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Perfluorooctane sulfonate (PFOS) is one of the dominant perfluoroalkyl substances (PFAS) detected in aquatic ecosystems. It has been used in a wide range of industrial and consumer products for decades. The unique properties of PFOS, including its stability and resistance to degradation, have made it highly persistent in the aquatic environment. Because of its persistence, potential toxicity, and occurrence in aquatic ecosystems, interest in PFOS has increased in recent decades. Despite this interest, current information on the environmental distribution of PFOS in ambient surface waters of the United States is fairly limited. This critical review summarizes the currently available literature on PFOS occurrence in surface waters across the United States and highlights existing data gaps. Available data are largely from a handful of study areas with known PFAS manufacturing or industrial uses, with much of the data collected from freshwater systems in eastern states and the upper Midwest. Measured PFOS concentrations in surface waters vary widely, over 8 orders of magnitude, with the highest concentrations occurring downstream from manufacturing and industrial use plants, areas near aqueous film-forming foam-use sites, and sites where PFOS precursors were used in textile treatment. Non-point source-related occurrences are highest near urbanized areas with high population densities. Current data illustrate the occurrence of PFOS in surface waters across multiple US states. Additional data are needed to better understand PFOS occurrence in US aquatic ecosystems, particularly in estuarine and marine systems and where monitoring data are not available (e.g., southwestern, central, and western United States). Additional PFOS occurrence data would provide valuable information on potential spatial and temporal variability in surface waters and possible risks posed to aquatic ecosystems. Environ Toxicol Chem 2021;40:2425-2442. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.

The potential for delayed mortality following short‐term episodic pollution events was evaluated by exposing cladocerans (Ceriodaphnia dubia) and rainbow trout (Oncorhynchus mykiss) to zinc (Zn) in various 1‐ to 48‐h and 1‐ to 96‐h exposures, respectively, followed by transferring the exposed organisms to clean water for up to 47 h for C. dubia and up to 95 h for trout for additional observation. For C. dubia, 1‐h exposures of up to 3790 µg Zn/L never resulted in mortality during the actual Zn exposures, but by 48 h, a 1‐h exposure to 114 µg/L, a concentration similar to the present US national water quality acute criterion for the test water conditions, ultimately killed 70% of C. dubia. With C. dubia, the speed of action of Zn toxicity was faster for intermediate concentrations than for the highest concentrations tested. For rainbow trout, pronounced delayed mortalities by 96 h only occurred following ≥8‐h exposures. For both species, ultimate mortalities from Zn exposures ≤8 h mostly presented as delayed mortalities, whereas for exposures ≥24 h, almost all ultimate mortalities presented during the actual exposure periods. With Zn, risks of delayed mortality following exposures to all concentrations tested were much greater for the more sensitive, small‐bodied invertebrate (C. dubia) than for the less sensitive, larger‐bodied fish (rainbow trout). These results, along with previous studies, show that delayed mortality is an important consideration in evaluating risks to aquatic organisms from brief, episodic exposures to some substances. Environ Toxicol Chem 2021;40:2484–2498. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article has been contributed to by US Government employees and their work is in the public domain in the USA., Rainbow trout could withstand extreme Zn pulses of 1 to 3 h, with few subsequent deaths. Few Ceriodaphnia dubia died during 1‐ to 3‐h Zn pulses, but after 48 h, most were dead. Time to effects decreased as expected as rainbow trout were exposed to increasing Zn concentrations. Not so with C. dubia: time to effects was fastest in intermediate Zn exposures, with longer survivals in higher Zn exposures.

Vol. 1, No. 2 (2019) This issue of SourceLab presents a famous editorial cartoon, published in the weekly journal Fun during the Second Anglo-Afghan War (1878-1880). This publication is part of the digital documentary edition series SourceLab, based at the University of Illinois at Urbana-Champaign. Our Editorial Board conducts rigorous peer-review of every edition.

What accounts for the longevity of the traditional–contemporary musical divide in so many American churches? The pattern of labeling worship with the organ and chancel choir as traditional and a se...

Freshwater gastropods represent common and important members of aquatic ecosystems, but emerging chemical contaminants may challenge gastropod fitness. As the use of nanosilver (n-Ag) increases, the potentially adverse effects of n-Ag on aquatic ecosystems remain largely unknown. In aquatic ecosystems, we hypothesized that n-Ag at trace concentrations may affect the ability of organisms to sense predation by interfering with chemoreception. We performed a microcosm experiment to assess the freshwater gastropod, Physa acuta, to detect and respond to natural predator cue derived from pumpkinseed sunfish (Lepomis gibbosus), at environmentally relevant nominal n-Ag concentrations over 24 h. For the first 6 h exposure, gastropod predator avoidance behavior measured 30–47% less in treatments with environmentally relevant n-Ag concentrations compared to treatments without n-Ag. Regardless of predator cue presence or absence, the proportion of gastropods occupying near surface habitat in 30 µg/liter n-Ag...

