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Dislocation structures in neutron irradiated Zircaloy-2 fuel cladding and channel material have been characterized by means of high-resolution synchrotron x-ray diffraction combined with whole peak profile analysis and by transmission electron microscopy (TEM). The samples available for this characterization were taken from high burnup fuel assemblies and offer insight into the evolution of the dislocation structure after the formation of dislocation loops containing a c component. Absolute dislocation density values are about 4–15 times higher for the whole peak profile compared to TEM analysis. Most interestingly, the diffraction analysis suggests that the total dislocation density, as well as the a loop density, increases with fluence for the cladding material type. This trend is also inferred from a Williamson-Hall representation but contradicts the TEM observations. The c loop density evolution is more complicated and doesn't display any particular trend. In addition, the diffraction analysis highlights the presence of well-developed shoulders adjacent to the basal reflections and noticeable peak asymmetry particularly for the channel samples that experienced slightly lower operation temperatures than the clad. The findings are discussed in respect of the perceived irradiation induced growth mechanisms in Zr alloys. [ABSTRACT FROM AUTHOR]

During corrosion of zirconium alloys a highly textured oxide is formed, the degree of this preferred orientation has previously been shown to be an important factor in determining the corrosion behaviour of these alloys. Two distinct experiments were designed in order to investigate the origin of this oxide texture development on two commercial alloys. Firstly, sheet samples of Zircaloy-4 were oxidised between 500 and 800 °C in air. The resulting monoclinic oxide texture strength was observed to decrease with increasing oxidation temperature. In a second experiment, orthogonal faces of Low Tin ZIRLO ™ 1 were oxidised in 360 °C water, providing different substrate textures but identical microstructures. The substrate texture was observed to have a negligible effect on the corrosion performance whilst the major orientation of both oxide phases was found to be independent of substrate orientation. It is concluded that the main driving force for oxide texture development in single-phase zirconium alloys is the compressive stress caused by the Zr ZrO 2 transformation. [ABSTRACT FROM AUTHOR]

As a nuclear fuel cladding material, zirconium alloys act as a barrier between the fuel and pressurised steam or lithiated water environment. Controlling degradation mechanisms such as oxidation is essential to extending the in-service lifetime of the fuel. At temperatures of ∼360 °C zirconium alloys are known to exhibit cyclical, approximately cubic corrosion kinetics. With acceleration in the oxidation kinetics occurring every ∼2 μm of oxide growth, and being associated with the formation of a network of lateral cracks. Finite element analysis has been used previously to explain the lateral crack formation by the development of localised out-of-plane tensile stresses at the metal–oxide interface. This work uses the Abaqus finite element code to assess critically current approaches to representing the oxidation of zirconium alloys, with relation to undulations at the metal–oxide interface and localised stress generation. This includes comparison of axisymmetric and 3D quartered modelling approaches, and investigates the effect of interface geometry and plasticity in the metal substrate. Particular focus is placed on the application of the anisotropic strain tensor used to represent the oxidation mechanism, which is typically applied with a fixed coordinate system. Assessment of the impact of the tensor showed that 99% of the localised tensile stresses originated from the out-of-plane component of the strain tensor, rather than the in-plane expansion as was previously thought. Discussion is given to the difficulties associated with this modelling approach and the requirements for future simulations of the oxidation of zirconium alloys. [ABSTRACT FROM AUTHOR]

Background:Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.Methods:Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7-1.4 mg m−2 and CP 60-75 mg m−2. Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m−2, CP 60 mg m−2) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.Results:On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m−2, 60 mg m−2); G 3 anorexia/fatigue/hypokalemia (1.2 mg m−2, 60 mg m−2); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m−2, 60 mg m−2). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m−2, 60 mg m−2); G 4 mucositis (1.4 mg m−2, 60 mg m−2); and G 3 hypokalemia (1.2 mg m−2, 75 mg m−2). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m−2 (days 1, 8) and CP 75 mg m−2 (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).Conclusions:On the 21-day cycle, eribulin mesylate 1.2 mg m−2, administered on days 1 and 8, in combination with CP 75 mg m−2, administered on day 1 is well tolerated and showed preliminary anticancer activity. [ABSTRACT FROM AUTHOR]

