Proton Shell Gaps in N=28 Nuclei from the First Complete Spectroscopy Study with FRIB Decay Station Initiator.

The first complete measurement of the ß-decay strength distribution of _{17}^{45}Cl_{28} was performed at the Facility for Rare Isotope Beams (FRIB) with the FRIB Decay Station Initiator during the second FRIB experiment. The measurement involved the detection of neutrons and γ rays in two focal planes of the FRIB Decay Station Initiator in a single experiment for the first time. This enabled an analytical consistency in extracting the ß-decay strength distribution over the large range of excitation energies, including neutron unbound states. We observe a rapid increase in the ß-decay strength distribution above the neutron separation energy in _{18}^{45}Ar_{27}. This was interpreted to be caused by the transitioning of neutrons into protons excited across the Z=20 shell gap. The SDPF-MU interaction with reduced shell gap best reproduced the data. The measurement demonstrates a new approach that is sensitive to the proton shell gap in neutron rich nuclei according to SDPF-MU calculations.

Observation of New Isotopes in the Fragmentation of

Five previously unknown isotopes (^{182,183}Tm, ^{186,187}Yb, ^{190}Lu) were produced, separated, and identified for the first time at the Facility for Rare Isotope Beams (FRIB) using the Advanced Rare Isotope Separator (ARIS). The new isotopes were formed through the interaction of a ^{198}Pt beam with a carbon target at an energy of 186 MeV/u and with a primary beam power of 1.5 kW. Event-by-event particle identification of A, Z, and q for the reaction products was performed by combining measurements of the energy loss, time of flight, magnetic rigidity Bρ, and total kinetic energy. The ARIS separator has a novel two-stage design with high resolving power to strongly suppress contaminant beams. This successful new isotope search was performed less than one year after FRIB operations began and demonstrates the discovery potential of the facility which will ultimately provide 400 kW of primary beam power.

Discovery of

The new isotope ^{39}Na, the most neutron-rich sodium nucleus observed so far, was discovered at the RIKEN Nishina Center Radioactive Isotope Beam Factory using the projectile fragmentation of an intense ^{48}Ca beam at 345 MeV/nucleon on a beryllium target. Projectile fragments were separated and identified in flight with the large-acceptance two-stage separator BigRIPS. Nine ^{39}Na events have been unambiguously observed in this work and clearly establish the particle stability of ^{39}Na. Furthermore, the lack of observation of ^{35,36}Ne isotopes in this experiment significantly improves the overall confidence that ^{34}Ne is the neutron dripline nucleus of neon. These results provide new key information to understand nuclear binding and nuclear structure under extremely neutron-rich conditions. The newly established stability of ^{39}Na has a significant impact on nuclear models and theories predicting the neutron dripline and also provides a key to understanding the nuclear shell property of ^{39}Na at the neutron number N=28, which is normally a magic number.

Location of the Neutron Dripline at Fluorine and Neon.

A search for the heaviest isotopes of fluorine, neon, and sodium was conducted by fragmentation of an intense ^{48}Ca beam at 345 MeV/nucleon with a 20-mm-thick beryllium target and identification of isotopes in the large-acceptance separator BigRIPS at the RIKEN Radioactive Isotope Beam Factory. No events were observed for ^{32,33}F, ^{35,36}Ne, and ^{38}Na and only one event for ^{39}Na after extensive running. Comparison with predicted yields excludes the existence of bound states of these unobserved isotopes with high confidence levels. The present work indicates that ^{31}F and ^{34}Ne are the heaviest bound isotopes of fluorine and neon, respectively. The neutron dripline has thus been experimentally confirmed up to neon for the first time since ^{24}O was confirmed to be the dripline nucleus nearly 20 years ago. These data provide new keys to understanding the nuclear stability at extremely neutron-rich conditions.

Discovery of

The discovery of the important neutron-rich nucleus _{20}^{60}Ca_{40} and seven others near the limits of nuclear stability is reported from the fragmentation of a 345 MeV/u ^{70}Zn projectile beam on ^{9}Be targets at the radioactive ion-beam factory of the RIKEN Nishina Center. The produced fragments were analyzed and unambiguously identified using the BigRIPS two-stage in-flight separator. The eight new neutron-rich nuclei discovered, ^{47}P, ^{49}S, ^{52}Cl, ^{54}Ar, ^{57}K, ^{59,60}Ca, and ^{62}Sc, are the most neutron-rich isotopes of the respective elements. In addition, one event consistent with ^{59}K was registered. The results are compared with the drip lines predicted by a variety of mass models and it is found that the models in best agreement with the observed limits of existence in the explored region tend to predict the even-mass Ca isotopes to be bound out to at least ^{70}Ca.

Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma.

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.

A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer.

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<0.0001) and quality-adjusted OS (P=0.0303). CONCLUSION: In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone.

Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer.

BACKGROUND: Progression-free survival (PFS) was significantly longer for the lapatinib plus trastuzumab (L+T) arm than for L alone in a phase III, randomized, open-label study of women with human epidermal growth factor receptor 2 positive metastatic breast cancer who had documented progression on at least one T-containing regimen in the metastatic setting. This analysis focused on impact of treatments on health-related quality of life (HRQOL). METHODS: HRQOL was assessed using the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. Changes from baseline and time to deterioration were analyzed in the intent-to-treat population. RESULTS: Differences between the treatment arms in adjusted mean change from baseline favored the L+T arm, ranging from 0.0 to 4.1 (FACT-B), 1.0-4.0 [Functional Assessment of Cancer Therapy-General (FACT-G)], and 0.5-2.7 (Trial Outcome Index). Most differences were not statistically significant, except for FACT-G at week 12 (delta = 4.0, P = 0.037). Similar results were found in a sensitivity analysis that included HRQOL records up to patient withdrawal from original randomized treatment. The longer time to HRQOL deterioration in the L+T arm was not statistically significant (FACT-B hazard ratio, 0.82; 95% confidence interval 0.56-1.20). CONCLUSION: The addition of lapatinib to trastuzumab prolonged PFS while improving or maintaining near-term HRQOL, suggesting a meaningful clinical benefit to patients.

Impact of lapatinib monotherapy on QOL and pain symptoms in patients with HER2+ relapsed or refractory inflammatory breast cancer.

OBJECTIVE: EGF103009 (ClinicalTrials.gov identifier: NCT00105950) was a phase 2, open-label, multicenter study that showed lapatinib monotherapy to be clinically active in women with relapsed or refractory HER2+ (ErbB2+) inflammatory breast cancer that progressed following prior therapy with anthracyclines, taxanes, and trastuzumab. The objective of the present study was to assess the impact of lapatinib on quality of life (QOL) and pain symptoms in these patients. RESEARCH DESIGN AND METHODS: QOL and pain assessments were added during a study amendment and hence only 33 of 126 HER2+ patients were available for baseline assessment. QOL and pain were assessed using the EORTC QLQ-C30 and Brief Pain Inventory-Short Form (BPI-SF) questionnaires, respectively. Both questionnaires were completed at baseline and every 4 weeks thereafter. Change from baseline in QOL and pain scores were summarized by visit. In a post hoc analysis, scores were compared between patients with different clinical response status. RESULTS: Over 60% of the 33 HER2+ patients with the baseline assessments completed the first three postbaseline assessments (week 4, n = 26; week 8, n = 21; week 12, n = 20). At week 8, improvement from baseline in mean EORTC QLQ-C30 scores was observed for global QOL (delta = 14.5; 95% CI: 4.0, 25.0), role functioning (delta = 15; 95% CI: 0.9, 29.1), social functioning (delta = 14.9; 95% CI: -0.5, 30.3), and physical functioning subscales (delta = 9.0; 95% CI: 1.2, 16.8). All symptom scales (except diarrhea) improved from baseline at most scheduled visits during the 20-week follow-up period. Mean scores for all four BPI-SF summary pain scores at week 8 suggested improvement in pain severity and pain interference. Clinical responders had improved scores on most aspects of QOL, compared with declining scores among nonresponders to treatment. CONCLUSIONS: The QOL improvement among the small number of patients with QOL data indicates that lapatinib monotherapy may improve level of functioning/QOL and provide relief from symptoms, including pain, in the short term. These QOL benefits add to the clinical improvement associated with lapatinib therapy in heavily pretreated patients with an aggressive form of breast cancer.

Evidence for a change in the nuclear mass surface with the discovery of the most neutron-rich nuclei with 17

The results of measurements of the production of neutron-rich nuclei by the fragmentation of a 76Ge beam are presented. The cross sections were measured for a large range of nuclei including 15 new isotopes that are the most neutron-rich nuclides of the elements chlorine to manganese (50Cl, 53Ar, ;{55,56}K, ;{57,58}Ca, ;{59,60,61}Sc, ;{62,63}Ti, ;{65,66}V, 68Cr, 70Mn). The enhanced cross sections of several new nuclei relative to a simple thermal evaporation framework, previously shown to describe similar production cross sections, indicates that nuclei in the region around 62Ti might be more stable than predicted by current mass models and could be an indication of a new island of inversion similar to that centered on 31Na.