Background: Pathologic complete response (pCR) is a proposed surrogate endpoint for predicting long-term clinical benefit on endpoints such as disease-free survival (DFS), event-free survival (EFS), or overall survival (OS). A meta-analysis is needed to establish the magnitude of pCR improvement on a trial level that results in improved DFS, EFS, or OS. Methods: We identified 12 neoadjuvant randomized trials (N = 13,125) with pCR clearly defined and long-term follow-up available for EFS and OS. Trials included AGO 1 (n = 668), ECTO (n = 1355), EORTC 10994/BIG 1–00 (n = 1856), GeparDuo (n = 907), GeparQuattro (n = 1495), GeparTrio (n = 2072), GeparTrio-Pilot (n = 285), NOAH (n = 234), NSABP B18 (n = 760), and NSABP B27 (n = 2411), PREPARE (n = 733), and TECHNO (n = 217). Key objectives of the meta-analysis were to determine: (1) the relationship of pCR to EFS and OS, (2) the definition of pCR that correlates best with long-term outcome, (3) the breast cancer subtypes in which pCR is best correlated with long-term outcome and (4) the magnitude of pCR effect needed to improve EFS and OS. We compared three pCR definitions: absence of invasive cancer and in situ cancer in the breast and axillary nodes (ypT0ypN0), absence of invasive cancer in the breast and axillary nodes with DCIS allowed (ypT0/isypN0), and absence of invasive cancer in the breast with DCIS allowed irrespective of nodal involvement (ypT0/is). Results: Overall 13%, 18% and 22% of patients achieved a pCR defined as ypT0ypN0, ypT0/isypN0, and ypT0/is, respectively. Eradication of tumor from both the breast and lymph nodes (ypT0ypN0 or ypT0/isypN0) was better associated with improved EFS and OS compared to eradication of tumor from the breast alone (ypT0/is). Patients who achieved a pCR (ypT0/isypN0) had an improved EFS (HR = 0.48) and OS (HR = 0.36) compared to those who did not. pCR was uncommon in patients with low-grade hormone receptor-positive (HR+) tumors (7%) and more common in the following tumor subtypes: high-grade HR+ (16%), triple negative (34%), HR+/HER2+ (30%), and hormone receptor-negative (HR−)/HER2+ (50%). Patients with more aggressive tumor subtypes who achieved pCR had greater EFS compared to patients who did not achieve pCR as follows: HR+ high grade (HR = 0.27), HR+/HER2+ (HR = 0.58), HR−/HER2+ (HR = 0.25), and triple negative (HR = 0.24). A trial level analysis on the relationship between pCR effect size and EFS did not show a correlation. Conclusions: Individual patients who attain a pCR, defined as either ypT0ypN0 or ypT0/isypN0, have a more favorable long-term outcome. The data show comparable EFS or OS regardless of the presence or absence of DCIS. For consistency, a standard pCR definition (ypT0ypN0 or ypT0/isypN0) should be used in future trials. Impact of pCR effect is limited to patients with HR+/grade 3, HR−/HER2−, and HER2+ tumors. This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS. This may be due to low pCR rates and the heterogeneity of the patient population included in this meta-analysis. The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials and may vary according to breast cancer subtype. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-11.

In part A of this study, patients were randomised to cohorts receiving darbepoetin alfa at doses of 0.5 to 8.0 m.c.g. kg−1 wk−1 or to a control group receiving epoetin alfa at an initial dose of 150 U kg−1 three times weekly. In part B, the cohorts were darbepoetin alfa 3.0 to 9.0 m.c.g. kg−1 every 2 weeks or epoetin alfa, initial dose 40 000 U wk−1. Safety was assessed by adverse events, changes in blood pressure, and formation of antibodies to darbepoetin alfa. Efficacy was assessed by several haematologic endpoints, including change in haemoglobin from baseline. The adverse event profile of darbepoetin alfa was similar to that of epoetin alfa. No relationship between the rapidity of haemoglobin response and any adverse event was observed. No antibodies to darbepoetin alfa were detected. Higher doses of darbepoetin alfa increased the proportion of patients with a haemoglobin response and decreased the median time to response. The overall dose of darbepoetin alfa required to produce a mean increase in haemoglobin does not increase when the dosing interval is increased from 1 to 2 weeks. Therapy with darbepoetin alfa is safe and effective in producing a dose-related increase in haemoglobin levels in patients with cancer receiving chemotherapy. British Journal of Cancer (2002) 87, 268–276. doi:10.1038/sj.bjc.6600465 www.bjcancer.com © 2002 Cancer Research UK

