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Novel allele HLA-DPB1*906:01 is possibly a recombinant between DPB1*04:02:01:01 and DPB1*06:01:01:01.

HLA-DPB1*417:01:02 differs from HLA-DPB1*417:01:01 by a synonymous nucleotide substitution at codon 43.

Background: Study CA184024 was a multinational, randomised, double-blind, phase 3 study comparing ipilimumab/dacarbazine (DTIC) vs placebo/DTIC in patients with untreated stage III/IV melanoma, which showed that ipilimumab significantly improves survival in patients with metastatic melanoma. The objective of this analysis was to compare the quality-adjusted survival experience among patients in this trial. Methods: Survival time was partitioned into health states: toxicity, time before progression without toxicity, and relapse until death or end of follow-up. Q-TWiST (quality-adjusted time without symptoms of disease or toxicity of treatment) was calculated as the utility-weighted sum of the mean health state durations. Analyses were repeated over extended follow-up periods. Results: Based on a combination of trial-based and external utility scores, the Q-TWiST difference in this trial was 0.50 months (P=0.0326) favoring ipilimumab after 1 year. The Q-TWiST difference was 1.5 months with 2 years of follow-up (P=0.0091), 2.36 months at 3 years (P=0.005) and 3.28 months at 4 years (P=0.0074). Conclusion: During the first year of study, there was little difference between groups in quality-adjusted survival. However, after 2, 3 and 4 years follow-up for patients with extended survival, the benefits of IPI+DTIC vs PLA+DTIC for advanced melanoma continue to accrue.

Since the discovery of RNA interference (RNAi), researchers have identified a variety of small interfering RNA (siRNA) structures that demonstrate the ability to silence gene expression through the classical RISC-mediated mechanism. One such structure, termed “Dicer-substrate siRNA” (dsiRNA), was proposed to have enhanced potency via RISC-mediated gene silencing, although a comprehensive comparison of canonical siRNAs and dsiRNAs remains to be described. The present study evaluates the in vitro and in vivo activities of siRNAs and dsiRNAs targeting Phosphatase and Tensin Homolog (PTEN) and Factor VII (FVII). More than 250 compounds representing both siRNA and dsiRNA structures were evaluated for silencing efficacy. Lead compounds were assessed for duration of silencing and other key parameters such as cytokine induction. We identified highly active compounds from both canonical siRNAs and 25/27 dsiRNAs. Lead compounds were comparable in potency both in vitro and in vivo as well as duration of silencing in vivo. Duplexes from both structural classes tolerated 2′-OMe chemical modifications well with respect to target silencing, although some modified dsiRNAs demonstrated reduced activity. On the other hand, dsiRNAs were more immunostimulatory as compared with the shorter siRNAs, both in vitro and in vivo. Because the dsiRNA structure does not confer any appreciable benefits in vitro or in vivo while demonstrating specific liabilities, further studies are required to support their applications in RNAi therapeutics.

The addition of lapatinib (Tykerb/Tyverb) to capecitabine (Xeloda) delays disease progression more effectively than capecitabine monotherapy in women with previously treated HER2+ metastatic breast cancer (MBC). The quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) method was used to compare treatments. The area under survival curves was partitioned into health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse period until death or end of follow-up (REL). Average times spent in each state, weighted by utility, were derived and comparisons of Q-TWiST between groups performed with varying combinations of the utility weights. Utility weights of 0.5 for both TOX and REL, that is, counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favouring combination therapy (P=0.0013). The Q-TWiST difference is clinically meaningful and was statistically significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses. An analysis with utilities based on EQ-5D scores was consistent with the above findings. Combination therapy of lapatinib with capecitabine resulted in greater quality-adjusted survival than capecitabine monotherapy in trastuzumab-refractory MBC patients.

