by transduction, exogenous CITED1 enhanced sensitivity of MCF-7 cells to estrogen, stabilizing the estrogen-dependent interaction between p300 and ERalpha. The estrogen-induced expression of the transforming growth factor-alpha (TGF-alpha) mRNA transcript was enhanced in the CITED1-expressing MCF-7 cells, whereas estrogen-induced expression of the mRNA transcripts for progesterone receptor or pS2 was not affected. Chromatin immunoprecipitation assay revealed that endogenous CITED1 is recruited to the chromosomal TGF-alpha promoter in MCF-7 cells in an estrogen-dependent manner but not to the pS2 promoter. These results suggest that CITED1 may play roles in regulation of estrogen sensitivity in a gene-specific manner.

Animals↗
PubMed2001

Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history.

Women who have inherited a germ-line mutation in the BRCA1 or BRCA2 (BRCA1/2) genes have a greatly increased risk of developing breast cancer compared with the general population. However, there is also substantial interindividual variability in the occurrence of breast cancer among BRCA1/2 mutation carriers. We hypothesize that genes involved in endocrine signaling may modify the BRCA1/2-associated age-specific breast cancer penetrance. We studied the effect of alleles at the AIB1 gene using a matched case-control sample of 448 women with germ-line BRCA1/2 mutations. We found that these women were at significantly higher breast cancer risk if they carried alleles with at least 28 or 29 polyglutamine repeats at AIB1, compared with women who carried alleles with fewer polyglutamine repeats [odds ratio (OR), 1.59; 95% confidence interval (CI), 1.03-2.47 and OR, 2.85; 95% CI, 1.64-4.96, respectively]. Late age at first live birth and nulliparity have been associated with increased breast cancer risk. We observed increases in BRCA1/2-associated breast cancer risk in women who were either nulliparous or had their first live birth after age 30 (OR, 3.06; 95% CI, 1.52-6.16). Women were at significantly increased risk if they were nulliparous or had a late age at first live birth and had AIB1 alleles no shorter than 28 or 29 or more AIB1 polyglutamine repeats (OR, 4.62; 95% CI, 2.02-10.56 and OR, 6.97; 95% CI, 1.71-28.43, respectively) than women with none of these risk factors. Our results support the hypothesis that pathways involving endocrine signaling, as measured through AIB1 genotype and reproductive history, may have a substantial effect on BRCA1/2-associated breast cancer risk.

Adult↗
PubMed2001

Human CARD12 is a novel CED4/Apaf-1 family member that induces apoptosis.

The CED4/Apaf-1 family of proteins functions as critical regulators of apoptosis and NF-kappaB signaling pathways. A novel human member of this family, called CARD12, was identified that induces apoptosis when expressed in cells. CARD12 is most similar in structure to the CED4/Apaf-1 family member CARD4, and is comprised of an N-terminal caspase recruitment domain (CARD), a central nucleotide-binding site (NBS), and a C-terminal domain of leucine-rich repeats (LRR). The CARD domain of CARD12 interacts selectively with the CARD domain of ASC, a recently identified proapoptotic protein. In addition, CARD12 coprecipitates caspase-1, a caspase that participates in both apoptotic signaling and cytokine processing. CARD12 may assemble with proapoptotic CARD proteins to coordinate the activation of downstream apoptotic and inflammatory signaling pathways.

Animals↗
PubMed2001

AIB1 enhances estrogen-dependent induction of cyclin D1 expression.

AIB1 was isolated as a gene amplified in breast cancer and encodes a protein that acts as a steroid receptor coactivator. The role of steroid receptor coactivators such as AIB1 in breast cancer development is not clear. It is possible that AIB1 cooperates with estrogen receptor alpha in regulating estrogen-dependent cell proliferation. Ectopic expression of the estrogen receptor alpha in different cell lines does not confer estrogen-induced proliferation. This inability of the estrogen receptor to drive proliferation has been recently correlated with a lack of estrogen-dependent cyclin D1 expression in cells engineered to express the estrogen receptor. In this study, we evaluated whether high levels of AIB1 enable the estrogen receptor to direct the transcription of cyclin D1. We show here that AIB1 and other steroid receptor coactivators can enhance the functional interaction of the estrogen receptor with the cyclin D1 promoter. Increases of AIB1 levels in breast cancer cells by amplification and/or overexpression may represent one way to confer estrogen-dependent mitogenic stimulation to breast cancer cells.

Breast Neoplasms↗
PubMed2001

Cost comparison of mastectomy versus breast-conserving therapy for early-stage breast cancer.