Background: There is little information on the incidence of AIDS-defining events which have been reported in the literature to be associated with immune reconstitution inflammatory syndrome (IRIS) after combined antiretroviral therapy (cART) initiation. These events include tuberculosis, mycobacterium avium complex (MAC), cytomegalovirus (CMV) retinitis, progressive multifocal leukoencephalopathy (PML), herpes simplex virus (HSV), Kaposi sarcoma, non-Hodgkin lymphoma (NHL), cryptococcosis and candidiasis. Methods: We identified individuals in the HIV-CAUSAL Collaboration, which includes data from six European countries and the US, who were HIV-positive between 1996 and 2013, antiretroviral therapy naive, aged at least 18 years, hadCD4+ cell count and HIV-RNA measurements and had been AIDS-free for at least 1 month between those measurements and the start of follow-up. For each AIDS-defining event, we estimated the hazard ratio for no cART versus less than 3 and at least 3 months since cART initiation, adjusting for time-varying CD4+ cell count and HIV-RNA via inverse probability weighting. Results: Out of 96 562 eligible individuals (78% men) with median (interquantile range) follow-up of 31 [13,65] months, 55 144 initiated cART. The number of cases varied between 898 for tuberculosis and 113 for PML. Compared with non-cART initiation, the hazard ratio (95% confidence intervals) up to 3 months after cART initiation were 1.21 (0.90-1.63) for tuberculosis, 2.61 (1.05-6.49) for MAC, 1.17 (0.34-4.08) for CMV retinitis, 1.18 (0.62-2.26) for PML, 1.21 (0.83-1.75) for HSV, 1.18 (0.87-1.58) for Kaposi sarcoma, 1.56 (0.82-2.95) for NHL, 1.11 (0.56-2.18) for cryptococcosis and 0.77 (0.40-1.49) for candidiasis. Conclusion: With the potential exception of mycobacterial infections, unmasking IRIS does not appear to be a common complication of cART initiation in high-income countries. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

13 Present address: Vector Research Company, 6903 Rockledge Drive, Bethesda, MD 20817, USA . Present address : University of North Carolina-Asheville, Asheville, NC 28804, USA . Present address: STX Inc., 4400 Forbes Blvd ., Lanham, MD 20706, USA . Present address : University of Colorado, Boulder, CO 80309, USA . Present address : Fermilab, Batavia, IL 60510, USA. Present address : Dipartimento di Elettronica, University dl Pavia, Pavia, Italy. Present address : Dipartimento di Fisica Nucleate e Teorica dell'Universita and INFN Pavia, 1-27100 Pavia, Italy Present address : State University of New York, Stony Brook, NY 11794, USA. Present address : NIKHEF-H, 1009 DB, Amsterdam, The Netherlands . Present address : University of Alabama, Tuscaloosa, AL 35487, USA . Present address : Brandeis University, Waltham, MA 02254, USA. Present address : University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Present address : Nevis Labs, Columbia University, Irvington, NY 10533, USA.

The magnetic spectrometer and charged particle tracking system used in Fermilab experiment 687 to study the photoproduction and decay of charm particles are described in detail. The photons are produced by a wideband electron beam which can operate at energies up to 600 GeV/ c . The spectrometer consists of a high resolution silicon microstrip detector, a large aperture dipole magnet, proportional chambers, a second large aperture dipole, and more proportional chambers. Three multi-cell threshold Cherenkov counters provide charged particle identification. The tracking system is capable of resolving the secondary decay vertices of charm and beauty mesons and baryons from the primary interaction vertex. It also determines the invariant mass of the multibody final states of particles containing heavy quarks with excellent resolution. The particle identification system allows one to identify kaons and protons present in these final states clearly. This collection of detectors produces very clean signals for charm particles and permits one to make many cross checks of the apparatus. The performance is illustrated for a variety of charm signals. Of particular interest is a description of the tracking through the silicon microstrip detector and its use in isolating downstream decay vertices. Two complementary approaches to the reconstruction of secondary decay vertices are presented and insight is gained by comparing their strengths and weaknesses.

Twenty iridoid glycosides, including four few ones (10- O -foliamenthoylaucubin, 6″ R ,7″-dihydro-10- O - foliamenthoylaucubin, 6β-hydroxy-8-epiboschnaloside and aldoxoside), were identified from eight taxa of Cordylanthus (Scrophulariaceae). Pairs of C-8 epimeric iridoids (e.g. boschnaloside/8-epiboschnaloside and their 6β-hydroxy derivatives) were found together in the same plant for the first time in the Scrophulariaceae. Verbascoside was found in all species.

The optimal hemoglobin concentration at which to initiate erythropoietic therapy for chemotherapy-induced anemia (CIA) is not well defined. This randomized, open-label, multicenter study evaluated the ability of darbepoetin alfa (300 μg every 3 weeks) to maintain hemoglobin levels ≥10g/dl in patients with CIA (hemoglobin ≥10.5 g/dl and ≤12.0 g/dl) randomized 1:1 to an immediate-intervention group (received darbepoetin alfa immediately) or observation group (received darbepoetin alfa if hemoglobin fell to

Capecitabine results in superior response rate, improved safety, and improved convenience compared with 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (MCRC). Irinotecan in combination with 5-FU/LV has been shown to improve efficacy compared with 5-FU/LV alone in MCRC. Therefore, we evaluated the efficacy and safety of capecitabine plus irinotecan every 3 weeks (XELIRI regimen) as first-line treatment.Patients with MCRC who were65 years of age received irinotecan 250 mg/m i.v. on day 1 + capecitabine 1000 mg/m orally twice daily on days 1 to 14, every 3 weeks. Patientsor=65 years of age and those with impaired renal function or with a history of prior radiotherapy received lower doses of both agents (200 mg/m and 750 mg/m twice daily, respectively).A total of 52 patients (29 men, 23 women) were enrolled between October 2001 and August 2003. Median age was 57.5 years (range, 30-79 years); median Karnofsky performance status was 90 (range, 70-100). Treatment led to a response rate of 50% (ITT population) and a disease control rate of 71%. With a median cohort follow-up of 30.5 months, median time to progression and overall survival are 7.8 months (95% confidence interval, 5.6-10.0) and 16.8 months (95% confidence, 11.9 to not reached), respectively. Most common treatment-related grade 3/4 adverse events were neutropenia (25%), diarrhea (20%), vomiting (16%), dehydration (10%), nausea (6%), abdominal pain (6%), and hand-foot syndrome (6%).XELIRI is an active first-line treatment of MCRC. Implementation of upfront dose reductions for both agents in patients with risk factors for toxicity appears to have produced a safer regimen compared with previous studies of XELIRI without such dose reductions.

