Phase I Trial of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination with Docetaxel in Patients with Metastatic Breast Cancer

Abstract Purpose: The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer. Experimental Design: Docetaxel was administered at an initial dose of 60 mg/m2 followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m2/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m2, followed by escalating doses of flavopiridol (starting dose, 26 mg/m2/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry. Results: Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol). Conclusions: Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved

Background ozone over the United States in summer: Origin, trend, and contribution to pollution episodes

Observations indicate that ozone (O3) concentrations in surface air over the United States in summer contain a 20–45 ppbv background contribution, presumably reflecting transport from outside the North American boundary layer. We use a three-dimensional global model of tropospheric chemistry driven by assimilated meteorological observations to investigate the origin of this background and to quantify its contribution to total surface O3 on both average and highly polluted summer days. The model simulation is evaluated with a suite of surface and aircraft observations over the United States from the summer of 1995. The model reproduces the principal features in the observed distributions of O3 and its precursors, including frequency distributions of O3 concentrations and the development of regional high-O3 episodes in the eastern United States. Comparison of simulations with 1995 versus 1980 global fossil fuel emissions indicates that the model captures the previously observed decrease in the high end of the O3 probability distribution in surface air over the United States (reflecting reduction of domestic hydrocarbon emissions) and the increase in the low end (reflecting, at least in the model, rising Asian emissions). In the model, background O3 produced outside of the North American boundary layer contributes an average 25–35 ppbv to afternoon O3 concentrations in surface air in the western United States. and 15–30 ppbv in the eastern United States during the summer of 1995. This background generally decays to below 15 ppbv during the stagnation conditions conducive to exceedances of the 8-hour 0.08 ppmv (80 ppbv) National Ambient Air Quality Standard (NAAQS) for O3. A high background contribution of 25–40 ppbv is found during 9% of these exceedances, reflecting convective mixing of free tropospheric O3 from aloft, followed by rapid production within the U.S. boundary layer. Anthropogenic emissions in Asia and Europe are found to increase afternoon O3 concentrations in surface air over the United States by typically 4–7 ppbv, under both average and highly polluted conditions. This enhancement is particularly large (up to 14 ppbv) for O3 concentrations in the 50–70 ppbv range, and would represent a major concern if the NAAQS were to be tightened

Association of Socioeconomic Disadvantage With Long-term Mortality After Myocardial Infarction: The Mass General Brigham YOUNG-MI Registry

Importance: Socioeconomic disadvantage is associated with poor health outcomes. However, whether socioeconomic factors are associated with post-myocardial infarction (MI) outcomes in younger patient populations is unknown. Objective: To evaluate the association of neighborhood-level socioeconomic disadvantage with long-term outcomes among patients who experienced an MI at a young age. Design, Setting, and Participants: This cohort study analyzed patients in the Mass General Brigham YOUNG-MI Registry (at Brigham and Women\u27s Hospital and Massachusetts General Hospital in Boston, Massachusetts) who experienced an MI at or before 50 years of age between January 1, 2000, and April 30, 2016. Each patient\u27s home address was mapped to the Area Deprivation Index (ADI) to capture higher rates of socioeconomic disadvantage. The median follow-up duration was 11.3 years. The dates of analysis were May 1, 2020, to June 30, 2020. Exposures: Patients were assigned an ADI ranking according to their home address and then stratified into 3 groups (least disadvantaged group, middle group, and most disadvantaged group). Main Outcomes and Measures: The outcomes of interest were all-cause and cardiovascular mortality. Cause of death was adjudicated from national registries and electronic medical records. Cox proportional hazards regression modeling was used to evaluate the association of ADI with all-cause and cardiovascular mortality. Results: The cohort consisted of 2097 patients, of whom 2002 (95.5%) with an ADI ranking were included (median [interquartile range] age, 45 [42-48] years; 1607 male individuals [80.3%]). Patients in the most disadvantaged neighborhoods were more likely to be Black or Hispanic, have public insurance or no insurance, and have higher rates of traditional cardiovascular risk factors such as hypertension and diabetes. Among the 1964 patients who survived to hospital discharge, 74 (13.6%) in the most disadvantaged group compared with 88 (12.6%) in the middle group and 41 (5.7%) in the least disadvantaged group died. Even after adjusting for a comprehensive set of clinical covariates, higher neighborhood disadvantage was associated with a 32% higher all-cause mortality (hazard ratio, 1.32; 95% CI, 1.10-1.60; P = .004) and a 57% higher cardiovascular mortality (hazard ratio, 1.57; 95% CI, 1.17-2.10; P = .003). Conclusions and Relevance: This study found that, among patients who experienced an MI at or before age 50 years, socioeconomic disadvantage was associated with higher all-cause and cardiovascular mortality even after adjusting for clinical comorbidities. These findings suggest that neighborhood and socioeconomic factors have an important role in long-term post-MI survival

