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To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2007.01369.x Byline: Leona Downey (*), Robert Livingston (*), Alison Stopeck (*) Keywords: breast; cancer; diagnosis; treatment; elderly Abstract: Breast cancer is the most common nondermatological malignancy in women, and the incidence increases with age until the eighth decade. Breast cancer pathology and biology appear to be different in elderly patients than in younger ones, and therefore treatment recommendations cannot be generalized from one group to the other. Most elderly women can tolerate breast cancer surgery without significant complications and should be offered a definitive surgical procedure. Improved mechanisms to predict which patients will tolerate and benefit from various therapies are under development. Because most breast cancers in the elderly are hormone responsive, hormonal therapy remains the mainstay of systemic treatment in the adjuvant and metastatic settings. Chemotherapy can be used in elderly women, but treatment decisions must be individualized based upon risk-benefit analyses. Elder-specific studies are underway to identify the most-efficacious and best-tolerated therapies for breast cancer in this population. Primary care physicians must be aware of these issues to provide adequate counseling and care to these patients. Author Affiliation: (*)Section of Hematology and Oncology, University of Arizona, Arizona Cancer Center, Tucson, Arizona Article note: Address correspondence to Leona B. Downey, MD, 1515 N Campbell Ave, Tucson, AZ 85724. E-mail: ldowney@email.arizona.edu

Background: Abnormal expression of the cell cycle regulatory proteins [p27.sup.Kip1] (p27) and cyclin E may be associated with breast cancer survival and relapse. We studied these markers in a clinical trial setting with patients with breast cancer treated by a uniform drug regimen so that treatment was not associated with variability in outcome. Methods: We used tissue microarrays to evaluate the expression of p27 and cyclin E proteins by immunohistochemistry in tumor tissue from 2123 (68%) of 3122 patients with moderate-risk primary breast cancer who were enrolled in Southwest Oncology Group--Intergroup Trial $9313, in which patients were assigned to receive doxorubicin and cyclophosphamide administered concurrently (n = 1595) of sequentially (n = 1527). Disease-free and overall survival were equivalent in the two arms. Expression of the proteins was rated on a scale of 1-7, and the median value was used as the cut point. Log-rank tests and Cox regression analyses were used to assess associations with survival. Overall survival was defined as time to death from all causes; disease-free survival was defined as time to recurrence of death. All P values were from two-sided statistical tests. Results: Lower p27 expression was associated with worse overall survival (unadjusted hazard ratio [HR] = 1.50, 95% confidence interval [CI] = 1.21 to 1.86) and disease-free survival (unadjusted HR = 1.31, 95% CI = 1.10 to 1.57) than higher p27 expression. Among hormone receptor--positive patients, lower p27 expression was associated with worse overall survival (HR = 1.42, 95% CI = 1.05 to 1.94) and worse disease-free survival (HR = 1.27, 95% CI = 0.99 to 1.63) than higher p27 expression after adjustment for treatment, menopausal status, tumor size, and number of positive lymph nodes. Among these patients, 5-year overall survival associated with higher p27 expression (0.91, 95% CI = 0.89 to 0.93) was similar to that associated with lower p27 expression (0.85, 95% CI = 0.82 to 0.87). No association between p27 expression and survival was found in hormone receptor--negative patients. Cyclin E expression was not statistically significantly associated with overall survival (HR = 1.12, 95% CI = 0.91 to 1.38) or disease-free survival (HR = 1.09, 95% CI = 0.92 to 1.29). Conclusions: Low p27 expression appears to be associated with poor prognosis, especially among patients with steroid receptor--positive tumors.

A significant correlation, was found, between the Tajima's D test statistic in full resequencing data and Tajima's D in a dense, genome-wide data set of genotyped polymorphisms for a set of 179 genes. Identification of the functional polymorphism (and/or halpotype) responsible for the selective sweeps within each CRTR may provide interesting insights into the strongest selective pressures experienced by the human genome.

Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P

Former Chancellor Helmut Kohl's secret, illegal fundraising has corroded the German public's trust in its political parties and in the party-dominated system itself. The revelations that surfaced in late autumn [...]