This is the first randomized, open-label, multicenter trial designed and powered to directly compare the hemoglobin (Hb) response to epoetin alfa (EPO), 40,000 U once weekly (QW), with that to darbepoetin alfa (DARB), 200 μ g every 2 weeks (Q2W), in anemic patients with cancer receiving chemotherapy (CT). Transfusion requirements, quality of life (QOL), and safety also were evaluated. Adults with solid tumors scheduled to receive CT for ≥12 weeks and with baseline Hb ≤11 g/dl were randomized to receive either EPO 40,000 U QW (n = 178) or DARB 200 μg Q2W (n = 180) s.c. for up to 16 weeks. Doses were increased for nonresponders (Hb increase 1.3 g/dl [EPO] or >1.0 g/dl [DARB] within any 2-week period) or for an Hb level >13 g/dl. The proportion of patients achieving a ≥1-g/dl Hb rise by week 5, the primary end point, was significantly higher with EPO (47.0%) than with DARB (32.5%), and EPO-treated patients achieved a ≥1-g/dl Hb increase significantly earlier than those receiving DARB (median, 35 days versus 46 days). The mean increase in Hb from baseline was significantly higher at weeks 5, 9, 13, and the end of the study with EPO than with DARB. The number of units transfused per patient was significantly lower for the EPO group than for the DARB group. The proportions of patients requiring transfusions, mean QOL improvements, and tolerability profiles were similar in the two groups.

A polar modulation transmitter, fabricated in BiCMOS technology, is presented. It uses an offset loop transmitter to achieve both GSM and EDGE phase modulation. For the 8PSK modulation, the amplitude information is reconstructed through the use of a saturated GSM power amplifier with collector voltage modulation. This solution does not require the use of SAW filters and RF isolators and maintains excellent EVM and good ACPR over a wide range of VSWR. This transmitter is part of a quad band GSM/EDGE highly integrated transceiver.

An E-GPRS power amplifier controller, designed in a 5 V 0.5 /spl mu/m CMOS technology, is presented. Based on an open-loop polar modulation transmitter strategy for both GMSK in GSM and 8PSK in EDGE, the power control for both ramping and modulation depth is provided from collector supply control, and critical power amplifier (PA) temperature and process variability is compensated through the use of an automated bias calibration procedure detailed herein. Leveraging the architecture's capability for removal of transmit SAW filters, removal of isolators and maintenance of critical adjacent channel power ratio (ACPR) and error vector magnitude (EVM) performance into PA output mismatched impedance environments, the controller provides excellent linearity for higher power 8PSK power, and performance of transient spectrum due to switching even when run into the battery headroom limit of the supply rail.

BACKGROUND Anemia in patients receiving chemotherapy can be ameliorated with recombinant human erythropoietin (rHuEPO), which is administered one to three times per week. Darbepoetin α, a new erythropoietic agent, has longer serum residence time, allowing it to be administered less frequently. METHODS Patients (n = 127) were randomized to receive study drug for 12 weeks: either rHuEPO 40,000 U with escalations to 60,000 U for nonresponders or darbepoetin α at doses of 4.5 μg/kg per week until hemoglobin concentration ≥ 12 g/dL, then 1.5 μg/kg per week (Group 1); 4.5 μg/kg per week for 4 weeks, then 2.25 μg/kg per week for 8 weeks (Group 2); or 4.5 μg/kg per week for 4 weeks, then 3.0 μg/kg every 2 weeks (Group 3). Efficacy was measured using the mean change in hemoglobin level, the proportion of patients achieving a hemoglobin response, the time to response, and the mean change in Functional Assessment of Cancer Therapy-Fatigue Scale scores. Safety was assessed by reports of adverse events. RESULTS Overall, after 4 weeks of treatment, the mean change (95% confidence interval [95%CI]) in hemoglobin concentration was 0.53 g/dL (95%CI, 0.05–1.02 g/dL), 0.70 g/dL (95%CI, 0.11–1.29 g/dL), and 0.90 g/dL (95%CI, 0.47–1.33 g/dL) in darbepoetin α Groups 1, 2, and 3, respectively, and 0.39 g/dL (95%CI, − 0.22–1.00 g/dL) in the rHuEPO group. By the end of the study, the mean change (95%CI) in hemoglobin concentration was 1.35 g/dL (95%CI, 0.67–2.02 g/dL), 1.35 g/dL (95%CI, 0.57–2.12 g/dL), and 1.28 g/dL (95%CI, 0.84–1.73 g/dL) in darbepoetin α Groups 1, 2, and 3, respectively, and 1.03 g/dL (95%CI, 0.53–1.53 g/dL) in the rHuEPO group. The early erythropoietic response in patients who were treated with darbepoetin α was associated with an early and maintained reduction in patient-reported fatigue. The adverse event profile was comparable with all doses of darbepoetin α and rHuEPO. CONCLUSIONS Darbepoetin α, given as a front-loaded dose for 4 weeks and followed by lower and/or less frequent doses, appears to be efficacious and may decrease the time to response relative to treatment with rHuEPO. Cancer 2003;97:1312–20. © 2003 American Cancer Society. DOI 10.1002/cncr.11186