BACKGROUND: Choice of treatment for early-stage breast cancer depends on many factors, including the size and stage of the cancer, the woman's age, comorbid conditions, and perhaps the costs of treatment. We compared the costs of all medical care for women with early-stage breast cancer cases treated by breast-conserving therapy (BCT) or mastectomy. METHODS: A total of 1675 women 35 years old or older with incident early-stage breast cancer were identified in a large regional nonprofit health maintenance organization in the period 1990 through 1997. The women were treated with mastectomy only (n = 183), mastectomy with adjuvant hormonal therapy or chemotherapy (n = 417), BCT with radiation therapy (n = 405), or BCT with radiation therapy and adjuvant hormonal therapy or chemotherapy (n = 670). The costs of all medical care for the period 1990 through 1998 were computed for each woman, and monthly costs were analyzed by treatment, adjusting for age and cancer stage. All statistical tests were two-sided. RESULTS: At 6 months after diagnosis, the mean total medical care costs for the four groups differed statistically significantly (P:<.001), with BCT being more expensive than mastectomy. The adjusted mean costs were $12 987, $14 309, $14 963, and $15 779 for mastectomy alone, mastectomy with adjuvant therapy, BCT plus radiation therapy, and BCT plus radiation therapy with adjuvant therapy, respectively. At 1 year, the difference in costs was still statistically significant (P:<.001), but costs were influenced more by the use of adjuvant therapy than by type of surgery. The 1-year adjusted mean costs were $16 704, $18 856, $17 344, and $19 081, respectively, for the four groups. By 5 years, BCT was less expensive than mastectomy (P:<.001), with 5-year adjusted mean costs of $41 930, $45 670, $35 787, and $39 926, respectively. Costs also varied by age, with women under 65 years having higher treatment costs than older women. CONCLUSIONS: BCT may have higher short-term costs but lower long-term costs than mastectomy.

Adult↗
PubMed2001

Progressive functional adaptation of segmental bowel graft from living related donor.

We report a patient with short gut syndrome successfully treated with living related bowel transplantation. A 27-year-old Caucasian man was referred after traumatic loss of almost the entire bowel from the third portion of duodenum to the sigmoid colon. His HLA-identical sister volunteered as a donor. A 200-cm segment of ileum was successfully transplanted under tacrolimus-based immunosuppression. The posttransplant course was uneventful, without rejection or infectious complication. Total parenteral nutrition was discontinued 1 week posttransplant. At 6 months the patient had returned to his preinjury weight. Water and D-xylose absorption as well as fecal fat studies were markedly abnormal 1 month posttransplant but normalized by 6 months. The donor recovery was uneventful. A well-matched segmental ileal graft from living donor can provide complete rehabilitation for patients with short gut syndrome. We documented a progressive functional adaptation of the ileal graft, resulting in normal absorption by 5 months posttransplantation.

Adult↗
PubMed2001

Identification of four novel human G protein-coupled receptors expressed in the brain.

We report the discovery and tissue distributions of four novel human genes, GPR61, GPR62, GPR63 and GPR77, all of which encode G protein-coupled receptors (GPCRs). GPR61 was discovered in a search of the patent literature which retrieved a rabbit DNA sequence partially encoding a novel GPCR. This sequence was used to obtain a full-length human cDNA encoding GPR61, a receptor of 417 amino acid length. A search of the GenBank genomic sequence databases revealed three previously unrecognized intronless genes encoding the orphan GPCrs (oGPCRs) GPR62, GPR63 and GPR77, with respective amino acid lengths of 368, 419 and 337. Sequence analysis revealed that GPR61 and GPR62, and a published orphan receptor p47MNR, shared the highest level of identities to each other, ranging from 36 to 45% in the transmembrane (TM) domains. Together, these three oGPCRs appear to comprise a novel subfamily of GPCRs, most closely related to the serotonin 5-HT(6) receptor. Sequence analysis of GPR63 and GPR77 revealed highest sequence identities in the TM regions with the oGPCR PSP24 (58%) and the anaphylatoxin C5a receptor (49%) respectively. Tissue distribution analyses detected the expression of all four novel genes in the human brain. GPR61 mRNA expression was detected in the caudate, putamen and thalamus of human brain, with a more widespread expression pattern in rat brain, with mRNA signals in areas of the cortex, hippocampus, thalamus, hypothalamus and midbrain. GPR62 mRNA expression was detected in the basal forebrain, frontal cortex, caudate, putamen, thalamus and hippocampus. GPR63 mRNA expression was detected in the frontal cortex, with lower levels in the thalamus, caudate, hypothalamus and midbrain. Analysis of GPR77 mRNA expression revealed signals in the frontal cortex, hippocampus and hypothalamus with high transcript levels in the liver.

