Rod Ellis The Study Of Second Language Acquisition Pdf Editor

Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer Edward H. Romond, M.D., Edith A. Perez, M.D., John Bryant, Ph.D., Vera J. Suman, Ph.D., Charles E.

Geyer, Jr., M.D., Nancy E. Davidson, M.D., Elizabeth Tan-Chiu, M.D., Silvana Martino, D.O., Soonmyung Paik, M.D., Peter A.

Kaufman, M.D., Sandra M. Swain, M.D., Thomas M. Pisansky, M.D., Louis Fehrenbacher, M.D., Leila A. Kutteh, M.D., Victor G. Vogel, M.D., Daniel W.

Visscher, M.D., Greg Yothers, Ph.D., Robert B. Jenkins, M.D., Ph.D., Ann M. Brown, Sc.D., Shaker R. Dakhil, M.D., Eleftherios P. Mamounas, M.D., M.P.H., Wilma L.

Lingle, Ph.D., Pamela M. Klein, M.D., James N. Ingle, M.D., and Norman Wolmark, M.D. N Engl J Med 2005; 353:1673-1684 DOI: 10.1056/NEJMoa052122. Methods The National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks (group 1) with the same regimen plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The North Central Cancer Treatment Group trial N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group).

Group B was excluded because trastuzumab was not given concurrently with paclitaxel. Results By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (hazard ratio, 0.48; P. Trastuzumab, a monoclonal antibody targeting the extracellular domain of the HER2 protein, was approved in 1998 as a first-line treatment in combination with paclitaxel for HER2-positive metastatic breast cancer. The benefit of this approach in patients with metastatic disease and the poor prognosis of HER2-positive breast cancer motivated the National Cancer Institute (NCI) to sponsor two trials of adjuvant treatment with trastuzumab, led by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the North Central Cancer Treatment Group (NCCTG). NSABP trial B-31, which began accrual in February 2000, compares four cycles of doxorubicin and cyclophosphamide followed by paclitaxel (group 1) with the same chemotherapy plus 52 weeks of trastuzumab beginning on day 1 of paclitaxel therapy (group 2).

NCCTG trial N9831 began enrollment in May 2000 and compares three regimens: four cycles of doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks (group A), four cycles of doxorubicin and cyclophosphamide followed by 52 weeks of trastuzumab after the completion of paclitaxel therapy (group B), and four cycles of doxorubicin and cyclophosphamide followed by 52 weeks of trastuzumab beginning on day 1 of paclitaxel therapy (group C). The control groups of the trials, as well as group 2 in trial B-31 and group C in trial N9831, differed in terms of the scheduling of paclitaxel treatment and some aspects of hormonal therapy and radiotherapy but were otherwise identical.

For this reason, the NCI and the Food and Drug Administration approved a joint-analysis plan developed by the NSABP and NCCTG to combine data from group 1 and group A (referred to as the control group) for comparison with group 2 and group C (referred to as the trastuzumab group). Group B of trial N9831 was excluded because the protocol required trastuzumab to be administered after the completion of chemotherapy. The plan required a first interim analysis after the occurrence of 355 events. Before the data were locked, 2043 patients (of a planned total of 2700) were enrolled in trial B-31 and 1633 patients (of a total of 2000 for the comparison of group A with group C) were enrolled in trial N9831. In April 2005, the independent data-monitoring committees of each trial recommended closing enrollment and releasing the results. Eligibility and Enrollment Enrollment required a pathological diagnosis of adenocarcinoma of the breast with immunohistochemical staining for HER2 protein of 3+ intensity or amplification of the HER2 gene on fluorescence in situ hybridization.

Initially, both trials required patients to have histologically proven, node-positive disease; as of May 2, 2003, patients with high-risk node-negative disease (defined as a tumor that was more than 2 cm in diameter and positive for estrogen receptors or progesterone receptors or as a tumor that was more than 1 cm in diameter and negative for both estrogen receptors and progesterone receptors) were eligible for trial N9831. Other requirements were adequate hematopoietic, hepatic, and renal function and a left ventricular ejection fraction (LVEF) that met or exceeded the lower limit of normal. Patients with clinical or radiologic evidence of metastatic disease were excluded. Findings suggestive of metastasis were confirmed or refuted by additional radiologic evaluation or biopsy.

Complete resection of the primary tumor and axillary-node dissection were required (negative sentinel-node biopsy was allowed in trial N9831). Patients were ineligible if they had angina pectoris requiring antianginal medication, arrhythmia requiring medication, a severe conduction abnormality, clinically significant valvular disease, cardiomegaly on chest radiography, left ventricular hypertrophy on echocardiography (trial B-31 only), poorly controlled hypertension, clinically significant pericardial effusion (trial N9831 only), or a history of myocardial infarction, congestive heart failure, or cardiomyopathy. Participating institutions obtained the approval of their human investigations committee or institutional review board and filed assurances with the Department of Health and Human Services. Written informed consent was required for enrollment. Torrent Power Ahmedabad Office here. In trial B-31, treatment assignments were balanced according to nodal status, the planned hormonal therapy, the type of surgery (lumpectomy vs. Mastectomy), the intended radiotherapy, and institution with the use of a biased-coin minimization algorithm.

Trial N9831 used a dynamic allocation procedure that balanced the marginal distributions of nodal status and hormone-receptor status between groups. The procedures used for HER2 testing in the two trials are provided in the (available with the full text of this article at www.nejm.org). Assessment of Cardiac Function In both trials, LVEF was assessed before entry, after the completion of doxorubicin and cyclophosphamide therapy, and 6, 9, and 18 months after randomization. Trial B-31 required multiple gated acquisition scanning, whereas trial N9831 allowed multiple gated acquisition scanning or echocardiography.