As with other drugs, applications for marketing approval of new chemopreventive agents in the United States must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. Knowledge of a drug's pharmacologic actions and metabolism may benefit protocol design, by identifying the patient populations and dosing schedules associated with a favorable risk/benefit profile. With availability of appropriate preclinical data, including standard assessments of an agent's toxicology, effects on reproductive performance, and genotoxicity, initial Phase I studies of 1-3 months may be performed in normal volunteers or an appropriate higher risk population. For chronic dosing studies of longer duration, preclinical toxicology studies of longer duration are relevant. Enrollment in chemoprevention studies should be directed toward individuals at sufficient risk of developing cancer so that potential benefit may counterbalance the unpredictable and possibly serious adverse effects that may be observed with prolonged administration of a study drug. Phase I and II studies with clinical dosing lasting up to 12 months often afford opportunities to assess drug effect on surrogate endpoint biomarkers that may correlate with endpoints of clinical effectiveness. Phase III and late phase II chemopreventive investigations should routinely utilize a prospective, randomized study design (double-masked and placebo-controlled, when possible). To support marketing approval, there must be evidence that a chemopreventive agent significantly delays or prevents the occurrence of malignancy, with acceptable safety. In some circumstances, modulation of a surrogate marker may provide a basis for marketing approval, before more definitive endpoint data become available. However, the acceptability of a surrogate depends on the nature and quality of the data supporting its predictive value. Given the considerations of large study size, long duration, and high cost that may hamper development of potential agents, studies designed to examine the predictive value of surrogate endpoint biomarkers are of great importance to the future development of chemoprevention research.

Increasingly, quality-of-life (QOL) end points are being incorporated into randomized, controlled clinical trials in oncology. The Oncologic Drugs Advisory Committee (U.S. Food and Drug Administration) has recommended that beneficial effects on QOL and/or survival be the basis for approval of new anticancer drugs. Therefore, from a regulatory standpoint, for drugs that do not have an impact on survival, demonstration of a favorable effect on QOL is more important than most other traditional measures used to assess efficacy, such as objective tumor response. Trials incorporating QOL questions will be evaluated on the basis of how well they address the stated objectives. The clinical protocol should delineate investigators' hypotheses and choice of validated instruments and should specify a detailed statistical analysis plan describing strategies for handling missing data. The U.S. Food and Drug Administration welcomes the opportunity to explore with investigators the use of QOL instruments in the design of cancer clinical trials.

e11529 Background: Improved disease-free survival (DFS) in randomized controlled trials (RCT) is the primary basis for approval of adjuvant breast cancer (ABC) treatments. Methods: Review of clinical trials leading to new drug approvals for ABC. Results: DFS is a composite endpoint defined as the time from randomization to the earliest occurrence of invasive loco-regional recurrence, invasive contralateral breast cancer, DCIS, distant metastases, second primary tumors or death from any cause. Trials supporting marketing approval have used inconsistent DFS definitions that included different components of this endpoint. Basis of paclitaxel approval following AC was superior DFS (HR= 0.78; 95% CI 0.67–0.91, p=0.002) and overall survival (HR=0.74; 95% CI 0.60–0.92, p=0.0065). Trastuzumab approval as part of a treatment regimen was based on 4 clinical trials that showed improved DFS. Docetaxel approval was based on improved DFS of the docetaxel-containing combination regimen TAC compared to FAC (HR: 0.74; 2- sided 95% CI=0.60–0.92, p=0.0047). Doxorubicin approval was based on a meta-analysis of six ABC trials comparing doxorubicin- containing regimens to CMF. Analyses demonstrated that doxorubicin-containing regimens retained at least 75% of the historical CMF adjuvant effect on DFS (HR: 0.91; 95% CI 0.82–1.01) and OS (HR: 0.91; 95% CI 0.81–1.03). Epirubicin approval was based on a longer relapse free survival (RFS) of the epirubicin-containing combination therapy (CEF-120) compared to CMF (HR=0.76; 95% CI 0.60–0.96, p=0.013). Tamoxifen approval was based on an overview of tamoxifen adjuvant therapy. Ten-year survival was 61.4% for tamoxifen vs. 50.5% for control (p < 0.00001) and RFS was 59.7% for tamoxifen vs. 44.5% for control (p < 0.00001). Anastrozole approval was based on a longer DFS (HR: 0.87; 95% CI=0.78–0.97, p=0.0127). Letrozole was based on a superior DFS (HR= 0.62; 95% CI 0.49–0.78, p=0.00003). Exemestane approval was based on improved DFS (HR: 0.65; 95% CI=0.53–0.79, p=0.00001). Conclusions: Although DFS was the basis for approval in most of the ABC clinical trials, the endpoint definition varies between trials. DFS definition should be standardized in ABC clinical trials to permit consistent interpretation and analysis and to facilitate cross-trial comparisons. No significant financial relationships to disclose.