Animals↗
PubMed2001

The impact of including future medical care costs when estimating the costs attributable to a disease: a colorectal cancer case study.

A source of controversy in the economic literature concerns whether to include or exclude future medical care costs when computing attributable costs for lifesaving interventions. Although it is hypothesized that including future medical care costs will offset the cost savings achieved through prevention, the magnitude of the effect is not known. The objectives of the present study are to develop a methodology for estimating the excess costs of care among colorectal cancer patients, including and excluding future costs of care, and comparing these results with previous studies that do not include costs in added years of life. Subjects in the study included those identified with colorectal cancer drawn from the Surveillance, Epidemiology and End Results (SEER)-Medicare database and an age- and gender-matched control group drawn from the general Medicare population. Using the Kaplan-Meier Sample Average estimator, we directly estimate expected 11-year costs, and then, with the addition of some simple extrapolating assumptions, determine expected 25-year costs. The latter time horizon captures lifetime costs for over 90% of the cohort. Males results for discounted, stage-specific 11- versus 25-year excess costs: in situ, 22411 dollars versus 23494 dollars; Stage 1, 29365 dollars versus 32510 dollars; Stage 2, 28114 dollars versus 25263 dollars; Stage 3, 27397 dollars versus 19647 dollars; Stage 4, 3006 dollars versus 7837 dollars. Trends were similar for females. It can be concluded that adding costs of care in future years for those whose colorectal cancer is prevented owing to screening greatly alters the estimate of lifetime excess costs for colorectal cancer patients, and can produce negative results for advanced stage disease. The results emphasize the need to adopt a standard approach for dealing with future costs when evaluating lifesaving interventions for cost-effectiveness analyses.

Cohort Studies↗
PubMed2001

Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model.

BACKGROUND: We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. PROCEDURES: We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. RESULTS: Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved). CONCLUSIONS: Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.

Age Distribution↗
PubMed2001

Treatment of epidermolysis bullosa acquisita with the humanized anti-Tac mAb daclizumab.

Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease characterized by IgG anti-basement membrane autoantibodies to collagen VII. Since autoantibody formation in EBA patients is thought to be T-cell-dependent, the degree of T cell activation in three patients (all males, ages 33-44 years) was assessed by quantitation of soluble Tac, a fragment of the alpha-subunit of the high-affinity IL-2 receptor (CD25). Soluble Tac levels in all patients were elevated [highest random values, 2430, 920, and 560 IU/ml (normal range, 112-502)]. Based on such findings, these patients were treated with the humanized murine monoclonal anti-Tac antibody daclizumab (1 mg/kg, 6-12 iv treatments at 2- to 4-week intervals). All patients had a significant, rapid, and persistent decrease in lymphocyte CD25 expression. Though a moderate decrease in lymphocyte expression of 7G7, an IL-2 receptor epitope not bound by daclizumab, was noted, stable levels of CD3 cells and in vitro saturation studies indicated that daclizumab effectively bound CD25 and did not promote clearance of such cells from peripheral blood. There were no complications and no patient developed antibodies against daclizumab. While no apparent clinical benefit was seen in two patients with dermolytic disease, one patient with inflammatory EBA had a favorable response. While on daclizumab, this patient stopped prednisone, significantly reduced dapsone, and improved clinically. Furthermore, his disease flared when treatment was stopped, and resumption of daclizumab again effected improvement within 2 weeks. Daclizumab therapy is safe and well tolerated in EBA patients. It may be effective as a corticosteroid sparing agent in patients with inflammatory EBA.

Adult↗
PubMed2001

Reliability of the time trade-off technique of utility assessment in patients with retinal disease.