Multilingualism is the use of more than one language, either by an individual speaker or by a community of speakers. It is believed that multilingual speakers. Ellis, who is known as an expert in Second Language Acquisition, is author of the Oxford University Press Duke of Edinburgh Award-Winning Classic 'The Study of Second Language Acquisition', as well as numerous student and teacher-training textbooks for Prentice Hall and Oxford University Press, Prof.

The initiation of trastuzumab required an LVEF after doxorubicin and cyclophosphamide therapy that met or exceeded the lower limit of normal and a decrease of less than 16 percentage points from baseline. Patients in whom clinically significant cardiac symptoms developed while they were receiving doxorubicin and cyclophosphamide were excluded from subsequent trastuzumab therapy. The six- and nine-month cardiac assessments were used to determine whether trastuzumab should be continued in patients without cardiac symptoms. If the LVEF had declined 16 or more percentage points from baseline or 10 to 15 percentage points from baseline to below the lower limit of normal, trastuzumab was withheld for four weeks, at which time the LVEF was reassessed.

If the LVEF remained below these levels or if the patient had symptomatic cardiac dysfunction while receiving trastuzumab, administration of the antibody was permanently discontinued. Role of the Sponsor Both studies were conducted under a corporate research and development agreement between Genentech and the NCI. Genentech provided trastuzumab and partial funding support but did not participate in the design of the studies or the collection of data. The joint analysis was developed and analyzed by the NSABP and the NCCTG. The lead authors wrote the manuscript, which was reviewed by all authors. A draft was provided to Genentech for comment, but no changes in content or conclusions were requested by Genentech. The authors vouch for the completeness and accuracy of the data.

Statistical Analysis The primary end point was disease-free survival. Events determining disease-free survival were local, regional, and distant recurrence; contralateral breast cancer, including ductal carcinoma in situ; other second primary cancers; and death before recurrence or a second primary cancer. Comparison of the two groups was based on a log-rank test, stratified according to the study (trial B-31 vs. Trial N9831), intended paclitaxel schedule (every three weeks vs. Weekly), nodal status (0, 1 to 3, 4 to 9, or 10 or more positive nodes), and hormone-receptor status (estrogen-receptor–positive or progesterone-receptor–positive vs.

Estrogen-receptor–negative and progesterone-receptor–negative). Disease-free survival was estimated according to the Kaplan–Meier method. The primary cohort included all enrolled patients with follow-up data, analyzed according to the intention-to-treat principle ( ). All reported P values are two-sided. Other end points were overall survival, time to distant recurrence, death from breast cancer, contralateral breast cancer, and other second primary cancers. The defines these end points. We counted deaths as having been caused by breast cancer if they took place after recurrence or if they were attributed to breast cancer.

Timing of Analyses Definitive analysis was scheduled after 710 primary end-point events had occurred to provide the study with a statistical power of 90 percent to detect a 25 percent reduction in the event rate, allowing for a number of attenuating factors. The first interim analysis was to take place after 355 events had been reported. Subsequent interim analyses were scheduled to take place semiannually. Consideration was to be given to early reporting if disease-free survival differed at the nominal 0.0001 level.

If this boundary was not crossed, alpha spending function was to be applied to the final test so that the overall type I error rate would be 0.05. Secondary Analyses Cox models were fitted to adjust for nodal status (0 to 3, 4 to 9, or 10 or more positive nodes), tumor size (2.0 cm or less, 2.1 to 4.0 cm, or 4.1 cm or more), receptor status (estrogen-receptor–positive or progesterone-receptor–positive vs. Estrogen-receptor–negative and progesterone-receptor–negative), age (39 years or younger, 40 to 49 years, 50 to 59 years, or 60 years of age or older), grade (poor vs. Other), histologic findings (ductal carcinoma vs.

Other), and trial (B-31 vs. Forest plots were constructed to show the effects according to the study and subgroups of patients. Hazard ratios were computed and compared according to the length of follow-up (one year or less, one to two years, two to three years, or more than three years after randomization). Patients As of February 15, 2005, 2043 patients had been enrolled in trial B-31; 1736 of these women had at least one follow-up evaluation (end-point follow-up was not required for six months after randomization). By November 1, 2004, 1633 patients had been enrolled in groups A and C of trial N9831, 1615 of whom had follow-up data submitted by March 15, 2005 ( ). Table 1 Characteristics of the Patients.

Shows the characteristics of patients with follow-up. Except for 191 patients with node-negative breast cancer who were enrolled in trial N9831, the groups from each study were similar. Discontinuation of Trastuzumab Of 1159 patients with an adequate LVEF after doxorubicin and cyclophosphamide treatment who began treatment with trastuzumab and have completed therapy, 364 (31.4 percent) discontinued the treatment before 52 weeks. Reasons for discontinuation were recurrence in the case of 22 patients (1.9 percent), a confirmed asymptomatic decline in LVEF in 164 (14.2 percent), symptoms of congestive heart failure or other adverse cardiac effect in 54 (4.7 percent), noncardiac adverse effect or death in 27 (2.3 percent), patient-initiated discontinuation in 70 (6.0 percent), and other reasons in 27 (2.3 percent).