6579 Background: In Oct 2006, FDA approved vorinostat for treatment of cutaneous manifestations of CTCL–based on response rate and duration of response observed in CTCL skin lesions. Response was determined by change in SWAT score at follow up compared to the baseline score. SWAT Score: sum of % Body Surface Area weighted by factor 1, 2, or 4 for patch (no elevation from normal skin), plaque (< 5 mm elevation) and tumor (= 5 mm elevation), respectively. All responses but one were partial. A partial response required = 50% reduction in whole body SWAT score lasting = 4 weeks. FDA also reviewed serial photographs of all patients (standard whole body views and close-ups of skin lesions), submitted as supportive evidence. Methods: An expert external reviewer, blind to SWAT scores, adjudicated responses by examining photographs and response determinations by photographs and by SWAT scores were compared. Results: Based on SWAT scores, skin lesions in 18 of 61 stage = IIB CTCL patients responded to vorinostat; there were 17 partial and 1 complete responses. Blinded reviewer adjudicated 4 photographs not evaluable (reasons: blurred image, color or light problem, wrong label), easily confirmed 7 responses, and called 7 responses equivocal. Responses seemed easier to determine in skin lesions with tumors or ulcers. Predominantly patch or plaque lesions were harder to evaluate: patches due to poor color reproduction and plaques due to inability to palpate. A response from plaque to patch morphology decreases SWAT score 50%, but the change may not manifest adequately in a photograph. Small sample size did not allow a reliable statistical analysis for correlation between different lesion types and ability to confirm objective responses (based on SWAT scores) by photography. Conclusions: Photography allows a limited evaluation of skin lesions in CTCL: inability to measure lesion thickness in photographs limits direct confirmation of SWAT scores. Photography complements SWAT evaluation: in half the cases in the vorinostat pivotal trial, a response by SWAT score was easily confirmed by the reviewer blind to SWAT scores. Further experience and technological advances in photography may reduce the number of not evaluable photographs. No significant financial relationships to disclose.

Background: We recently reported final results of a randomized, open-label, multicenter study assessing the efficacy of DA (Aranesp®) 300 mcg Q3W (Rearden et al, ASCO 2004). In this study of 201 pts, pts with grade 1 anemia were treated early with DA (n=102; early group) compared with pts treated late after developing grade 2/3 anemia (ie, hemoglobin [Hb] < 10 g/dL; n=99; observation/late intervention group [obs]). When pts were untreated in the obs group, Hb declined. DA treatment maintained Hb within the NCCN Hb target range for pts in the early group and increased Hb once administered in the obs group. The objective of this analysis was to explore the impact of declining Hb levels on pt-reported outcomes using the FACT-Fatigue (FACT-F) subscale. Methods: Pts with baseline (BL) Hb ≥10.5 and ≤12 g/dL were randomized 1:1 to either the early or obs group for up to 22 weeks. To analyze pt-reported fatigue, the FACT-F subscale was administered Q3W and at the end of treatment. The FACT-F analysis set included pts who were randomized, received study drug, and had a BL and at least 1 post-BL FACT-F score. Analyses of changes in FACT-F scores during treatment from BL were conducted; missing values were not imputed. Results: In 201 randomized and treated pts, mean BL (SD) Hb was similar for each group, 11.1 (0.7) g/dL for the early and 11.2 (0.6) g/dL for the obs groups. In the early group, mean Hb increased to near 12 g/dL in approximately 7 weeks, and due to dose-withholding rules, remained near 12 g/dL for the remainder of the study. In the obs group, Hb declined to < 10 g/dL in 65% of pts. The FACT-F analysis set included 94 pts in the early group and 86 in the obs group. Mean (SD) FACT-F scores at BL were 31.6 (11.7) for the early group and 27.7 (12.8) for the obs group. With categories of Hb change at the end of treatment, a significant trend towards greater improvements in fatigue with increasing Hb levels was observed in both groups (table). In pts in whom Hb was stabilized or improved, no decrease in fatigue scores was noted. However, when Hb declined (Hb change < 0 g/dL), a statistically significant and clinically meaningful (>3 point change in FACT-F score) increase in fatigue was observed (negative change in FACT-F score). Consistent with previous studies, pts with Hb change > 2 g/dL had clinically and statistically significant improvements in fatigue. Conclusion: In the absence of treatment, most mildly anemic cancer pts receiving ctx are at risk of developing grade 2/3 anemia within approximately 7 weeks. This decline in Hb is associated with a statistically significant and clinically meaningful increase in pt-reported fatigue. Our results indicate that DA 300 mcg Q3W may effectively ameliorate the impact of ctx on Hb levels and consequently prevent a decline in fatigue. Further, Q3W DA may provide benefits associated with less-frequent dosing. Mean (95%CL) Change in FACT-F Scores At End of Treatment By Change in Hb Category Early Obs N=94 N=86 Categories of Hb Change < 0 g/dL −6.2 (−12.9, 0.6) −2.8 (−7.2, 1.5) n=23 n=38 >0 to 2 g/dL 0.9 (−2.2, 4.0) 1.7 (−3.9, 7.3) n=52 n=32 > 2 g/dL 8.3 (3.3, 13.2) 6.4 (0.3, 12.5) n=19 n=16 P -value (Jonckheere-Terpstra Trend Test) 0.0003 0.049

8153 Background: Epoetin alfa (EPO) and darbepoetin alfa (DARB) both decrease transfusion requirements and increase hemoglobin (Hb) in anemic cancer patients (pts) receiving chemotherapy (CT). Meth...