R. Reifarth et al: ; 12 págs.; 9 figs.; Open Access funded by Creative Commons Atribution Licence 3.0 ; Nuclear Physics in Astrophysics VI (NPA6), The nucleosynthesis of elements beyond iron is dominated by neutron captures in the s and r processes. However, 32 stable, proton-rich isotopes cannot be formed during those processes, because they are shielded from the s-process ow and r-process -decay chains. These nuclei are attributed to the p and rp process. For all those processes, current research in nuclear astrophysics addresses the need for more precise reaction data involving radioactive isotopes. Depending on the particular reaction, direct or inverse kinematics, forward or time-reversed direction are investigated to determine or at least to constrain the desired reaction cross sections. The Facility for Antiproton and Ion Research (FAIR) will oer unique, unprecedented opportunities to investigate many of the important reactions. The high yield of radioactive isotopes, even far away from the valley of stability, allows the investigation of isotopes involved in processes as exotic as the r or rp processes., This project was supported by the HGF Young Investigators Project VH-NG-327, EMMI, H4F, HGS-HIRe, JINA, NAVI, DFG and ATHENA.

Background: All states require some kind of testing for newborns, but the policies are far from standardized. In some states, newborn screening may include genetic tests for a wide range of targets, but the costs and complexities of the newer genetic tests inhibit expansion of newborn screening. We describe the development and technical evaluation of a multiplex platform that may foster increased newborn genetic screening.Methods: MultiCode® PLx involves three major steps: PCR, target-specific extension, and liquid chip decoding. Each step is performed in the same reaction vessel, and the test is completed in ∼3 h. For site-specific labeling and room-temperature decoding, we use an additional base pair constructed from isoguanosine and isocytidine. We used the method to test for mutations within the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The developed test was performed manually and by automated liquid handling. Initially, 225 samples with a range of genotypes were tested retrospectively with the method. A prospective study used samples from >400 newborns.Results: In the retrospective study, 99.1% of samples were correctly genotyped with no incorrect calls made. In the perspective study, 95% of the samples were correctly genotyped for all targets, and there were no incorrect calls.Conclusions: The unique genetic multiplexing platform was successfully able to test for 31 targets within the CFTR gene and provides accurate genotype assignments in a clinical setting.

Two additional bases (isoguanosine and isocytosine), generating a third base pair, have been implemented in PCR. Enzyme fidelity for the third base pair is demonstrated using molecular thermodynamic melting, chemical cleavage and molecular beacons. When amplifying as few as 15 targets containing multiple non-natural base pairs with 40 cycles of amplification, our results confirm sequence conservation. The additional sequence space provided by three base pairs allows for the construction of molecular tools that achieve higher complexity and better discrimination than those possible with natural DNA alone.

Organic chemistry has made possible the synthesis of molecules that expand on Nature's genetic alphabet. Using the previously described nonstandard DNA base pair constructed from isoguanine and 5-methylisocytosine, we report a highly specific and sensitive method that allows for the fast and specific quantitation of genetic sequences in a closed tube format. During PCR amplification, enzymatic site-specific incorporation of a quencher covalently linked to isoguanine allows for the simultaneous detection and identification of multiple targets. The specificity of method is then established by analysis of thermal denaturation or melting of the amplicons. The appropriate functions of all reactions are further verified by incorporation of an independent target into the reaction mixture. We report that the method is sensitive down to the single copy level, and specificity is demonstrated by multiplexed end-point genotypic analysis of four targets simultaneously using four separate fluorescent reporters. The method is general enough for quantitative and qualitative analysis of both RNA and DNA using previously developed primer sets. Though the method described employs the commonly used PCR, the enzymatic incorporation of reporter groups into DNA site-specifically should find broad utility throughout molecular biology.