AIDS vaccines made from the HIV gp120 or gp 160 protein appear to be safe enough to use in infants and children. Researchers vaccinated 72 HIV-infected children between one month and 18 years old with a gp120 vaccine, a gp160 vaccine, or a placebo approximately every month for about six months. Sixty-five percent of those who received the vaccine developed an immune response to it, which did not occur in the placebo group.

'His Eternality' is how the leader of Germany's Greens once referred to him. Indeed, Helmut Kohl has led his country for 15 years, the longest tenure of any chancellor this [...]

Study objective: To determine the efficacy of methotrexate, vinblastine, and platinum chemotherapy in patients with diffuse unresectable malignant mesothelioma. Design: Patients with histologically confirmed malignant mesothelioma were evaluated for treatment [...]

Objective: To determine the sensitivity and specificity of human immunodeficiency virus (HIV)-specific IgA for vertically transmitted HIV infection, particularly during the first month of life. Design/Setting/Patients: Prospective cohort study of 140 infants born to HIV-seropositive women in a large urban teaching hospital and of 248 older infants and children referred for diagnosis and treatment of HIV infection. Main Outcome Measures: The HIV-specific IgA immunoblot results were compared with the infection status of patients as determined by Centers for Disease Control and Prevention (Atlanta, Ga) criteria or by sequential early diagnostic assays for HIV. Sensitivity, specificity, and predictive values were calculated for each age range. Results: Among infants studied from birth, the rate of vertical transmission of HIV was 21.6% (25/116). The sensitivity of HIV-specific IgA for the first month of life was 8.0% (2/25), and the specificity was 90.1% (82/91). Sensitivity increased progressively during the first year of life, and the negative predictive value was 94.6% by 6 to 8 months of age. The positive predictive value of this assay was 18.2% for neonates but was 96% to 100% after the first month of life. Conclusions: False-positive test results for HIV-specific IgA occurred with diminishing frequency during the first 4 weeks of life, and the frequency of detectable HIV-specific IgA was similar among the HIV-infected and uninfected groups at this age. Beyond 1 month of age, detection of HIV-specific IgA is highly specific and is a useful serum-based assay for early diagnosis of HIV infection. These results suggest that maternal-fetal transfusion is common and support the hypothesis that the majority of maternal-fetal transmission of HIV occurs around the time of parturition., Finding HIV-specific immunoglobulin A (IgA) in the blood of infants born to HIV-infected mothers appears to be highly predictive of HIV infection but only after the first month of life. Of 116 infants born to HIV-positive women who were tested an average of 12 days after birth, 22% were infected. In the first month of life 2 of these 25 infants tested positive for HIV-specific IgA and 10% of infants had false-positive tests. By four weeks of age, the false-positive rate fell to zero. This suggests that maternal IgA is transmitted to the baby around the time of birth. The presence of HIV-specific IgA accurately identifies 96% to 100% of HIV-infected infants after the first month of life.

Objectives: To describe and to evaluate the longitudinal growth of children born to mothers with human immunodeficiency virus (HIV) infection. Design: Measurements of weight, length (measured in infants in a recumbent position) and height (measured in older children in an upright position), and head circumference were documented and evaluated longitudinally using generalized estimating equations in a group of children born to HIV-infected mothers. Children infected with HIV were compared with uninfected children and with National Center for Health Statistics standards. Setting: Primary care clinic in an urban hospital devoted to the medical care of children born to HIV-infected mothers. Patients: One hundred nine children born to HIV-infected mothers, 59 HIV-infected and 50 uninfected, between birth and 70 months of age. Results: The mean birth weights of both groups were below the 50th percentile. While the mean weight-for-age curve of uninfected children attained the 50th percentile by age 24 months, the mean birth weight-for-age curve of HIV-infected children remained below the 50th percentile. Weight gain became significantly different between the two groups by age 36 months. The mean birth length-for-age curves of HIV-infected and uninfected children was also below the 50th percentile. The mean height-for-age curve of uninfected children attained the 50th percentile by age 40 months, while that of HIV-infected children remained well below the 50th percentile. Linear growth between HIV-infected and uninfected children diverged earlier than weight, becoming significantly different by age 15 months. Conclusions: Although children born to HIV-infected mothers are born with weight and length below the 50th percentile, uninfected children catch up, while HIV-infected children remain below the 50th percentile and experience an earlier and more pronounced decrease in linear growth (height-for-age) than in weight-for-age. (Arch Pediatr Adolesc Med. 1995;149:497-502), Babies born to HIV-infected mothers may be smaller and weigh less than average for their age and those who are infected remain so. Researchers periodically measured weight, length, and head circumference on 109 children born to HIV-infected mothers between birth and 70 months. Fifty-nine children were infected with HIV. Average birth weights of both infected and non-infected children were below the 50th percentile for the general population. However, uninfected children achieved the 50th percentile for weight by 24 months old, whereas HIV-infected children remained below the 50th percentile. Length-for-age was also below the 50th percentile in both groups. By 40 months the uninfected children had achieved the 50th percentile for height, but HIV-infected children remained below the 50th percentile.