BACKGROUND: Studies in medical fields other than ophthalmology have given conflicting results regarding the reliability of the time trade-off technique of utility assessment. We performed a study to determine the test-retest reliability of the time trade-off technique for assessing utilities in patients with ocular diseases of the retina and to investigate possible factors associated with differences in utility over time. METHODS: Patients referred to the retina service of a tertiary care hospital in eastern Canada were eligible for the initial interview if they had best corrected vision of 20/30 or worse in at least one eye and were deemed competent to answer the required questions. Patients were interviewed prospectively between December 1999 and March 2000 during a normal 30-minute period needed for pharmacologic mydriasis to occur. Demographic, clinical (including Snellen visual acuity) and time trade-off utility information was collected through chart review and standardized interview. Patients who completed the interview successfully were called back 28 days later for follow-up. RESULTS: Of the 138 eligible patients 112 (81.2%) completed the initial interview. Of the 112, 96 (85.7%) completed the second interview. Half of the respondents were women, and all but one respondent were white. The mean age was 65.3 years. The primary reasons for visual loss included diabetic retinopathy (59 patients [61.4%]) and age-related macular degeneration (14 patients [14.6%]). The intraclass correlation coefficient between the initial and follow-up visual utilities was 0.7634 (95% confidence interval 0.6655-0.8355). INTERPRETATION: Our results show excellent reliability of the time trade-off technique of utility assessment in patients with ocular diseases of the retina.

Adult↗
PubMed2001

Client relevant care and quality of life: the trial of a Client Generated Index (CGI) tool for community nursing.

Community nursing organisations worldwide seek optimal ways to ensure adequate measurement of health outcomes for the client following nursing care, and to facilitate a consumer focus. This article presents a trial of the Client Generated Index (CGI) tool that subjectively assesses and measures the quality of life outcomes pertaining to a client's health status, whilst also facilitating individualised care. Sixty district nursing clients participated in the trial, which ascertained that the CGI tool effectively directs the client to list, grade and prioritise personally relevant quality of life issues. Consequently, this tool is being incorporated into client admission and discharge assessment within the organisation.

Activities of Daily Living↗
PubMed2001

Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy.

OBJECTIVE: CD40L restores the antigen-presenting cell (APC) function of some B-cell tumors and induces professional APC maturation. We therefore evaluated the effects of transgenic CD40L expression on the behavior and immunogenicity of human multiple myeloma (MM) cells. MATERIALS AND METHODS: CD40L expression was induced in a CD40(+) (RPMI 8226) and a CD40(-) (U266B1) human myeloma cell line (HMCL) by adenoviral vector gene transfer. The viability and proliferative activity of control HMCL and HMCL/CD40L were determined by daily trypan blue staining and methyl-3H-thymidine incorporation. Mixed lymphocyte reaction (MLR) with allogeneic mononuclear cells (MNCs) and coculture of allogeneic dendritic cells (DCs) with HMCL expressing transgenic CD40L were used to evaluate the APC function of modified HMCL as well as the role of bystander DCs in inducing an anti-tumor immune response. RESULTS: CD40L expression significantly inhibited the growth of the CD40(+) HMCL and induced apoptosis. These effects were less evident for the CD40(-) HMCL. There was no upregulation of costimulatory molecules on either HMCL following CD40L expression. Both HMCL expressing transgenic CD40L induced maturation of bystander DCs and enhanced their ability to stimulate the proliferation of MNCs. DCs cultured with the poorly immunogenic RPMI 8226 expressing CD40L upregulated T-lymphocyte release of IFN-gamma and other Th1 cytokines (interleukin-2, tumor necrosis factor-alpha). CONCLUSIONS: Our data suggest that transgenic expression of CD40L exerts a dual effect favoring generation of an immune response to human MM. Where the tumor cells are CD40(+), the engagement of CD40 antigen by CD40L on tumor cells induces their apoptosis, allowing uptake of tumor-associated antigen by professional APC. Independently of tumor-cell expression of CD40, transgenic expression of CD40L on tumor cells allows them to stimulate CD40(+) APC, to increase their maturation and their capacity to stimulate cytotoxic T lymphocytes (CTL) that recognize the tumor-derived antigens the APC may have engulfed.

Adenoviridae↗
PubMed2001

Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Sildenafil Study Group.

Oral sildenafil is an effective treatment for erectile dysfunction (ED), which is a common complaint for patients with hypertension and those taking antihypertensive agents. This post hoc subanalysis assessed the efficacy and safety of sildenafil in men with ED who were receiving concomitant antihypertensive medication. Efficacy was assessed in 3414 men (1218 of whom were taking antihypertensive medication) who received sildenafil (5 to 200 mg) or placebo for 6 weeks to 6 months in 10 double-blind, placebo-controlled studies. The significant improvements in erectile function demonstrated by sildenafil-treated patients were comparable in patients taking and those not taking antihypertensive medication. Safety was assessed in 3975 men (1094 of whom were taking one or more antihypertensive agent, classified as a diuretic, beta-blocker, alpha1-blocker, angiotensin converting enzyme inhibitor, or calcium channel blocker), who received sildenafil or placebo in 18 double-blind, placebo-controlled studies. For patients taking sildenafil and antihypertensive medication, the incidence of treatment-related adverse events (34%) was similar to that for sildenafil-treated patients not taking any antihypertensive agent (38%). The incidences of the most common adverse events and of adverse events potentially related to blood pressure decreases (eg, hypotension, dizziness, and syncope) were similar in both sildenafil groups. The number of antihypertensive medications taken from among the five classes had no effect on the adverse event profile of sildenafil. Sildenafil is an effective and well-tolerated treatment for ED in patients taking concomitant antihypertensive medication, including those on multidrug regimens.