3602 Background: The oral fluoropyrimidine X (Xeloda) has superior efficacy and improved safety compared to 5-FU/LV in MCRC. Twice-daily oral X mimics 5-FU infusion and is replacing 5-FU in combina...

8064 Background: Darbepoetin alfa (DA, Aranesp®) administered Q3W is effective for the treatment of CIA (Kotasek et al, 2003). NCCN guidelines recommend initiating erythropoietic therapy when hemoglobin (Hb) is < 11 g/dL with a suggested target Hb of 11 to 12 g/dL. This study was designed to evaluate the ability of DA to maintain Hb ≥ 10 g/dL in mildly anemic pts (early intervention) and pts who become moderately to severely anemic before treatment (late intervention). Methods: Pts with baseline Hb ≥ 10.5 and ≤ 12 g/dL were randomized 1:1 to early (DA 300 mcg Q3W) or late intervention (treated if Hb ≤ 10 g/dL with DA 300 mcg Q3W) groups for up to 23 weeks. The primary endpoint was the percentage of pts in each group with a Hb drop below 10 g/dL. Patient-reported outcomes included the FACT-Fatigue subscale. Proportion endpoints were calculated using Kaplan-Meier (KM) methods. Results: The study is fully enrolled with 204 pts. Data through week 17 for 201 evaluable pts (99 early and 102 late) were analyzed....

Cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone were administered for 165, 28-day cycles to 33 patients with metastatic breast cancer. Because of serious infections (fever larger than or equal to 101 degrees F. granulocytes less than 1,000/mm, 3 and hospitalization) and 1 drug death in the first 4 patients, oral calcium leucovorin, 20 to 30 mg/m2 orally, was given 2 days after methotrexate in subsequent treatment cycles. There were 26 cycles without calcium leucovorin and 6 serious infections; 139 cycles with calcium leucovorin and 5 serious infections (p = 0.002). Objective response was seen in 13 of 18 evaluable patients with no previous treatment and in only 2 of 11 patients with previous treatment (p = 0.0065). Equivalent doses were given to all subsets of patients. It is concluded that leucovorin added to the above combination of drugs can preserve antitumor activity while decreasing serious infections and that prior therapy significantly decreases the response rate to this combination.

The usual method of measuring electric field distributions comprises a receiving antenna at the point of observation, connected by means of a transmission line to receiving apparatus at some distant point. The principal advantage of the method described here is that it eliminates the transmission line and thus makes possible many measurements which cannot be done by the usual method. It is based on the fact that the echo from a thin straight conducting wire is proportional to the square of the component of electric field parallel to the wire. The practical application at centimeter wavelengths is described. The method has proven most valuable in a variety of problems involving flush mounted directional antennas, radomes, artificial transmission lines, etc.

It is shown that the properties of the radiation patterns of broadside and end-fire line radiators can be used to minimize the side-lobe level of the radiation patterns of uniformly excited rectangular arrays.

Experience with chemotherapy in advanced gynecologic malignancies is limited. In 6 patients, 2 of 4 with carcinoma of the cervix, and 1 patient with carcinoma of the ovary achieved partial remission when treated with a regimen of high dose methotrexate (240 mg/m2) followed by leucovorin rescue. On patient with metastatic trophoblastic disease achieved complete response (greater than 24 months). The number of doses of leucovorin 'rescue' was based on creatinine clearance. The advantage of rapid response and moderate toxicity indicate the need for further study of this regimen in the treatment of gynecologic malignancies.