The reactions of acrolein have been investigated on TiO2(0 0 1) single crystal surfaces by temperature programmed desorption (TPD), X-ray photoelectron spectroscopy (XPS) and near edge X-ray absorption fine structure (NEXAFS). Two carbon–carbon bond-forming reactions were observed. The first, on defect-containing surfaces, is reductive coupling to form olefins. The high reaction yield of ca. 80% shows the high activity of such surfaces for carbon–oxygen bond dissociation (needed for surface oxygen restoration) and carbon–carbon bond formation to make olefins. The second reaction, observed on the stoichiometric surface, is condensation of two acrolein molecules to give a C6H8O product tentatively identified as 2-methyl-2,4-pentadienal. Condensation reactions of carbonyls are characteristic of TiO2 surfaces; for acrolein, this reaction is proposed to involve initial hydrogen addition followed by nucleophilic attack on a second molecule of acrolein. This results in an aldol condensation followed by dehydration. NEXAFS analyses were conducted in order to differentiate the states of molecularly adsorbed acrolein on the two distinctly different surfaces. The CO bond of adsorbed acrolein is maintained in the case of the stoichiometric surface (evidenced by a π C  O ∗ transition at 286.6 eV), while it is absent on the reduced surface. The absence of this NEXAFS transition on the reduced surface suggests that the O atom of the CO bond has reacted with the oxygen-deficient lattice. The restoration of these oxygen deficiencies is concomitant with the formation of the reductive coupling products (as observed by TPD and XPS experiments).

Background: With the invention of the DNA chip, genome-wide analysis is now a reality. Unfortunately, solid-phase detection systems such as the DNA chip suffer from a narrow range in quantification and sensitivity. Today the best methodology for sensitive, wide dynamic range quantification and genotyping of nucleic acids is real-time PCR. However, multiplexed real-time PCR technologies require complicated and costly design and manufacturing of separate detection probes for each new target.Methods: We developed a novel real-time PCR technology that uses universal energy transfer probes constructed from An Expanded Genetic Information System (AEGIS) for both quantification and genotyping analyses.Results: RNA quantification by reverse transcription-PCR was linear over four orders of magnitude for the simultaneous analysis of β-actin messenger RNA and 18S ribosomal RNA. A single trial validation study of 176 previously genotyped clinical specimens was performed by endpoint analysis for factor V Leiden and prothrombin 20210A mutation detection. There was concordance for 173 samples between the genotyping results from Invader® tests and the AEGIS universal energy transfer probe system for both factor V Leiden and prothrombin G20210A. Two prothrombin and one factor V sample gave indeterminate results (no calls).Conclusion: The AEGIS universal probe system allows for rapid development of PCR assays for nucleic acid quantification and genotyping.

Near edge x-ray absorption fine structure (NEXAFS) and density functional theory (DFT) calculations have been applied to study the interaction of 1-epoxy-3-butene (EpB) with the Ag(110) surface. Th...

Near-edge X-ray absorption fine structure (NEXAFS) was used to investigate the reaction of benzaldehyde on reduced surfaces of TiO2(0 0 1) to form stilbene by reductive coupling of the carbonyl groups. Reductive coupling of carbonyls (commonly referred to as the “McMurry reaction”) has been extensively studied in both liquid slurries containing reduced metals and as a gas–solid reaction on reduced surfaces of titania. The reactive intermediate proposed for both slurry and surface chemistry is a metal pinacolate. Previous investigations of this chemistry on reduced TiO2(0 0 1) have yielded circumstantial evidence supporting such an intermediate on the surface. However, spectroscopic evidence has proven difficult to obtain. In the current study, we employ NEXAFS to probe the chemical identity and orientation of reactive intermediates in the reductive coupling reaction further. By heating benzaldehyde-covered surfaces of TiO2(0 0 1) to progressively higher temperatures and recording polarization-dependent NEXAFS spectra at the Ti L-edge and the O and C K-edges, one can track the progression of the reaction from benzaldehyde to the product, stilbene. These results support an adsorbate structure consistent with a pinacolate intermediate.