Disease-Free Survival, Overall Survival, and Time to Distant Recurrence The median follow-up was 2.0 years (2.4 years in trial B-31 and 1.5 years in trial N9831). There were 261 events in the control group and 133 events in the trastuzumab group. The hazard ratio for a first event in the trastuzumab group, as compared with the control group, was 0.48 (95 percent confidence interval, 0.39 to 0.59; P. Sites of First Reported Events The benefit of trastuzumab was evident at both local–regional and distant sites ( Table 2 Sites of First Events. The number of contralateral breast cancers was insufficient to evaluate the effect of trastuzumab. There was a reduction in nonbreast second primary cancers in trial B-31 in the trastuzumab group as compared with the control group, but the results of trial N9831 did not confirm (or refute) this trend. Six patients in the control group died without recurrence or second cancers, as did eight patients in the trastuzumab group.

These included three treatment-related deaths that occurred in patients who received paclitaxel and trastuzumab, one as a result of cardiomyopathy and two as a result of interstitial pneumonitis. An increased frequency of brain metastases has been reported among patients with metastatic breast cancer treated with trastuzumab. In both trials, the incidence of isolated brain metastases as first events was higher in the trastuzumab group than in the control group (21 vs. 11 in trial B-31 and 12 vs.

4 in trial N9831). Since patients in trial B-31 were followed for additional recurrences beyond the first distant event, we could determine whether the imbalance was due to masking of the incidence of brain metastases in the control group as a result of earlier failures in other organs. In trial B-31, brain metastases as a first or subsequent event were diagnosed in 28 patients in the trastuzumab group, as compared with 35 patients in the control group (hazard ratio, 0.79; P=0.35). The imbalance in brain metastases as first events can therefore be attributed to earlier failures at other distant sites among patients in the control group. Estimated Treatment Benefit after Adjustment for Additional Characteristics A Cox model was fitted to disease-free survival to control for treatment assignment, nodal status, pathological tumor size, hormone-receptor status, age, tumor grade, histologic appearance of the tumor, and trial. Adjustment for these factors minimally altered the effect of trastuzumab, as compared with that of control therapy (hazard ratio for a first event, 0.46; 95 percent confidence interval, 0.37 to 0.56; P.

Sensitivity Analysis A secondary analysis excluded ineligible patients, those who had received only doxorubicin and cyclophosphamide, those found on central testing to be HER2-negative, and those who had symptomatic cardiac dysfunction during therapy with doxorubicin and cyclophosphamide or reductions in LVEF that would preclude treatment with trastuzumab. As compared with the control group, the trastuzumab group had improved disease-free survival (hazard ratio for a first event, 0.45; P. Adverse Cardiac Events The principal adverse event associated with trastuzumab therapy among patients with prior exposure to anthracycline is cardiac dysfunction. In trial B-31, of the patients who remained free of cardiac symptoms during doxorubicin and cyclophosphamide therapy and who had LVEF values that met requirements for the initiation of trastuzumab therapy, the cumulative incidence of New York Heart Association class III or IV congestive heart failure or death from cardiac causes at three years was 0.8 percent in the control group (4 patients had congestive heart failure, and 1 died from cardiac causes) and 4.1 percent in the trastuzumab group (31 patients had congestive heart failure). Of the 31 women in the trastuzumab group who had congestive heart failure, 27 have been followed for at least six months after the onset of heart failure, and only 1 reported persistent symptoms of heart failure at the most recent follow-up visit. Details of the cardiac effects of trastuzumab in trial B-31 are reported elsewhere. In trial N9831, the three-year cumulative incidence of New York Heart Association class III or IV congestive heart failure or death from cardiac causes was 0 percent in the control group and 2.9 percent in the trastuzumab group (20 patients had congestive heart failure, 1 of whom died of cardiomyopathy).

Other Adverse Events During treatment with paclitaxel alone or with trastuzumab, there was little imbalance between treatment groups in the incidence of any Common Toxicity Criteria version 2.0 category except for a higher incidence of left ventricular dysfunction in the trastuzumab group. However, rare cases of interstitial pneumonitis were reported that in some cases appeared to be related to trastuzumab therapy.

In trial B-31, four patients in the trastuzumab group had interstitial pneumonitis, one of whom died. In the N9831 trial, five patients in the trastuzumab group had grade 3+ pneumonitis or pulmonary infiltrates, one of whom died. Discussion The addition of trastuzumab to paclitaxel after a regimen of doxorubicin and cyclophosphamide reduced the rates of recurrence by half among women with HER2-positive breast cancer. The absolute decreases in distant recurrence were 8.8 percentage points after three years and 15.9 percentage points after four years, although the latter value had a wide confidence interval (11.1 to 20.8 percentage points).

The reduction was similar among women with hormone-receptor–negative tumors and women with hormone-receptor–positive tumors. No subgroups that did not appear to benefit from trastuzumab therapy were identified. Since only 191 women with node-negative breast cancer were included in these studies and only 3 had had an event at the time of the analysis, we cannot comment on the effect of trastuzumab in this subgroup.

The addition of trastuzumab reduced the mortality rate by one third (P=0.015). Among eligible patients who continued treatment after doxorubicin and cyclophosphamide and who were HER2-positive on central testing, the relative reduction in the mortality rate associated with trastuzumab was 39 percent (P=0.01). Although relatively little follow-up information is available beyond three years, current data rule out a risk of distant recurrence among trastuzumab-treated women of greater than 27 per 1000 women per year, in contrast to a risk of 90 per 1000 women per year in the control group (see Figure 4 in the ). Since the risk of distant recurrence should remain appreciable in the control group for some time, a substantial additional survival benefit related to trastuzumab can be anticipated. The effect of trastuzumab was substantial in both trials (see Figure 1 in the ), a finding that is noteworthy given differences in the paclitaxel schedule and the timing of hormonal therapy. The benefit of trastuzumab was evident at local or regional and distant sites. Although isolated brain metastases were more common first events in the trastuzumab group than in the control group, the imbalance can be attributed to the occurrence of earlier failures at other distant sites in the control group.