Current evidence is inconclusive regarding the possibility that positive end-expiratory pressure (PEEP) redistributes flow and may be directly responsible for systemic organ dysfunction. This study tests the hypothesis that PEEP may induce abnormalities in the distribution of cardiac output (CO). Eight anesthetized dogs were studied during (1) 0 cm H2O PEEP (Z1), (2) 15 cm H2O PEEP (P), (3) Z2, and (4) bleeding (B) to reduce the CO to the same level as P. At each of the four periods, a different 15 mu radiolabelled microsphere was injected into the left atrium. Another four dogs were used to varify that each type of microsphere had the same flow distribution. CO fell from 3.1 liters/min to 1.9 during P (P smaller than 0.01) and to 2.0 during B (P smaller than 0.01). Mean arterial pressure (MAP) declined from 102 to 83 mm Hg (P smaller than 0.01) and 86 mm Hg (P smaller than 0.01(, respectively. Left atrial pressure (LAP) rose from 5.0 to 7.9 mm Hg during P (P smaller than 0.01) and fell during B to 2.7 mm Hg. c0 and its distribution were the same during Z1 and Z2. P caused selective reductions in hepatic (52%), adrenal (25%), and bronchial (24%) blood flows (P smaller than 0.01). In contrast, total flow to these organs during B was the same as during Z. Total renal flow was unchanged by P or B, but the cortical:medullary flow ratio increased during P from 24 to 49 (P smaller than 0.01) and was unchanged by B. P induced a decrease in fundal nucosal flow as compared with Z (P smaller than 0.01). Total coronary flow fell from 100 to 64 ml/min during both P and B (P smaller than 0.01). P led to a selective fall in subendocardial flow (67 ml/min X 100 gm) as compared with B (82.5 ML/MIN X 100 gm, P smaller than 0.01) as well as in the subendocardial:subepicardial flow ratio (1.069 vs. 1.112 ml/min X 100 gm, P smaller than 0.05). It is likely that the higher left ventricular filling pressure (LAP) during P as compared with during B compressed the endocardium and induced relative ischemia. Similarly the high airway pressure during P may have impeded bronchial mucosal flow. The causes and consequences of the other P-induced variations in flow are speculative.

A major protein component of the gel-like, embryonic hyaline layer of Strongylocentrotus purpuratus has been purified and characterized. The protein retains the ability to form an insoluble gel in the presence of specific divalent cations, a property characteristic of the hyaline material. Using a light scattering assay developed to measure the initial rate of hyalin gelation, we have been able to show that calcium alone is capable of initiating this reaction but that calcium and magnesium are synergistic in their effect. In the absence of divalent cations, the major hyalin protein has a molecular weight of 9.2 +/- 0.5 X 10(5) and a sedimentation coefficient of 11.6 S; these and other data indicate that the protein assumes a very elongated, rod-like structure in solution. Smaller amounts of two additional proteins, 8.8 and 6.5 S, are present in the hyalin fraction when the jelly coat and vitelline layer are subjected to a more stringent acid treatment early in the isolation procedure.

A cooperative cable design exercise is described in which the goals were a torque-balanced array cable with 20 conductors, a design strength of at least 15,000 pounds, a maximum diameter of 1 inch, and zero weight in seawater. These goals were to be achieved without increasing normal cable diameter; i.e., with no component the sole function of which was to decrease in-water weight. Three design approaches are discussed. The first is a model design, offered by the Naval Undersea Center to two cable companies for consideration. The others are changes to the model independently recommended by the companies. Each approach begins with the use of KEVLAR-49 composite tension members as the loadbearing core, and continues with substitution of lightweight materials for other components of the cable. All three end with a 20- conductor cable light enough to float in seawater. Each design is synopsized and explained. The result is an insight into three different ways in which "zero weight" electromechanical cables can be achieved.

The tumor-associated transplantation antigen expressed by several transplacentally induced lung tumors of C3HfeB/HeN mice (H-2kb haplotype) has previously been shown to exist as a normal tissue alloantigen in mice of known H-2k and H-2a haplotypes. This antigen is not expressed in normal tissues of C3HfeB/HeN mice but is expressed in C3H/HeN mice, the strain from which the C3HfeB/HeN mice were originally derived. The present study indicates that spleen cells from C3HfeB/HeN and C3H/HeN mice respond reciprocally in the mixed lymphocyte reaction. Cytotoxic T lymphocytes specific for the tumor-associated alloantigen can be readily generated in mixed lymphocyte reactions in which spleen cells from C3HfeB/HeN mice are reacted with x-irradiated spleen cells from C3H/HeN or A strain mice. These cells are effective in suppressing the growth of the C3HfeB/HeN-derived lung tumor 85 in x-irradiated syngeneic recipients.

Primary lymphoma of the central nervous system (CNS) is extremely rare. A case of mixed histiocytic lymphocytic lymphoma of the CNS that initially occurred in the spinal cord is reported. Multicentric recurrence following radiotherapy was successfully treated with intrathecal methotrexate and the patient remains free of disease after 4 years. The role of intrathecal methotrexate as alternative therapy following irradiation failure is discussed.

Columbiana, Ohio, Dec. 25, 1894. To the Editor: —In response to the physician who has been using Dr. Woodbridge's treatment for typhoid fever and has not met with the success he had hoped for and that Dr. Woodbridge had assured him he would meet with; and to all who would try it, I desire to say that I have been carefully testing it for the past three months, and so far it has proved very successful in my hands. In that time I have had an unusual number of cases of typhoid fever. Not being satisfied with the old method of treatment, I was induced to try the plan proposed by Dr. Woodbridge. Some of my cases presented unusually severe symptoms, temperature ranging as high as 105.5. While I was not able to abort it entirely in all of my cases, yet the temperature was materially reduced in a very

The hair loss in a young woman with an obscure diffuse alopecia was traced to her chronic ingestion of mouthwashes containing boric acid. Cessation of this occult source of boric acid resulted in complete regrowth of hair. It appears that boric acid may have accumulated in the hair follicles, with a resultant toxic effect on the susceptible hair bulbs. This case indicates that boric acid poisoning should be suspected in patients with profuse unexplained alopecia, since cessation of the boric acid ingestion results in complete hair regrowth and may be lifesaving.