Cyclotrimerization of alkynes to form aromatics can be carried out catalytically with low valent transition metal complexes in solution, with supported and single-crystal metal catalysts, and with partially reduced TiO2 surfaces. In each of these cases the reaction has been proposed to proceed via formation of a metallacyclopentadiene intermediate, i.e., by association of a pair of acetylene molecules to form a C4 ligand bound to the catalytic site. At least one group of authors has proposed that on late-transition metal surfaces a pair of C4 ligands combine to form the C8 ligand, cyclooctatetraene (COT). In this alternative mechanism, benzene is then formed by the elimination of a C2 fragment from the C8 intermediate. This reaction channel was previously examined on Pd(111) and Cu(110), and was found to be a minor or nonexistent channel on each, reinforcing the case for direct addition of a third acetylene molecule to the metallacyclopentadiene intermediate to form the aromatic product. We have examined ...

Projectile - photon coincidences were measured for the scattering of an 80 MeV/nucleon Zn-64 beam from Pb-208 and Bi-209 targets at the GANIL heavy ion accelerator facility. Projectile-like particles between 0.5-degrees and 4.5-degrees relative to the incident beam direction were detected in the SPEG energy loss spectrometer where their momentum, charge, and mass were determined. Photons were detected in the BaF2 scintillation detector array TAPS. Light charged particles produced in the reaction were detected in the KVI Forward Wall.The analysis of the data acquired in this experiment is focused on three different phenomena: (1) the two phonon giant dipole resonance, (2) time dependence of the decay of the one phonon giant dipole resonance, and (3) giant resonance strength in projectile nuclei.

Background: Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS. Methods: For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states. Results: There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P

The relationship between overall survival (OS) and disease progression end points has been demonstrated in colorectal, colon, and non-small cell lung cancers. We assessed the association between OS and time-to-progression (TTP) or progression-free survival (PFS) in metastatic breast cancer (MBC) studies. A literature search retrieved all randomised controlled trials since 1994 in patients with MBC in which OS and either TTP or PFS were reported. Summary data on trial and patient characteristics were abstracted. Study effect sizes were derived as the ratio of median progression (or survival) times, which approximates the hazard ratio. Effects were centred at zero for regression analyses weighted by sample size. Numerous treatments were represented in 67 studies (17 081 patients). Modeling showed a positive association between outcomes for progression and survival (R(2)=0.30) with a slope of 0.32 (P

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (ageor =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.

The Department of Energy’s Office of Nuclear Physics, within the Office of Science (SC), has given high priority to consider and analyze design concepts for the target areas for the production of rare isotopes via the ISOL technique at the Rare-Isotope Accelerator (RIA) Facility. Key criteria are the maximum primary beam power of 400 kW, minimizing target change-out time, good radiological protection, flexibility with respect to implementing new target concepts, and the analysis and minimization of hazards associated with the operation of the facility. We will present examples of on-going work on simulations of radiation heating of targets, surrounding components and shielding, component activation, and levels of radiation dose, using the simulation codes MARS, MCNPX, and PHITS. These results are important to make decisions that may have a major impact on the layout, operational efficiency and cost of the facility, hazard analysis, shielding design, civil construction, component design, and material selection overall layout, and remote handling concepts.

Five hundred and eighty-one patients with stage II-IV breast cancer were treated at Duke University Medical Center with high-dose chemotherapy, followed by hematopoietic support. All patients received a conditioning regimen of cyclophosphamide, cisplatin and carmustine. Of these patients, 15 (2.6%) developed symptoms similar to the hemolytic-uremic syndrome with evidence of thrombotic microangiopathy (TMA). The time of onset ranged from 75 days to 281 days post-transplant, with a median of 143 days. Hemolytic anemia and thrombocytopenia, without alternative cause, were required for diagnosis. All patients were treated with steroid therapy. In addition, 12 patients were treated primarily with plasmapheresis, and received a median of 46 treatments. Additional therapy included staphylococcal protein A column apheresis (eight patients), vincristine (three patients) and danazol (one patient). The mortality rate was 11 of 15 patients (73%). These patients had a median survival of 41 days from diagnosis of TMA (range 2-76 days). The four survivors are alive at 76, 186, 1837 and 2387 days from diagnosis of TMA. Three of these patients received twice daily plasmapheresis and protein A column apheresis therapy. One patient recovered without specific therapy. TMA is an infrequent complication of high-dose chemotherapy, but is associated with a high mortality. It frequently follows significant pulmonary drug toxicity. Survival may be improved with early diagnosis and aggressive plasmapheresis therapy.