Salem Teen Mother Program : a follow-up study

Society has, historically, reacted to teenage pregnancies with a mixture of embarrassment, apathy and neglect. It wasn\u27t until the 1960\u27s that an attempt was made to design and implement programs to meet the needs of pregnant adolescents. An example of such a program is the Salem Teen Mother Program. This program was begun in 1966 and is affiliated with the local YWCA. If offers a comprehensive program to approximately 150 students each year. The services it offers include day care, social services and counseling, education, health services, parenting skills and employment counseling. The following chapters include a literature review which describes the problems facing teenage mothers in the nation. Programs that have been implemented to deal with those problems and the results of related research studies are also discussed. Subsequent chapters are devoted to the follow-up study of the Salem Teen Mother Program. First a description of the program is presented followed by chapters on methodology, data analysis, results and the conclusions from the study

The maternity journey in an organisational context : a case study

The transition to motherhood is a significant life event impacting on all spheres of a woman\u27s life. In an organisational context, changes to women\u27s relationships with their employer and to their social identity occur as they adjust to their new role. A case study was undertaken to describe and compare the workplace experiences of three female employees from one health organisation who were either preparing to commence, currently on or recently returned to work from maternity leave. At all stages of the maternity journey, women expected flexibility from their employer in negotiating their return to work and managing parenting responsibilities. Women\u27s obligations to their employer included being open about their capacity to work and parenting situations which may interfere with their work, as well as maintaining their work performance. Within a supportive work environment that included a shared identity with managers who were also mothers, women\u27s social identity as a worker was not significantly threatened and did not change. Social identity change may be most apparent during the transition to first-time motherhood

Long-Term Follow-Up for Locally Advanced and Inflammatory Breast Cancer Patients Treated With Multimodality Therapy

Purpose To determine long-term event-free (EFS) and overall survival (OS) for patients with stage III breast cancer treated with combined-modality therapy. Patients and Methods Between 1980 and 1988, 107 patients with stage III breast cancer were prospectively enrolled for study at the National Cancer Institute and stratified by whether or not they had features of inflammatory breast cancer (IBC). Patients were treated to best response with cyclophosphamide, doxorubicin, methotrexate, fluorouracil, leucovorin, and hormonal synchronization with conjugated estrogens and tamoxifen. Patients with pathologic complete response received definitive radiotherapy to the breast and axilla, whereas patients with residual disease underwent mastectomy, lymph node dissection, and radiotherapy. All patients underwent six additional cycles of adjuvant chemotherapy. Results OS and EFS were obtained with a median live patient follow-up time of 16.8 years. The 46 IBC patients had a median OS of 3.8 years and EFS of 2.3 years, compared with 12.2 and 9.0 years, respectively, in stage IIIA breast cancer patients. Fifteen-year OS survival was 20% for IBC versus 50% for stage IIIA patients and 23% for stage IIIB non-IBC. Pathologic response was not associated with improved survival for stage IIIA or IBC patients. Presence of dermal lymphatic invasion did not change the probability of survival in clinical IBC patients. Conclusion Fifteen-year follow-up of stage IIIA and inflammatory breast cancer is rarely reported; IBC patients have a poor long-term outlook