Background: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. Purpose: On the basis of these results, the Radiation Therapy Oncology Group RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. Methods: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m[sup.2]) on days 1 and 29 and 5 mg/m[sup.2] vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). Results: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy - 46%, 11.4 months; chemotherapy plus radiotherapy - 60%, 13.8 months; and hyperfractionated radiation therapy - 51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). Conclusions: In 'good-risk' patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.

'Dose response' refers to a direct relationship between the amount of chemotherapy administered and observed degree of antitumor effect. What is often implied by the term is the administration of pulsed, high dose therapy, resulting, in very high peak concentrations. Clinically, this has been translated as multiple alkylating agent-based regimens requiring intensive supportive care and associated with substantial morbidity and an appreciable mortality risk. Such regimens typically are given as consolidation after an initial period of standard outpatient therapy and may require autologous hematopoietic stem cell support. 'Dose intensity' is defined as the amount of drug administered per unit of time, typically reported in mg/[m.sup.2]/ week. This is a more precise term than 'dose response.' A dose-intensive regimen may or may not be one associated with high peak concentrations. For example, prolonged or continuous administration of an agent like cyclophosphamide may be quite dose-intensive, but will be associated with lower peak concentrations and less acute toxicity than a similarly dose-intensive, pulsed high dose regimen of the same drug. Retrospective analyses and prospective, randomized trials suggest the importance of dose intensity in the treatment of breast cancer. The evidence that high dose therapy (associated with high pea k plasma levels) is beneficial in breast cancer rests on a number of Phase II trials. In the setting of poor prognosis Stage IV disease, these trials suggest little improvement in median survival, but better long term survival (at or beyond 2 years) in 15-25% of such patients. This benifiting cohort appears to be in unmaintained disease free remission, whereas standard therapy in the past has almost never produced such remissions in the poor prognosis subgroup of Stage IV disease. In the setting of high risk Stage II disease, Phase II trials of similar high dose therapy indicate a higher proportion of patients who are free of recurrence at 2-3 years than expected from available historic controls. Randomized trials are now underway in Stage IV poor prognosis patients and in Stage II high risk patients to see whether the apparent improvements in outcome associated with pulsed high dose chemotherapy can be validated prospectively. The regimens under study in these randomized trials include agents that require autologous support with harvested bone marrow and/or peripheral blood progenitor cells. Such obligate stem cell support carries with it the risk of tumor cell contamination in the collection and subsequent iatrogenic dissemination of disease. The frequency and magnitude of this contamination are under study, and methods to purge the autologous collection of tumor cells are under development, but both types of research are embryonic. Alternative approaches to pulsed, high dose chemotherapy not requiring autologous stem cell support exist, and reported results in poor prognosis Stage IV disease appear comparable to those achieved by obligate stem cell programs. Development of genetically engineered hematopoietic growth factors has facilitated approaches to improved dose intensity as well as to pulsed high dose consolidation. Thrombocytopenia and mucositis, however, are little affected by the available growth factors. Further improvements in therapeutic index for both approaches may result from new growth factors now under study. The use of peripheral blood progenitor cells shortens thrombocytopenia after high dose regimens. A new area of investigation involves the suppression of negative regulators of hematopoiesis (e.g., tumor necrosis factor), which may be overexpressed after bone marrow injury by high dose therapy. The future may involve combining concepts of dose response (e.g., dose intensive induction to pulsed consolidation). Optimal results are likely to be achieved through the integration of dose response with other approaches (local irradiation to high risk sites, biologic response modifiers). Cancer 1994; 74:1177-83. Key words: dose intensity, dose response, peak dose level, breast cancer, hematopoietic growth factors.