Data from trial B-31 suggested that trastuzumab reduced the incidence of nonbreast second primary cancers, an unanticipated effect requiring independent verification. There was no obvious pattern of site or histologic type ( ). The primary concern regarding the safety of trastuzumab is the increased risk of cardiac dysfunction associated with past or concurrent anthracycline treatment.

In both studies, the cumulative three-year incidence of congestive heart failure increased by about 3 percentage points with the addition of trastuzumab. Most episodes occurred during trastuzumab treatment, but additional follow-up will be needed to define the long-term cardiotoxicity of trastuzumab. Clearly, appropriate selection and careful cardiac monitoring of patients are essential.

Trastuzumab did not increase the overall frequency or severity of noncardiac adverse effects associated with the chemotherapy regimens, but we did see rare cases of interstitial pneumonitis in patients receiving trastuzumab during or shortly after the paclitaxel phase of treatment. Two cases were fatal.

Trial N9831 was also designed to address the efficacy of trastuzumab initiated concurrently with paclitaxel as opposed to sequentially (group C vs. Group B), but this comparison requires substantially longer follow-up than was needed for the assessment of concurrent trastuzumab therapy in the joint analysis.

However, after reviewing the results of the first joint interim efficacy analysis, the data-monitoring committee overseeing trial N9831 requested an unplanned comparison of groups B and C and subsequently recommended disclosure of the results. Though early, the comparison suggested delayed administration of trastuzumab may be less effective than concurrent administration. Recent data from the Herceptin Adjuvant (HERA) Trial showed that treatment with trastuzumab begun after the completion of chemotherapy substantially reduced the rate of recurrence relative to the rate associated with chemotherapy alone.

Since only 26 percent of patients received taxanes in the HERA trial, comparison of those results with ours may be problematic. Therefore, further follow-up of groups B and C in trial N9831 is necessary for an adequate evaluation of the efficacy of concurrent as compared with sequential administration of trastuzumab. Supported by Public Health Service grants (U10-CA-12027, U10-CA-69651, U10-CA-37377, and U10-CA-69974 to the NSABP; U10-CA-25224 to the NCCTG; U10-CA-021115 to the Eastern Cooperative Oncology Group; U10-CA-32102 to the Southwest Oncology Group; and U10-CA-31946 to Cancer and Leukemia Group B) from the NCI, Department of Health and Human Services. Genentech, South San Francisco, Calif., provided trastuzumab and partial funding for both trials.

The Breast Cancer Research Foundation, New York, provided partial funding to Dr. Romond, Perez, Bryant, Geyer, Tan-Chiu, Paik, Kaufman, and Mamounas report having received compensation for time served on Genentech Breast Cancer Advisory Boards; Drs. Romond, Tan-Chiu, Bryant, Kaufman, and Mamounas, lecture fees from Genentech; and Drs. Perez and Kaufman, grant support from Genentech. Klein is an employee of Genentech and holds equity stock. Romond and Perez contributed equally to the article.

We are indebted to Dr. Good, director of scientific publications for the NSABP, for editorial assistance; to all the women participating in NSABP trial B-31 and NCCTG trial N9831 for their contribution to this research effort; to the investigators of the Eastern Cooperative Oncology Group, the Southwest Oncology Group, Cancer and Leukemia Group B, the NCCTG, and the NSABP for their dedicated efforts in support of these trials; and to Dr. Jeff Abrams, for support in the development and approval of the joint-analysis plan. Source Information From the National Surgical Adjuvant Breast and Bowel Project, Pittsburgh (E.H.R., J.B., C.E.G., E.T.-C., S.P., S.M.S., L.F., V.G.V., G.Y., A.M.B., E.P.M., N.W.); University of Kentucky, Lexington (E.H.R.); North Central Cancer Treatment Group, Rochester, Minn. (E.A.P., V.J.S., T.M.P., L.A.K., D.W.V., R.B.J., S.R.D., W.L.L., J.N.I.); Mayo Clinic Jacksonville, Jacksonville, Fla. (E.A.P.); University of Pittsburgh, Pittsburgh (J.B., G.Y.); Mayo Clinic, Rochester, Minn. (V.J.S., T.M.P., D.W.V., R.B.J., W.L.L., J.N.I.); Allegheny General Hospital, Pittsburgh (C.E.G., N.W.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore (N.E.D.), the Cancer Research Network, Plantation, Fla.

(E.T.-C.); Angeles Clinic and Research Institute, Santa Monica, Calif. (S.M.); Norris Cotton Cancer Center, Dartmouth–Hitchcock Medical Center, Lebanon, N.H. (P.A.K.); Cancer Therapeutics Branch, National Cancer Institute, Bethesda, Md.

(S.M.S.); Kaiser Permanente Medical Center Northern California, Vallejo (L.F.); Oncology Associates of Cedar Rapids, Cedar Rapids, Iowa (L.A.K.); University of Pittsburgh Cancer Institute, Pittsburgh (V.G.V.); Wichita Community Clinical Oncology Program, Wichita, Kans. (S.R.D.); Aultman Health Foundation, Canton, Ohio (E.P.M.); and Genentech, South San Francisco, Calif. Address reprint requests to Dr.