Relationship between effects on time-to-disease progression and overall survival in studies of metastatic breast cancer.

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<0.001) and a non-significant intercept. Thus, a treatment effect on TTP/PFS translated into a concordant effect on OS, but with attenuated effect size. Similar results were found in models of subsets and sensitivity analyses. These results demonstrate that treatment effects on progression end points in MBC trials are expected to result in treatment differences on OS that are smaller yet consistently in the same direction.

PROCEED: Prospective Obesity Cohort of Economic Evaluation and Determinants: baseline health and healthcare utilization of the US sample.

AIM: To summarize baseline characteristics, health conditions, resource utilization and resource cost for the US population for the 90-day period preceding enrolment, stratified by body mass index (BMI) and the presence of abdominal obesity (AO). METHODS: PROCEED (Prospective Obesity Cohort of Economic Evaluation and Determinants) is a multinational, prospective cohort of control (BMI 20-24.0 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI >or= 30 kg/m(2)) subjects with AO and without AO [non-abdominal obesity (NAO)], defined by waist circumference (WC) >102 and 88 cm for males and females, respectively. Subjects were recruited from an Internet consumer panel. Outcomes were self-reported online. Self-reported anthropometric data were validated. Prevalence of conditions and utilization is presented by BMI class and AO within BMI class. Differences in prevalence and means were evaluated. RESULTS: A total of 1067 overweight [n = 474 (NAO: n = 254 and AO: n = 220)] and obese [n = 493 (NAO: n = 39 and AO: n = 454)] subjects and 100 controls were recruited. Self-reported weight (r = 0.92) and WC (r = 0.87) were correlated with measured assessments. Prevalence of symptoms was significantly higher in groups with higher BMI, as were hypertension (p < 0.0001), diabetes (p < 0.0001) and sleep apnoea (p < 0.0001). Metabolic risk factors increased with the BMI class. Among the overweight class, subjects with AO had significantly more reported respiratory, heart, nervous, skin and reproductive system symptoms. Overweight subjects with AO reported a significantly higher prevalence of diabetes (13%) compared with overweight subjects with NAO (7%, p = 0.04). Mean healthcare cost was significantly higher in the higher BMI classes [control ($456 +/- 937) vs. overweight ($1084 +/- 3531) and obese ($1186 +/- 2808) (p < 0.0001)]. CONCLUSION: An increasing gradient of symptoms, medical conditions, metabolic risk factors and healthcare utilization among those with a greater degree of obesity was observed. The independent effect of AO on health and healthcare utilization deserves further study with a larger sample size.

Q-TWiST analysis of lapatinib combined with capecitabine for the treatment of metastatic breast cancer.

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.

Discovery of 40Mg and 42Al suggests neutron drip-line slant towards heavier isotopes.

A fundamental question in nuclear physics is what combinations of neutrons and protons can make up a nucleus. Many hundreds of exotic neutron-rich isotopes have never been observed; the limit of how many neutrons a given number of protons can bind is unknown for all but the lightest elements, owing to the delicate interplay between single particle and collective quantum effects in the nucleus. This limit, known as the neutron drip line, provides a benchmark for models of the atomic nucleus. Here we report a significant advance in the determination of this limit: the discovery of two new neutron-rich isotopes--40Mg and 42Al--that are predicted to be drip-line nuclei. In the past, several attempts to observe 40Mg were unsuccessful; moreover, the observation of 42Al provides an experimental indication that the neutron drip line may be located further towards heavier isotopes in this mass region than is currently believed. In stable nuclei, attractive pairing forces enhance the stability of isotopes with even numbers of protons and neutrons. In contrast, the present work shows that nuclei at the drip line gain stability from an unpaired proton, which narrows the shell gaps and provides the opportunity to bind many more neutrons.

Meta-analysis of trials comparing ximelagatran with low molecular weight heparin for prevention of venous thromboembolism after major orthopaedic surgery.