Background. Survival after relapse or progression of small cell lung cancer (SCLC) is poor. The Southwest Oncology Group (SWOG) initiated a study of modulation of cyclophosphamide (Cy) resistance in this population. At study closure, the value of testing new regimens in previously treated patients was being debated nationally: Is there an independent impact of treatment over favorable prognostic factors? Thus, the authors analyzed the SWOG recurrent SCLC data base. Methods. A 12-hour infusion of cytosine arabinoside (ara-C) was used as a potential repair inhibitor of Cy-induced DNA damage in patients with relapsed SCLC. A data base of successive SWOG studies in recurrent SCLC was formed. The independent contribution to survival of prognostic factors, type of prior chemotherapy (CT), time from diagnosis, and type of CT on relapse were then assessed. Results. There were 3 partial responses observed in 67 patients, with substantial myelotoxicity. The median survival was 2.5 months, and 16% lived beyond 6 months. The multivariate analysis of the recurrent SCLC data base found that a normal lactate dehydrogenase (LDH) and second-line treatment with etoposide plus cisplatin (EP), if not initially treated with either alternating or complex multidrug regimens, were the only independent predictors of improved survival. The 2-year survival of this subset was 20%. Conclusions. The Cy/ara-C program cannot be recommended for patients with recurrent SCLC. However, EP independently contributed to improved survival in patients without complex prior CT and a normal LDH. This finding supports future trials of new approaches in certain subsets of SCLC patients with limited prior treatment. Cancer 1993; 72:1184-91.

Background. Etoposide may be schedule dependent in small cell lung cancer (SCLC), and some data suggest a benefit for increased dose intensity in this disease. This study attempted to optimize dose intensity using an out-patient program that included prolonged, oral etoposide administration. Methods. Cisplatin-etoposide (PE) and cyclophosphamide, doxorubicin, and vincristine (CAV) were alternated at monthly intervals in patients with extensive SCLC. PE was given as cisplatin 50 mg/[m.sup.2] on days 1 and 8 intravenously (IV) and etoposide 50 mg/[m.sup.2]/day for 14 days by mouth. CAV was administered as cyclophosphamide 60 mg/[m.sup.2]/day for 21 days orally, doxorubicin 20 mg/[m.sup.2]/week for three doses, and vincristine 2 mg IV on day 1 only. At the end of 4 months, responding patients received an additional course of PE alternating with CAV, and whole-brain irradiation (3000 cGy in 15 fractions) was delivered to clinical complete responders (CR). Results. Among 61 eligible patients, 4 achieved CR, and 11 had a partial remission, by strict Southwest Oncology Group criteria. An additional 20 patients demonstrated greater than 50% tumor shrinkage on one disease assessment but did not have confirming measurements at all sites 4 weeks later. The overall response rate was 57%, including the latter group. The toxicity was primarily hematologic, with three treatment-related deaths from neutropenic infection (5%). Grade 4 neutropenia (< 500/[mu]l) occurred in nine patients (15%) and Grade 4 thrombocytopenia (< 25,000/,[mu]l), in three (5%). Analysis of the delivered dose intensity (in milligrams per square meter per week) as a function of that which was planned revealed a mean of 93% for all courses. Conclusions. Although substitution of prolonged oral etoposide in PE and oral cyclophosphamide in CAV proved to be feasible, these results suggest no advantage over those from other reported series using these alternating regimens in which the agents are pulsed. Experience with alternating PE-CAV for extensive SCLC is reviewed.