Geyer at the Allegheny Cancer Center, 5th Fl., 320 E. North Ave., Pittsburgh, PA 15212,. Appendix The following institutions and principal investigators enrolled at least 25 patients in the B-31 trial or N9831 trial: Trial B-31 — Kaiser Permanente, Northern California Region, Vallejo, Calif., L. Fehrenbacher; University of Pittsburgh, Pittsburgh, V.G. Vogel; Atlanta Regional Community Clinical Oncology Program (CCOP), Atlanta, T.E. Seay; Colorado Cancer Research Program, CCOP, Denver, E.R.

Pajon; Metro Minnesota CCOP, St. Louis Park, Minn., P.J. Flynn; Franklin Square Hospital Center, Baltimore, J.L. Zapas; Kaiser Permanente, San Diego, Calif., J. Polikoff; Dayton CCOP, Dayton, Ohio, H.M. Gross; Christiana Care Health Services CCOP, Newark, Del., D.D.

Biggs; Southeast Cancer Control Consortium CCOP, Winston-Salem, N.C., J.N. Atkins; Huntsman Cancer Institute, Salt Lake City, Utah, R.D. Noyes; Puget Sound Oncology Consortium, Seattle, R.B. Imsai Arasan 23am Pulikesi Mp3 Songs Free Download there. Clarfeld; Columbus CCOP, Columbus, Ohio, J.P. Kuebler; Northwest CCOP, Tacoma, Wash., L.K. Colman; Scripps Clinic, La Jolla, Calif., J.F.

Kroener; Illinois Oncology Research Association CCOP, Peoria, J.W. Kugler; Evanston Northwestern Healthcare CCOP/Kellogg Cancer Center, Evanston, Ill., D. Merkel; Kansas City CCOP, Kansas City, Mo., W.T. Stephenson; Montana Cancer Consortium CCOP, Billings, P.W.

Cobb; Trial N9831 — Indiana University Cancer Center, Indianapolis, P.J. Loehrer; Johns Hopkins University, Baltimore, A.A. Forastiere; Vanderbilt University, Nashville, D.H. Johnson; Northern New Jersey CCOP, Hackensack, R.J.

Rosenbluth; University of Chicago Medical Center, Chicago, G. Fleming; Dana–Farber Cancer Institute, Boston, G.P. Canellos; Duke University Medical Center, Durham, N.C., J. Crawford; Mount Sinai School of Medicine, New York, L.R.

Silverman; Memorial Sloan-Kettering Cancer Center, New York, C. Hudis; Loyola University Medical Center, Maywood, Ill., P.J. Stiff; Ohio State University Medical Center, Columbus, C.D.

Bloomfield; Georgetown University Medical Center, Washington, D.C., E. Gelmann; Moffitt Cancer Center, Tampa, Fla., J.A. Kish; Mayo Clinic, Rochester, Minn., S.R. Alberts; Toledo CCOP, Toledo, Ohio, P.L. Schaefer; Metro Minnesota CCOP, St. Louis Park, Minn., P.J. Flynn; Wichita CCOP, Wichita, Kans., S.

Dakhil; Ann Arbor CCOP, Ann Arbor, Mich., P.J. Stella; Missouri Valley Cancer Consortium CCOP, Omaha, Nebr., J.A. References • 1 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.

N Engl J Med 2001;344:783-792 • 2 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182 • 3 Paik S, Bryant J, Tan-Chiu E, et al. HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 20-1998 • 4 White SJ, Freedman LS. Allocation of patients to treatment groups in a controlled clinical study.

Br J Cancer 1978;37:849-857 • 5 Pocock SL, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975;31:103-115 • 6 Albain KS, Green S, Ravdin P, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from North American Intergroup Trial 0100 (SWOG-8814). Proc Am Soc Clin Oncol 2002;21:37A abstract-37A abstract • 7 Baum M, Buzdar AU, Cuzick J, et al.

Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002;359:2131-2139[Erratum, Lancet 2002;360:1520.] • 8 Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ 2001;322:1479-1480 • 9 Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 20-2977 .

Results At two years of age, 17 percent of infants had severe cognitive delay, 10 percent had severe psychomotor delay, 10 percent had cerebral palsy, and 11 percent had neurosensory impairment. Moderate-to-severe cerebral white-matter abnormalities present in 21 percent of infants at term equivalent were predictive of the following adverse outcomes at two years of age: cognitive delay (odds ratio, 3.6; 95 percent confidence interval, 1.5 to 8.7), motor delay (odds ratio, 10.3; 95 percent confidence interval, 3.5 to 30.8), cerebral palsy (odds ratio, 9.6; 95 percent confidence interval, 3.2 to 28.3), and neurosensory impairment (odds ratio, 4.2; 95 percent confidence interval, 1.6 to 11.3). Gray-matter abnormalities (present in 49 percent of infants) were also associated, but less strongly, with cognitive delay, motor delay, and cerebral palsy. Moderate-to-severe white-matter abnormalities on MRI were significant predictors of severe motor delay and cerebral palsy after adjustment for other measures during the neonatal period, including findings on cranial ultrasonography. Figure 1 Representative MRI Scans of Children in the Study. Representative coronal T 2-weighted MRI (Panel A) and T 1-weighted MRI (Panel B) show the four grades of white-matter abnormality (none, mild, moderate, or severe). With increasing grade of white-matter abnormality, there was increasing ventricular size, decreasing white-matter volume, increasing intensity of white-matter signal on T 2-weighted imaging, and decreasing myelination in the posterior limb of the internal capsule.