Corrosion is a key limiting factor in the degradation of zirconium alloys in light water reactors. Developing a mechanistic understanding of the corrosion process offers a route towards improving safety and efficiency as demand increases for higher burn-up of fuel. Oxides formed on zirconium alloys are composed of both monoclinic and meta-stable tetragonal phases, and are subject to a number of potential mechanical degradation mechanisms. The work presented investigates the link between the tetragonal to monoclinic oxide phase transformation and degradation of the protective character of the oxide layer. To achieve this, Abaqus finite element analysis of the oxide phase transformation has been carried out. Study of the change in transformation strain energy shows how relaxation of oxidation induced stress and fast fracture at the metal–oxide interface could destabilise the tetragonal phase. Central to this is the identification of the transformation variant most likely to form, and understanding why twinning of the transformed grain is likely to occur. Development of transformation strain tensors and analysis of the strain components allows some separation of dilatation and shear effects. Maximum principal stress is used as an indication of fracture in the surrounding oxide layer. Study of the stress distributions shows the way oxide fracture is likely to occur and the differing effects of dilatation and shape change. Comparison with literature provides qualitative validation of the finite element simulations. [ABSTRACT FROM AUTHOR]

The desire to improve the corrosion resistance of Zr cladding material for high burn-up has resulted in a general trend among fuel manufacturers to develop alloys with reduced levels of Sn. While commonly accepted, the reason for the improved corrosion performance observed for low-tin zirconium alloys in high-temperature aqueous environments remains unclear. High-energy synchrotron X-ray diffraction was used to characterize the oxides formed by autoclave exposure on Zr–Sn–Nb alloys with tin concentration ranging from 0.01 to 0.92wt.%. The alloys studied included the commercial alloy ZIRLO® (ZIRLO® is a registered trademark of Westinghouse Electric Company LLC in the USA and may be registered in other countries throughout the world. All rights reserved. Unauthorized use is strictly prohibited.) and two variants of ZIRLO with significantly lower tin levels, referred to here as A-0.6Sn and A-0.0Sn. The nature of the oxide grown on tube samples from each alloy was investigated via cross-sectional scanning electron microscopy. Atom probe analysis of ZIRLO demonstrated that the tin present in the alloy passes into the oxide as it forms, with no significant difference in the Sn/Zr ratio between the two. Synchrotron X-ray diffraction measurements on the oxides formed on each alloy revealed that the monoclinic and tetragonal oxide phases display highly compressive in-plane residual stresses with the magnitudes dependent on the phase and alloy. The amount of tetragonal phase present and, more importantly, the level of tetragonal-to-monoclinic phase transformation both decrease with decreasing tin levels, suggesting that tin is a tetragonal oxide phase stabilizing element. It is proposed that in Zr–Nb–Sn alloys with low Sn, the tetragonal phase is mainly stabilized by very small grain size and therefore remains stable throughout the corrosion process. In contrast, alloys with higher tin levels can in addition grow larger, stress stabilized, tetragonal grains that become unstable as the corrosion front continues to grow further inwards and stresses in the existing oxide relax. [ABSTRACT FROM AUTHOR]

Abstract: To improve the understanding of the oxidation mechanism in zirconium alloys for fuel clad applications, detailed residual stress and phase fraction analysis was carried out for the oxides formed on Zircaloy-4 after autoclave exposure at 360°C for various times by means of synchrotron X-ray diffraction. In a post-transition sample (220days), significant stress variation through the oxide thickness was found for the monoclinic phase in individual oxide layers, with maximum in-plane compressive stresses located towards the metal–oxide interface and a discontinuity in the residual stress profile. The depth of this discontinuity matched well with the depth at which electron microscopy analysis showed an interface between two distinct oxide layers. Analysis of the tetragonal phase with exposure time demonstrated changes of the total volume of tetragonal phase before and during transition. These observations are put into the context of residual stress evolution presented previously, to provide further insight into the importance of phase transformations and residual stresses in determining the corrosion kinetics of Zr alloys. [Copyright &y& Elsevier]