Background: Median PFS was significantly prolonged for a group of HER2+ post-menopausal patients taking lapatinib +letrozole (Lap+Let) as first-line therapy for hormone receptor positive (HR+) MBC compared with patients on Let plus placebo (Let+pla) in a phase III, randomized, double-blind study. Previous reports showed that QOL was generally stable for patients who stayed on study and that the proportion of QOL responders was similar in the treatment arms. Exploratory analyses were performed to examine the extent to which QOL change scores correlate with tumor progression events.Methods: Progression was assessed using RECIST criteria and QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B). QOL scores from each time point were pooled across treatment arms for patients who progressed or did not progress up to one week after the assessment; withdrawal assessments were analyzed when they occurred. Average change scores at each time point were compared using least squared means from ANCOVAs, adjusted for baseline value. Higher scores represent better QOL. Distribution of QOL responses stratified by whether change from baseline represented minimally important declines, increases or stability were compared using a chi-squared test.Results: Among 1286 randomized patients, 219 were identified as HER2+. By the Week 12 assessment (+1 week), 72 patients had progressed; another 37 progressed at Week 24; and 21 more at Week 36. Average changes from baseline in FACT-B total scores were statistically and clinically significant between patients who progressed and those who did not at Week 24 (p=0.0001) and Week 36 (p=0.04) but not at Week 12 (Table 1).Table 1. Average change (delta) from baseline on FACT-B totalProgressed at Week 12 (n=72) Delta = -2.9Not progressed at Week 12 (n=144) Delta = +0.78 Progressed at Week 24 (n=37) Delta = -10.6Not progressed at Week 24 (n=107) Delta = +2.9 Progressed at Week 36 (n=21) Delta = -8.6Not progressed at Week 36 (n=86) Delta = +1.5 At Week 12, the distribution of patients by FACT-B response level was similar between patients who progressed and those who did not (p=0.67). Table 2 shows that among patients who continued on study after Week 12, a higher proportion of patients whose tumors progressed had FACT-B declines >7 points from baseline (p= 7 points19%65%Stable4827Increased >= 7 points338 Conclusions: Results show that tumor progression is associated with clinically meaningful declines in QOL scores in patients with HR+, HER2+ MBC. Hence, the longer PFS for Lap+Let versus Let+pla is expected to translate into a QOL advantage. However, these hypothesis-generating analyses suggest that QOL declines may take more than a few months to evolve. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5106.

1024 Background: Previous studies in pts with MBC have shown that women with ER+ tumors have a longer survival time compared to women with ER- tumors. An exploratory analysis was conducted to describe the relationship between survival and ER status among MBC pts treated with combination therapy consisting of C+D. Methods: This analysis used data from an open-label, randomized phase III trial of C+D vs D alone in pts with advanced and/or MBC. Survival analysis was used to investigate the effect of baseline ER status of the primary and metastatic tumors on overall survival (OS). ER status was defined as positive if positive for any tumor, negative if at least 1 negative test, otherwise unknown. Results: Among 506 intent-to-treat pts (randomized, received ≥1 dose), ER status was identified in 356. C+D: 90 ER+, 88 ER-; D alone: 95 ER+, 83 ER-. The unadjusted log-rank test showed a significant difference in OS between the C+D and D groups for ER+ but not ER- pts. In the ER+ group, median OS was longer in C+D vs D pts (538.5 vs 379.0 d) (hazard ratio [HR] 0.65; P=0.007). OS was significantly longer in ER+ vs ER- pts in the C+D group (538.5 vs 329.0 d) (HR 0.68; P=0.019) but not in the D group (379.0 vs 301.0 d) (HR 0.90; P=0.514). OS by time from diagnosis to recurrence and baseline tumor size showed no significant differences between ER+ and ER- pts. Conclusions: This exploratory analysis suggested a significant difference in OS between the C + D and D groups in ER+ (HR 0.65) but not ER- (HR 0.90) pts. Also, within the C+D group, the median OS was significantly longer in ER+ than ER- pts (HR 0.68). [Table: see text] [Table: see text]