Also shown is axial T 2-weighted MRI at the level of the deep nuclear gray matter of infants with normal gray-matter scores (Panel C) and abnormal gray-matter scores (Panel D), demonstrating the simpler gyral patterns observed among infants with gray-matter abnormalities. Very preterm birth has profound ramifications for public health and education worldwide. Infants born before 32 weeks of gestation now represent more than 2 percent of all live births, and their survival rates exceed 85 percent.

Follow-up studies have revealed high rates of neurodevelopmental disability among very preterm infants who survive, with 5 to 15 percent having cerebral palsy, severe neurosensory impairment, or both and 25 to 50 percent having cognitive, behavioral, and social difficulties that impede progress in school and require special educational support. A major issue confronting clinicians who work with preterm infants and their families is the identification of infants who are most at risk for subsequent neurodevelopmental disability and who may benefit from early intervention services. Several factors (including bronchopulmonary dysplasia, sepsis, surgery, the postnatal use of corticosteroids, and evidence on ultrasonography of intraventricular hemorrhage and periventricular leukomalacia) are recognized to increase neurodevelopmental risks. However, risk indexes for neonates that incorporate these factors have shown limited effectiveness in identifying infants who are at high risk for poor neurodevelopmental outcomes.

One tool that may assist early prognostic evaluations of the preterm infant is magnetic resonance imaging (MRI) during the neonatal period. Currently, the most widely used imaging technique is cranial ultrasonography. This method is useful for the detection of intraventricular hemorrhage and cystic periventricular leukomalacia, but it has poor sensitivity for diffuse white-matter abnormalities detected by MRI. Neonatal MRI studies have revealed that the majority of very preterm infants have white-matter abnormalities, including signal abnormalities, loss of volume, cystic abnormality, enlarged ventricles, thinning of the corpus callosum, and delayed myelination. Gray-matter abnormalities, including decreased cerebral gray-matter volume and delayed cortical gyration, have also been reported in very preterm infants at term equivalent (gestational age of 40 weeks) with the use of neuroanatomical MRI techniques.

In smaller studies of preterm infants, such abnormalities have been found to be correlated with impaired working memory and early neurodevelopmental delay. We performed a prospective longitudinal study of very preterm infants studied from birth to two years of age, to examine associations between qualitatively defined cerebral white-matter and gray-matter abnormalities on MRI at term equivalent and neurodevelopmental outcomes at two years of age. We also compared the predictive value of MRI findings with that of findings derived from other assessments during the neonatal period, such as cranial ultrasonography, that are currently used to predict neurodevelopmental risk.

Subjects The study population included 167 very preterm infants (born at 30 weeks of gestation or less) at either Christchurch Women's Hospital, New Zealand, between November 1998 and December 2000 (81 children) or at the Royal Women's Hospital, Melbourne, Australia, between July 2001 and May 2002 (86 children). Fifty infants, all in the Christchurch cohort, received some early intervention services. Referral for these services was based on ultrasonographic findings, gestational age at birth, clinical history, and assessment of physical therapy; MRI results were not used to make referral decisions, nor were they made available to early intervention providers. In Christchurch, 92 percent of all eligible infants were enrolled. In Melbourne, 95 percent of eligible infants were approached, with a recruitment rate of 70 percent. Nonparticipation was primarily due to family circumstances or involvement in other studies. There were no significant (P.

MRI At term equivalent, all infants underwent MRI. Prior to undergoing MRI, each infant was fed, wrapped, and placed, unsedated, in a Vac Fix beanbag designed to keep the infant still and supported in the scanner. We performed MRI using a 1.5-tesla General Electric Signa System (GE Medical Systems) with previously documented sequences. All scans were scored independently by one of the authors and by a pediatric neuroradiologist (Christchurch) or neonatologist (Melbourne). Raters were unaware of the infants' perinatal history and ultrasonographic findings.

We used a standardized scoring system, developed in this study and consisting of eight 3-point scales ( Figure 1 Representative MRI Scans of Children in the Study. Representative coronal T 2-weighted MRI (Panel A) and T 1-weighted MRI (Panel B) show the four grades of white-matter abnormality (none, mild, moderate, or severe). With increasing grade of white-matter abnormality, there was increasing ventricular size, decreasing white-matter volume, increasing intensity of white-matter signal on T 2-weighted imaging, and decreasing myelination in the posterior limb of the internal capsule. Also shown is axial T 2-weighted MRI at the level of the deep nuclear gray matter of infants with normal gray-matter scores (Panel C) and abnormal gray-matter scores (Panel D), demonstrating the simpler gyral patterns observed among infants with gray-matter abnormalities. White-matter abnormality was graded according to five scales, which assessed the nature and extent of white-matter signal abnormality, the loss in the volume of periventricular white matter, and the extent of any cystic abnormalities, ventricular dilatation, or the thinning of the corpus callosum. Gray-matter abnormality was graded according to three scales, which assessed the extent of gray-matter signal abnormality, the quality of gyral maturation, and the size of the subarachnoid space (see, available with the full text of this article at www.nejm.org).

Composite white-matter scores and composite gray-matter scores were created and used to categorize infants according to the extent of their cerebral abnormalities. The categories of white-matter abnormality were none (a score of 5 to 6), mild (a score of 7 to 9), moderate (a score of 10 to 12), and severe (a score of 13 to 15). Gray matter was categorized as normal (a score of 3 to 5) or abnormal (a score of 6 to 9). Interrater agreement for the category assignments was 96 percent. Cranial Ultrasonography We also performed cranial ultrasonography through the anterior fontanelle, with a 7.5- or 8.5-MHz transducer (Acuson-Siemens), according to a standardized protocol.