Autoclave corrosion experiments were conducted on a number of zirconium alloys in different heat treatment conditions. The alloys tested in the present work were Zircaloy-4, ZIRLO® (ZIRLO is a registered trademark of Westinghouse Electric Company LLC in the USA and may be registered in other countries throughout the world. All rights reserved. Unauthorised use is strictly prohibited.) and two variants of ZIRLO with significantly lower Sn levels, referred to here as A-0·6Sn and A-0·0Sn. Typical corrosion kinetics with a change from pre- to post-initial transition was observed with ZIRLO and Zircaloy-4 displaying the shortest time to the initial transition after 120-140 days of autoclave exposure, followed by A-0·6Sn materials after 140-260 days. A-0·0Sn materials showed no sign of transition even after 360 days although one sample tested to 540 days had gone through transition. Material in the stress relieved condition generally experienced initial transition earlier than the same alloy in the recrystallised condition. Pretransition samples had a universally black oxide layer, which eventually developed grey patches when transition occurred. Practically, all non-hydrogen charged alloys showed a strong trend towards cubic oxide growth rates. Cathodic hydrogen charging was conducted to simulate end of life condition of cladding tubes, forming a hydride rich rim region at the outer surface of the cladding tubes. Hydrogen charged materials generally experienced accelerated corrosion of different degrees with the exception of recrystallised A-0·0Sn and partially recrystallised A-0·6Sn showing no sign of acceleration. It therefore seems that increasing tin levels has a negative impact on autoclave corrosion behaviour for materials with and without a hydride rich rim. In developing advanced alloys for use in cladding, this effect has been balanced against the benefits that Sn is known to provide in-reactor, including robustness in corrosion behaviour and reduced irradiation growth. It was noted that most materials with a hydride rich rim exhibit parabolic corrosion kinetics with decreased initial weight gain but increased overall weight gain. [ABSTRACT FROM AUTHOR]

Let 𝒳, 𝒴, 𝒵 be real Hilbert spaces, let f : 𝒳 → ℝ ∪ {+∞}, g : 𝒴 → ℝ ∪ {+∞} be closed convex functions and let A : 𝒳 → 𝒵, B : 𝒴 → 𝒵 be linear continuous operators. Given a sequence (γ n ) which increases towards infinity as n → +∞, we study the following alternating proximal algorithm: where α and ν are positive parameters. If the sequence (γ n ) increases moderately slowly towards infinity, the algorithm (𝒜) tends to minimize the function over the set C = argmin f × argmin g (assumed to be nonempty). An illustration of this result is given in the area of domain decomposition for PDE's. [ABSTRACT FROM PUBLISHER]

Purpose: The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs). Methods: Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not. Results: Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (>8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL) on day 9 was 51% of the CL on day 2 ( P < 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 ( P < 0.01). The median bortezomib CL on days 2 and 9 was significantly higher ( P < 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower ( P < 0.04). Conclusions: The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m, respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients. [ABSTRACT FROM AUTHOR]

Abstract: Let V and H be Hilbert spaces such that with dense and continuous injections. Consider a linear continuous operator which is assumed to be symmetric, monotone and semi-coercive. Given a function and a map such that , our purpose is to study the asymptotic behavior of the following semilinear hyperbolic equation The nonlinearity f is assumed to be monotone and conservative. Condition guarantees that some suitable energy function tends toward its minimum. The main contribution of this paper is to provide a general result of convergence for the trajectories of (E): if the quantity behaves as , for some , and t large enough, then weakly converges in V toward an equilibrium as . Strong convergence in V holds true under compactness or symmetry conditions. We also give estimates for the speed of convergence of the energy under some ellipticity-like conditions. The abstract results are applied to particular semilinear evolution problems at the end of the paper. [Copyright &y& Elsevier]