1049 Background: A phase III randomized, multicenter, double-blind, placebo-controlled study compared first-line therapy with lapatinib and paclitaxel (L+P) versus paclitaxel alone (P) for MBC. In a sub-group analysis of HER2+ patients, time to tumor progression for L+P was significantly improved, with an emerging trend for survival benefit. This analysis models the QOL data in the subset of the randomized ITT population that overexpressed HER2 (FISH+ or IHC3+). Methods: QOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Outcome measures included FACT-B total score, trial outcome index (TOI) score and breast cancer subscale (BCS). Higher scores represent better QOL. Patients completed the FACT-B at the screening visit, week 9, every 12 weeks thereafter, and at discontinuation of therapy. The assessment at discontinuation was applied to the next scheduled visit for analyses. Changes from baseline were analyzed using repeated measures models with baseline score as a covariate. Pattern mixture modeling was implemented as a sensitivity analysis. Results: Of 579 randomized patients, 86 were HER-2+ and 85 completed at least one item from the FACT-B (n = 48 L+P; n = 37 P). The baseline characteristics of this subset were well-matched with regard to age, ECOG status, and prior anthracycline use. More patients in the L+P group than in the P group had visceral disease (69% vs 51%) and more were at stage IV (88% vs 78%).Over the first year, the L+P arm demonstrated stable FACT-B scores over time, whereas average scores for patients on paclitaxel monotherapy decreased (change from baseline: L+P p = 0.99; P p = 0.01). Statistically significant differences were observed between treatment arms on the FACT-B (p = 0.05), TOI (p = 0.03), and BCS (p = 0.01). Pattern mixture models suggested more QOL differentiation between treatments among patients who progressed or withdrew within 6 months of study start. Conclusions: Among patients with HER2+ MBC, treatment with L+P resulted in more stable QOL than with P monotherapy. These findings represent clinically important differences between treatment groups. [Table: see text]

1039 Background: A phase III randomized double-blind multicenter trial compared lapatinib plus letrozole (L+Let) with letrozole plus placebo (Let), as first-line therapy for hormone receptor positive (HR+) MBC. Median PFS, the primary endpoint of the study, in patients who were HER2+ was significantly prolonged for L+Let compared with Let (8.2 vs 3 months, Hazard Ratio (95% CI)=0.71(0.53,0.96), p=0.019). This analysis focuses on the impact of treatments on QOL in the HER2+ subgroup. Methods: QOL outcomes included the Functional Assessment of Cancer Therapy-Breast (FACT-B) total, FACT-general (FACT-G), and trial outcome index (TOI) scores assessed at screening, every 12 weeks and at withdrawal. Higher scores indicate better QOL. Changes from baseline were analyzed using analysis of covariance. In a responder analysis, patients achieving minimally important differences in QOL scores (QOL responders) were compared with Fisher's exact test. Results: Among 1,286 patients, 219 were identified as HER2+ (L+Let n=111; Let n=108). Baseline QOL scores were comparable in the two arms. In this population, mean changes in subscale and total QOL scores were generally stable over time in both treatment arms for patients who stayed on study. For example, on the FACT-B, the average change from baseline in both groups was positive at all scheduled visits through Week 48 and the maximum difference between arms was 2.6 points (CI: -5.8, 11). There were no significant differences between the two treatment arms in percentage of QOL responders (Table). Conclusions: The addition of lapatinib to letrozole significantly increases PFS while maintaining QOL when compared with letrozole alone thus confirming the clinical benefit of the combination therapy in the HR+, HER2+ MBC patient population. This combination provides an effective option in this patient population by maintaining QOL and delaying the need for chemotherapy and its accompanying side effects. [Table: see text] [Table: see text]