We acquired images within the first 48 hours of life, at five to seven days of age, and again at four to six weeks of age. If an abnormality was detected, more frequent ultrasonography was performed as clinically indicated. The scans were assessed for the presence and extent of white-matter echolucency or cystic periventricular leukomalacia and the highest grade of intraventricular hemorrhage. Neurodevelopmental Outcomes at Two Years of Age Within two weeks either before or after their second birthday (corrected for prematurity), children underwent a comprehensive neurodevelopmental assessment conducted by examiners who were unaware of the MRI findings and the perinatal course. The examiners assessed the cognitive and psychomotor development using the Bayley Scales of Infant Development (BSID-II): the Mental Development Index assesses environmental responsiveness and sensory and perceptual abilities, memory, learning, and early language and communication abilities; the Psychomotor Development Index assesses both gross and fine motor skills. The six children who had standard scores below 50 were assigned a score of 45, and the two children who were unable to be tested owing to impaired perceptual or cognitive ability were assigned a score of 40. A mild delay in development was defined by a score that was more than 1 SD below the normative mean, and a severe delay was defined by a score that was more than 2 SD below the normative mean.

Each child also underwent a standardized pediatric neurologic evaluation to assess the quality of their motor skills, coordination, gait, and behavior. Cerebral palsy was diagnosed with the use of standard criteria, including the location or body parts impaired (e.g., hemiplegia or diplegia), the degree of impairment of muscle tone and reflexes, and the effects of the condition on ambulation. Finally, evaluations of vision and hearing were completed by an ophthalmologist and an audiologist, respectively, or were recorded from recent hospital evaluations. A visual defect was defined by a requirement for corrective lenses, surgery, or both for strabismus or blindness.

A hearing defect was defined as a sensorineural hearing loss of more than 30 db. Statistical Analysis The associations between white-matter and gray-matter abnormalities on MRI and adverse neurodevelopmental outcomes at two years of age were examined with the use of either one-way analysis of variance for continuously distributed variables or the Mantel–Haenszel chi-square test for dichotomous variables, with tests for linear trend. Odds ratios (and 95 percent confidence intervals) from chi-square analyses were reported as measures of the strength of associations between early risk factors and subsequent neurodevelopmental outcomes. Logistic-regression models were then used to assess the associations between the MRI measures and subsequent neurodevelopmental abnormalities, after adjusting for other factors, including abnormalities on cranial ultrasonography (grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, or both), a gestational age at birth of less than 28 weeks, intrauterine growth restriction, sex, the use of oxygen therapy at 36 weeks, patent ductus arteriosus, multiple birth, and postnatal use of corticosteroids. Finally, we compared the diagnostic accuracy of the MRI and ultrasonographic measures by computing the sensitivity and specificity indexes (and the 95 percent confidence intervals) from chi-square analysis tables. A P value of less than 0.05 was used to indicate statistical significance.

Results On MRI at term equivalent, 47 infants (28 percent) had no white-matter abnormalities, whereas 85 infants (51 percent) had mild white-matter abnormalities, 29 (17 percent) had moderate white-matter abnormalities, and 6 (4 percent) had severe white-matter abnormalities. In addition, 82 infants (49 percent) had gray-matter abnormalities. The severity of white-matter abnormalities was highly correlated with the presence of gray-matter abnormalities (r=0.62, P. Discussion We found significant associations between the qualitative measures of cerebral white-matter and gray-matter abnormalities on MRI at term equivalent and the subsequent risks of adverse neurodevelopmental outcomes at two years of age among very preterm infants. The presence of moderate-to-severe white-matter abnormalities was predictive of severe psychomotor delay and cerebral palsy, independently of abnormalities on cranial ultrasonography and of other perinatal factors. As in previous studies, neurodevelopmental impairment was common among preterm infants in this cohort by two years of age. The most common impairment was severe cognitive delay; nearly one in five children scored six months or more below their corrected age level.

In addition, approximately 10 percent of children had severe psychomotor delay and a similar percentage received a diagnosis of cerebral palsy. Finally, 11 percent had neurosensory impairment (visual, hearing, or both).

These high rates of neurodevelopmental impairment underscore the importance of the early identification of infants who are at greatest neurodevelopmental risk. As in our study, prior studies have demonstrated associations between the presence of white-matter and gray-matter abnormalities on MRI at term equivalent and subsequent risks of neurobehavioral abnormalities, cerebral palsy, impaired working memory, and global developmental delay. However, these studies have been limited by the use of small or selected samples or both, the assessment of a narrow range of outcomes, and the combination of different outcomes that are likely to have different causes and correlates on MRI. Furthermore, it has been unclear to what extent information yielded by MRI during the neonatal period improves on other available clinical information for risk prediction. We found that white-matter abnormalities, especially those that are moderate and severe, were useful markers for the elevated risk of severe cognitive delay, severe psychomotor delay, cerebral palsy, and neurosensory impairment.

Gray-matter abnormalities, assessed qualitatively, were also associated with an increased risk of severe cognitive delay, psychomotor delay, and cerebral palsy, but to a lesser extent than white-matter abnormalities. These findings confirm the relevance of early structural neurologic abnormalities for subsequent neurodevelopmental risk across multiple domains spanning neurologic, cognitive, and motor functioning. A number of other factors during the neonatal period that are recognized to predict subsequent neurodevelopmental outcomes were also predictive of subsequent severe impairment in our cohort.

These factors included the postnatal use of dexamethasone and the ultrasonographic findings of grade III or IV intraventricular hemorrhage and cystic periventricular leukomalacia. However, these factors were infrequent in our cohort, accounting for only a small proportion of the children with severe impairment at two years of age. Furthermore, when MRI and other measures were taken into account, postnatal exposure to corticosteroids remained a significant predictor of subsequent motor impairment (psychomotor delay or cerebral palsy), but the presence of grade III or IV intraventricular hemorrhage or cystic periventricular leukomalacia was no longer a significant predictor of outcome (data not shown).