In this paper, the levels of residual stress in the vicinity of linear friction welds in Ti 6Al-4V (Ti-64), a conventional α-β titanium alloy, and Ti-6Al-2Sn-4Zr-2Mo (Ti-6242), a near α titanium alloy with higher temperature capability, are mapped and contrasted. The alloys have significantly different high temperature properties and the aim of this work was to investigate how this might affect their propensity to accumulate weld residual stresses and their response to post-weld heat treatment. Measurements are reported using high energy synchrotron X-ray diffraction and the results are compared to those made destructively using the contour method. The strain free lattice plane do variation across the weld has been evaluated using the biaxial sin²ψ technique with laboratory X-rays. It was found that failure to account for the do variation across the weld line would have led to large errors in the peak tensile stresses. Contour method measurements show fairly good correlation with the diffraction results, although the stresses are underestimated. Possible reasons for the discrepancy are discussed. The peak tensile residual stresses introduced by the welding process were found to be greater for Ti-6242 (~750 MPa) than for Ti-64 (~650 MPa). Consistent with the higher temperature capability of the alloy, higher temperature post-weld heat treatments have been found to be necessary to relieve the stresses in the near α titanium alloy compared to the α+β titanium alloy. [ABSTRACT FROM AUTHOR]

Background: While aromatase inhibitors are effective for ER/PR positive breast cancer, resistance frequently develops. EXE is a steroidal AI and has a weak hormone-like activity. Long-term EXE treatment up-regulated amphiregulin-mediated EGFR activation and EXE resistance could result from ER-EGFR cross-talk. In cell culture and animal studies, acquired resistance to EXE was significantly delayed with intermittent use, associated with decreased production of amphiregulin. For first line therapy in MBC, EXE had a median progression free survival (PFS) of 10 mos. As second and third line therapies, PFS decreased to 4.7 mos and 2 mos, respectively. After ≥ 2 of prior endocrine therapy, PFS to EXE ranged between 3.4 mos to 3.7 mos. The rationale for this study was that after long-term estrogen deprivation clinically equivalent to long-term exposure to AI, estrogen may induce apoptosis. With intermittent EXE use, we hope to delay the acquired AI resistance. Methods: Aims were to: 1) assess the PFS and 2) compete response (CR), partial response (PR) and clinical benefit rate [CBR=CR +PR + Stable disease (SD)≥ 6 mos], assessment of toxicity, compliance with medication adherence, and quality of life with assessment of bone health. The study included: 1) ER/PR positive MBC in first, second line/third line hormonal therapy, and one prior chemotherapy for MBC with no prior EXE allowed. EXE was given 25 mg daily x 14 days then 7 days off treatment, each 21-day cycle, imaging was done after every three cycles. Correlatives with estradiol level were drawn at day 1 and day 15 in each cycle. Results: From June 2008 to 2012 we enrolled 33 MBC patients ER/PR positive MBC with a median age of 60 yrs (42-79). At this cut off data date, 2 were inevaluable due to incidental colon cancer and change in treatment choice. 17 patients received treatment as first line (52%), 10 as second or third line hormonal therapy (30%), and 6 who received chemotherapy for MBC (18%). Median PFS and (95% CI) was 6.2 mos (1.9-12.2), 4.2 mos (2.1-10.1), and 3.2 mos (2.1-NR), respectively. For first line patients, there were 3 PRs and 4 with SD>6 mos for a CBR of 7/14 (50%). For second/third line, there were 3 with SD>6 mos for a CBR of 3/9(33%), no response seen in the prior chemotherapy group. The major metastatic sites included bone, liver, lung. 4 patients were Her2+ (13%). Adverse effects including hot flashes (62%), insomnia (31%), nausea (24%), bone pain (17%), fatigue (41%), joint pain (31%) were observed. Median number of cycles delivered is 6 (2-24) for first line, 5.5 (1-15) for second/third line, and 5 (2-9) for prior chemotherapy. Correlatives and QOL assessments are ongoing. Conclusions: Compared to the standard continuous EXE, PFS and CBR is inferior in the intermittent EXE as first line therapy, as second and third line therapy, the median PFS was 4.2 comparable to reported 3.7 mos with the CBR was 33% to 31.5% observed in the EFFECT trial. Interestingly, hot-flash rate was much higher at 62% compared to 11.2% in the EFFECT trial. Arthralgia is comparable at 31%. Patients who already received chemotherapy do not appear to respond favorably to intermittent hormonal therapy. Full response data with correlatives regarding the estradiol levels will be presented. [ABSTRACT FROM AUTHOR]