Adult↗
PubMed2001

Linoleic acid partially restores the triglyceride content of conjugated linoleic acid-treated cultures of 3T3-L1 preadipocytes.

We have previously demonstrated that a crude mixture of commercially available conjugated linoleic acid (CLA) isomers suppressed triglyceride (TG) content and induced apoptosis in post-confluent cultures of murine 3T3-L1 preadipocytes. Furthermore, we found that 100 &mgr;M of trans-10, cis-12 isomer of CLA had a greater TG-lowering and apoptotic effect than the crude mixture of CLA isomers. Therefore, the purpose of this study was to: 1) compare the potencies of the two main isomers found in the crude mixture of CLA isomers, e.g. cis-9, trans-11 (41%) and trans-10, cis-12 (44%); and 2) determine if the TG-reducing actions of CLA could be attenuated by the addition of increasing levels of linoleic acid to the cultures. Preadipocyte differentiation was assessed on day 7 of the differentiation protocol by measuring TG content (per 10(6) cells), cell size, and lipid staining. In experiment 1, post-confluent cultures of 3T3-L1 preadipocytes treated for the first 6 d of differentiation with 100 &mgr;M of a crude mixture of CLA isomers or 44 &mgr;M of trans-10, cis-12 CLA had less TG content than all other cultures. In contrast, cultures supplemented with 41 &mgr;M of the cis-9, trans-11 CLA isomer had the same amount of TG as the BSA controls. In experiment 2, post-confluent cultures of 3T3-L1 preadipocytes treated for the first 6 d of differentiation with 50 &mgr;M trans-10, cis-12 CLA had less TG content and a greater number of smaller cells (10-12.5 microns) compared to all other treatments. CLA-treated cultures supplemented with increasing levels of linoleic acid (50-200 &mgr;M) had greater TG contents and greater numbers of larger cells (15-20 microns) than cultures treated with 50 &mgr;M of the trans-10, cis-12 CLA isomer alone. These data demonstrate that: 1) the TG-lowering effects of the crude mixture of CLA isomers is due almost exclusively to the trans-10, cis-12 isomer; and 2) linoleic acid partially reverses CLA's attenuation of TG content, suggesting that these unsaturated fatty acids may compete for incorporation into TG or phospholipid-derived eicosanoids that regulate preadipocyte differentiation.

Journal Article↗
PubMed2001

Cardiac function following combination therapy with paclitaxel and doxorubicin: an analysis of 657 women with advanced breast cancer.

BACKGROUND: To determine the cardiotoxicity of paclitaxel (T) plus doxorubicin (A) combination therapy in women with advanced breast cancer. To define a dose range of A for use in AT. PATIENTS AND METHODS: The effect of cumulative A dose on risk of congestive heart failure (CHF) and alterations of myocardial contractility (left ventricular ejection fraction [LVEF] decrease > or = 20% or to <50%) was estimated from pooled data from 10 trials of AT. RESULTS: Thirty-one of 657 patients (4.7%) developed CHF at a median of 6.6 months (range 0.3-24.6) after initiation of AT. CHF was stabilized in 29 patients at a median of 17.3 months after diagnosis (range 4.1-31.2 months). The risk of developing CHF was < or = 5% at a total A dose < or = 380 mg/m2. In patients who received a total A dose > 440 mg/m2, the incidence of CHF was >25% but similar to that of A monotherapy. The risk of CHF was similar in women receiving AT or A monotherapy at a dose < or = 380 mg/m2 (2%-3%). LVEF progressively decreased in patients who received AT, especially at a cumulative A dose > 380 mg/m2. LVEF decreases were more frequent in patients who later developed CHF, but the majority of CHF patients did not experience LVEF alterations prior to symptoms. LVEF recovered after discontinuation of A in 25 of 67 women who developed LVEF < 50%. CONCLUSION: The reported cardiac effects are consistent with anthracycline-related cardiotoxicity. AT is associated with a cardiac risk similar to that of A monotherapy up to a cumulative A dose of 340-380 mg/m2.

Adult↗