1097 Background: Both in monotherapy and in combination with a taxane, C has been shown to improve OS in patients with MBC. Since C is often used in older adults because of tolerability and ease of administration (PO vs IV), and lack of alopecia, an exploratory analysis was conducted to see if an association exists between age and OS among patients with MBC treated with C. Methods: Data from the intermittent dose (2510 mg/m2) 2 wks on/1 wk off arms of 5 phase II/III monotherapy or combination therapy with C registration trials involving patients with MBC were analyzed. Intent-to-treat (ITT) was defined as all randomized patients who took at least 1 dose of study medication. Patients were divided into 3 groups by age. A Kaplan-Meier method was used to estimate the age-category specific survival by trial. Next, Cox proportional hazard regression analysis was conducted using pooled data from the 5 trials with stratification by trial and key baseline characteristics. Analyses were conducted at the 95% confidence level. Results: A total of 570 ITT patients were included in the analysis (median age 55.0 years; range, 26–83): 193 (34%) were 18–49 years old; 246 (43%) 50–64 years old; and 131 (23%) ≥65 years old. A baseline Karnofsky score ≥90 was observed in 65.3%, 56.5%, and 50.4% of patients, respectively. The median treatment duration (range) was 93.0 (2–397) days in the 18 to 49-year-old group, 109.5 (2–448) days in the 50 to 64-year-old group, and 80.0 (5–371) days in the ≥65-year-old group. Unadjusted log-rank tests for each of the 5 trials showed no significant differences in OS between age categories. In the pooled analysis, Cox regression did not detect significant differences in survival based on age. Using age ≥65 years as the reference group, the hazard ratios were 1.06 (95% CI 0.81, 1.41) for age 18–49 years and 0.99 (95% CI 0.77, 1.29) for age 50–64 years. The Cox model revealed consistent results after further controlling for the Karnofsky score and number of metastatic sites. Conclusions: No statistically significant effect of age on OS was observed in patients with MBC treated with C. OS outcomes appear comparable across predefined age groups of patients with MBC treated with C. [Table: see text]

1026 Background: Data for this analysis is from a Phase III randomized study that was stopped early by the IDMC since a planned interim analysis demonstrated the primary endpoint had been achieved i.e. longer time to disease progression for patients taking lapatinib plus capecitabine (L+C) versus capecitabine (C) alone. The study included women with refractory advanced or ErbB2+ MBC who had received prior therapy which included anthracyclines, taxanes and trastumuzab. The Q-TWiST method was used to compare the trade-off between toxicities and delayed progression. Methods: The area under overall survival curves for each treatment group was partitioned into three health states: toxicity (TOX), time without toxicity or disease progression (TWiST), and the period until death or end of follow-up following disease progression (REL). TOX is time spent with grade ¾ adverse events (AEs) during progression-free survival (PFS) time. TWiST is the remaining time prior to progression in which no serious AEs were experienced. The utility-weighted sum of the mean health state durations was derived and treatment comparisons of Q-TWiST were made at varying combinations of the utility weights using a threshold utility analysis. Results: The ITT population included 399 subjects ages 26–83 [L+C group N=198, C group N=201]. Overall median survival was 67 weeks based on data through 3APR2006. There was not a significant difference between groups in mean duration of serious AEs prior to progression. (L+C 1.7 weeks, C 1.5 weeks). Using utility weights of 0.5 for both TOX and REL, i.e. counting 2 days of TOX or REL as 1 day of TWiST, resulted in a 7-week difference in quality-adjusted survival favoring L+C (p = 0.0013). The Q-TWiST difference was significant across an entire matrix of possible utility weights. Results were robust in sensitivity analyses including all AEs. An observed-utility analysis based on EQ-5D scores is in progress. Conclusions: The longer time to disease progression with L+C versus C was achieved without increased time with serious AEs, resulting in more quality-adjusted survival for patients. No significant financial relationships to disclose.