In contrast, abnormalities on qualitative MRI at term equivalent were more strongly associated with neurodevelopmental impairment than were findings on cranial ultrasonography and other measurements performed during the neonatal period. The MRI findings also predicted impairment independently of those measures. The potential for MRI performed during the neonatal period to improve the prediction of adverse neurodevelopmental outcomes in preterm infants was further supported by analyses showing a high sensitivity of moderate-to-severe abnormalities on MRI for these outcomes. However, it is important to note that a substantial proportion of children with moderate-to-severe white-matter abnormalities were free of severe impairment at two years of age. Although a longer-term follow-up of these children is needed, this finding underscores the fact that worrisome MRI findings may not necessarily result in severe neurodevelopmental problems.

It also highlights the potential importance of other factors, both genetic and environmental, in influencing neurodevelopmental outcomes. The strengths of our study include its prospective design, the high rate of retention of subjects, and the assessment of a diverse range of outcomes by observers who were unaware of the MRI findings. However, the limitations of this study should also be noted.

First, despite a relatively large sample size, the low rate of hearing impairment precluded a separate analysis of hearing and visual problems. Second, the low rates of some factors during the neonatal period may have limited the statistical power of the study to assess their contributions to the outcomes.

Third, given that early delays in development may not correspond with subsequent impairment, further follow-up including neuropsychological, motor, educational, and behavioral assessments will be important to better understand the clinical implications of our MRI findings. Nonetheless, our findings suggest that the identification of early cerebral abnormalities with the use of MRI should offer a valuable complement to other neonatal and psychosocial risk factors in improving the identification of preterm infants at high risk for subsequent neurodevelopmental impairment. Supported by grants from the Neurological Foundation of New Zealand, the Lottery Grants Board of New Zealand, the Canterbury Medical Research Foundation, the Health Research Council of New Zealand, the Murdoch Children's Research Institute, and the National Health and Medical Research Council of Australia. No potential conflict of interest relevant to this article was reported.

We are indebted to John Horwood for biostatistical advice, to Nigel Anderson for ultrasonographic analysis, to Dr. Scott Wells and the Canterbury Radiology Group, to Michael Kean and the Medical Imaging Department of the Royal Children's Hospital, to our research team (Merilyn Bear, Michelle VanDyk, Michelle Davey, Carole Spencer, Rod Hunt, and Karli Treyvaud) for its dedicated efforts, and most importantly, to the families in the study for their willingness to share their children's lives with us.

Source Information From the University of Canterbury and the Van der Veer Institute for Parkinson's and Brain Research (L.J.W.) and Christchurch Women's Hospital (N.C.A.) — all in Christchurch, New Zealand; the Murdoch Childrens Research Institute (P.J.A., T.E.I.) and the Department of Psychology (K.H.), University of Melbourne, Melbourne, Australia; and the Department of Pediatrics, Neurology, and Radiology, St. Louis Children's Hospital, Washington University, St. Louis (T.E.I.). Address reprint requests to Dr. Woodward at the Canterbury Child Development Research Group, Department of Psychology, University of Canterbury, Private Bag 4800, Christchurch, New Zealand,.

References • 1 Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for very low birth weight infants, 1991-1999. Pediatrics 2002;110:143-151 • 2 Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19 • 3 Taylor HG, Klein N, Minich NM, Hack M. Middle-school-age outcomes in children with very low birthweight.

Child Dev 20-1511 • 4 Anderson P, Doyle LW. Neurobehavioural outcomes of school-age children born extremely low birth weight or very preterm in the 1990s.

JAMA 2003;289:3264-3272 • 5 Laptook AR, O'Shea TM, Shankaran S, Bhaskar B. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics 2005;115:673-680 • 6 Allen MC. Preterm outcomes research: a critical component of neonatal intensive care. Ment Retard Dev Disabil Res Rev 2002;8:221-233 • 7 Inder TE, Anderson NJ, Spencer C, Wells S, Volpe JJ.

White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term. AJNR Am J Neuroradiol 2003;24:805-809 • 8 Maalouf EF, Duggan PJ, Counsell SJ, et al. Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants.

Pediatrics 2001;107:719-727 • 9 Maalouf EF, Duggan PJ, Rutherford MA, et al. Magnetic resonance imaging of the brain in a cohort of extremely preterm infants. J Pediatr 1999;135:351-357 • 10 Inder TE, Wells SJ, Mogridge NB, Spencer C, Volpe JJ. Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study.

J Pediatr 2003;143:171-179 • 11 Ajayi-Obe M, Saeed N, Cowan FM, Rutherford MA, Edwards AD. Reduced development of cerebral cortex in extremely preterm infants. Lancet 2000;356:1162-1163 • 12 Huppi PS, Schuknecht B, Boesch C, et al. Structural and neurobehavioral delay in postnatal brain development of preterm infants. Pediatr Res 1996;39:895-901 • 13 Inder TE, Huppi PS, Warfield S, et al.

Periventricular white matter injury in the premature infant is followed by reduced cerebral cortical gray matter volume at term. Ann Neurol 1999;46:755-760 • 14 Woodward LJ, Edgin JO, Thompson D, Inder TE.

Object working memory deficits predicted by early brain injury and development in the preterm infant. Brain 2005;128:2578-2587 • 15 Inder TE, Warfield SK.