BACKGROUND: Use of low molecular weight heparin (LMWH) is standard practice for preventing postoperative venous thromboembolism (VTE). Ximelagatran is a new direct thrombin inhibitor for this indication. METHODS: A systematic review was conducted to compare the efficacy and safety of LMWH with ximelagatran in orthopaedic surgery. RESULTS: Six eligible, well conducted clinical trials (10 051 patients) were identified. Overall, the risk of VTE (OR (odds ratio) 1.22 (95 per cent confidence interval (c.i.) 0.89 to 1.67)) and serious bleeding (OR 0.70 (95 per cent c.i. 0.42 to 1.18)) was not significantly different for LMWH compared with ximelagatran. Exploratory analyses to investigate statistical heterogeneity found that results varied by surgical subtype and treatment regimen. Compared with postoperative ximelagatran, LMWH had a significantly lower rate of VTE (OR 0.68 (95 per cent c.i. 0.56 to 0.82); P < 0.001), with no significant difference in bleeding rate (OR 1.09 (95 per cent c.i. 0.62 to 1.94); P = 0.76), in hip surgery, and no significant differences in knee surgery. When ximelagatran was started immediately before surgery, LMWH had a significantly higher rate of VTE in both hip (OR 1.87 (95 per cent c.i. 1.20 to 2.92); P = 0.006) and knee (OR 1.49 (95 per cent c.i. 1.14 to 1.93); P = 0.003) surgery, but less bleeding: hip OR 0.30 (95 per cent c.i. 0.17 to 0.53; P < 0.001); knee OR 0.71 (95 per cent c.i. 0.30 to 1.67; P = 0.43). CONCLUSION: This review demonstrated no overall advantage for either LMWH or ximelagatran in thromboprophylaxis following orthopaedic surgery. Benefits in VTE prevention with ximelagatran were gained at the expense of an increased risk of serious bleeding.

Quality-adjusted survival in a crossover trial of letrozole versus tamoxifen in postmenopausal women with advanced breast cancer.

BACKGROUND: Results from a phase III study of postmenopausal women with advanced breast cancer demonstrated longer time to disease progression for patients taking letrozole versus tamoxifen. This analysis compares the trade-offs between progression-free survival and toxicity. DESIGN: Quality-adjusted survival was calculated using Q-TWiST (quality-adjusted time without symptoms or toxicity). Survival curves were partitioned into three health states: toxicity (TOX), disease progression (PROG) and periods without toxicity or disease progression (TWiST). The utility-weighted sum of the health state durations was derived and compared. RESULTS: There was not a significant difference in mean duration of serious adverse events prior to progression between the letrozole (n=453) and tamoxifen (n=454) groups (2.2 and 2 months, respectively). For TWiST, the mean duration for letrozole was 11.5 months, versus 8.5 months for tamoxifen (P <0.001). The mean duration of PROG was 11.5 months for letrozole and 12.7 months for tamoxifen (P=0.047). Using utility weights of 0.5 for TOX and PROG resulted in a 2.5-month difference in quality-adjusted survival favoring letrozole (P <0.0001). CONCLUSIONS: The longer time to disease progression with letrozole versus tamoxifen was achieved without increased time with adverse events and resulted in more quality-adjusted survival for patients on letrozole.

Reduced occupancy of the deeply bound 0d(5/2) neutron state in 32Ar.

The 9Be(32Ar, 31Ar)X reaction, leading to the 5/2+ ground state of a nucleus at the proton drip line, has a cross section of 10.4(13) mb at a beam energy of 65.1 MeV/nucleon. This translates into a spectroscopic factor that is only 24(3)% of that predicted by the many-body shell-model theory. We introduce refinements to the eikonal reaction theory used to extract the spectroscopic factor to clarify that this very strong reduction represents an effect of nuclear structure. We suggest that it reflects correlation effects linked to the high neutron separation energy (22.0 MeV) for this state.

New approach for measuring properties of rp-process nuclei.

A new experimental approach was developed that can reduce the uncertainties in astrophysical rapid proton capture (rp) process calculations due to nuclear data. This approach utilizes neutron removal from a radioactive ion beam to populate the nuclear states of interest. Excited states were deduced by the gamma-decay spectra measured in a semiconductor Ge-detector array. In the first case studied, 33Ar, excited states were measured with uncertainties of several keV. The 2 orders of magnitude improvement in the uncertainty of the level energies resulted in a 3 orders of magnitude improvement in the uncertainty of the calculated 32Cl(p,gamma)33Ar rate that is critical to the modeling of the rp process. This approach has the potential to measure key properties of almost all interesting nuclei on the rp-process path.

New direct reaction: two-proton knockout from neutron-rich nuclei.

The reaction 9Be(28Mg,26Ne+gamma)X has been studied at 82 MeV/nucleon together with two similar cases, 30Mg and 34Si. Strong evidence that the reactions are direct is offered by the parallel-momentum distributions of the reaction residues and by the inclusive cross sections. The pattern of the partial cross sections for 28Mg suggests the presence of correlations. A preliminary theoretical discussion based on eikonal reaction theory and the many-body shell model is presented. The reaction holds great promise for the study of neutron-rich nuclei.