The ground state Q value of the reaction 58Ni(7Li, 8He)57Cu has been measured [Q = -29.564(50) MeV]. The cross section for this reaction was found to be 130(30) nb/sr at 5.0 deg in the laboratory. This is the first report of the use of the (7Li,8He) reaction and the first measurement of the 57Cu mass excess. The deduced 57Cu atomic mass excess is -47.35(5) MeV. The implications of this result with respect to Coulomb displacement energy anomalies and nucleosynthesis of elements with A > 56 by the rp process are discussed.

alpha-Thrombin derivatives obtained either by site-specific modification at lysyl residues (phosphopyridoxylated) or by limited trypsinolysis (gamma T-thrombin) were compared to correlate structural modifications with the functional reactivity toward fibrin(ogen) and heparin. alpha-Thrombin phosphopyridoxylated in the absence of heparin (unprotected) showed approximately 2 mol of label incorporated/mol of thrombin, but only 1 mol of label incorporated/mol of proteinase when modified in the presence of added heparin (protected). In contrast to native alpha-thrombin, both phosphopyridoxylated alpha-thrombin derivatives failed to interact with a fibrin monomer-agarose column and had reduced fibrinogen clotting activity, which is very similar to gamma T-thrombin. Heparin accelerated the rate of antithrombin III inhibition of alpha-thrombin, heparin-protected modified-alpha-thrombin, and gamma T-thrombin in a manner consistent with a template mechanism but was without effect on unprotected modified alpha-thrombin. In a heparin-catalyzed antithrombin III inhibition assay of alpha-thrombin, we found that D-Phe-Pro-Arg chloromethyl ketone-active site-inactivated gamma T-thrombin competed for heparin binding. It has been shown that limited proteolysis/autolysis of the B-chain of alpha-thrombin in the area around Arg-B73 (in beta T/beta- and gamma T/gamma-thrombin), but not that around Lys-B154 (in gamma T/gamma-thrombin), diminishes specific interactions with fibrinogen (Hofsteenge, J., Braun, P. J., and Stone , S. R. (1988) Biochemistry 27, 2144-2151). In unprotected modified alpha-thrombin, lysyl residues B21, B65, B174, and B252 were phosphopyridoxylated. In heparin-protected modified alpha-thrombin, only lysyl residues B21 and B65 were phosphopyridoxylated. These observations suggest that lysyl residues 21/65 of the B-chain of alpha-thrombin are involved in fibrin(ogen) interactions, and lysyl residues 174/252 of the B-chain are important in heparin interactions.

Activated human factor IX (factor IXa) was treated under mildly acidic conditions with a mixture of formaldehyde and morpholine. This reagent has been shown to react preferentially with gamma-carboxyglutamyl (Gla) residues and to convert these residues to gamma-methyleneglutamyl residues (Wright, S.F., Bourne, C.D., Hoke, R.A., Koehler, K.A., and Hiskey, R.G. (1984) Anal. Biochem. 139, 82-90). The modified enzyme was evaluated for coagulant activity and calcium-dependent fluorescence quenching. [14C]Formaldehyde was employed to allow quantitation of the modification and to facilitate localization of the modified residues in the primary structure of factor IXa. In the presence of the [14C]formaldehyde/morpholine reagent, factor IXa rapidly lost coagulant activity, which corresponded to incorporation of radiolabel. Examination of the relationship between protein modification (radiolabel incorporation) and the loss of coagulant activity suggested that modification of 1 mol of Gla/mol of factor IXa results in complete loss of factor IXa coagulant activity. Primary structure analysis of the radioactivity labeled factor IXa suggested that modification of any one of 11 Gla residues was responsible for the loss of coagulant activity. In the presence of calcium, modified factor IXa exhibited a smaller Gla-dependent decrease in protein fluorescence than native factor IXa, but the Gla-independent fluorescence change was the same for both proteins. It therefore appears that the Gla domain of factor IXa must be completely intact for the enzyme to undergo a functionally important calcium-dependent conformational change necessary for coagulant activity.