While radium 223 dichloride (Ra-223) has been approved for metastatic castrate resistant prostate cancer, there is limited prospective data regarding its use in metastatic castrate-sensitive prostate cancer (mCSPC). We conducted a single-center open-label phase II clinical trial investigating Ra-223 combined with 36 weeks androgen deprivation therapy (ADT) and stereotactic body radiation therapy (SBRT) for patients with oligometastatic (≤5 metastases) CSPC (NCT03361735, SHARP trial). The primary objective was time to treatment failure (TTF), and secondary objectives included assessing toxicities, progression-free survival (PFS), and overall survival (OS). ADT (degarelix [n=4], relugolix [n=2], or leuprolide [n=19]) was administered starting at least 4 weeks prior to SBRT and continued for 36 weeks. SBRT was 27 Gy in 3 fractions to bone metastases. De novo patients also received definitive radiation therapy to their prostate primary ± pelvic lymph nodes. Patients received 6 infusions of Ra-223 at a dose of 55 kBq/kg, with one infusion every 28 days. The first infusion was ∼1 month after the first SBRT fraction. Blood samples for correlative studies were collected throughout treatment. 25 patients were enrolled between August 2018 and July 2023, including 6 de novo and 19 oligoprogressive mCSPC patients. Median Gleason score was 7 (range 6-9). Median number of metastases was 2 bone metastases (range 1-5). 21 patients completed study therapy. Median follow-up was 31.7 months (95% confidence interval [CI] 28.4, 44.1). Median TTF was 19.0 (13.1, not reached [NR]) months in all patients, 34.3 (2.8, NR) months in de novo patients and 17.7 (12.4, NR) months in oligoprogressive patients. 1-year OS was 95.5% (95%CI 71.9%, 99.3%) in all patients, 100% in de novo patients and 94% (95% CI 63%, 99%) in oligoprogressive patients. 1-year PFS was 82.1% (59.1%, 92.9%) in all patients, 83% (95% CI 27%, 98%) in de novo patients and 81% (95% CI 53%, 94%) in oligoprogressive patients. 4 de novo patients were free from progression at the 2-year interval. Grade 3 toxicities at least possibly related to protocol therapy included lymphopenia (n=8), hypertension (n=6), neutropenia (n=2), anemia (n=1), leukopenia (n=1), fracture (n=1), syncope (n=1), and cholecystitis (n=1). No grade 4+ toxicities occurred. 5 patients developed fractures (grade 1, n=2 (imaging only); grade 2, n=2; grade 3, n=1). IL-8 significantly increased from baseline to the end of treatment (p=0.04) and a reduction in proinflammatory IL-1β and TNFα from baseline was observed. Ra-223 combined with SBRT to oligometastases and 36 weeks ADT in mCSPC is well-tolerated and results in favorable OS and PFS compared to historical controls. Longer follow-up is necessary to assess if the early use of Ra-223 delays development of new bone metastases. [ABSTRACT FROM AUTHOR]

Proton-and neutron-irradiated Zircaloy-2 are compared in terms of the nano-scale chemical evolution within second phase particles (SPPs) Zr(Fe,Cr) 2 and Zr 2 (Fe,Ni). This is accomplished through ultra-high spatial resolution scanning transmission electron microscopy and the use of energy-dispersive X-ray spectroscopic methods. Fe-depletion is observed from both SPP types after irradiation with both irradiative species, but is heterogeneous in the case of Zr(Fe,Cr) 2 , predominantly from the edge region, and homogeneously in the case of Zr 2 (Fe,Ni). Further, there is evidence of a delay in the dissolution of the Zr 2 (Fe,Ni) SPP with respect to the Zr(Fe,Cr) 2 . As such, SPP dissolution results in matrix supersaturation with solute under both irradiative species and proton irradiation is considered well suited to emulate the effects of neutron irradiation in this context. The mechanisms of solute redistribution processes from SPPs and the consequences for irradiation-induced growth phenomena are discussed. [ABSTRACT FROM AUTHOR]

Prior studies have demonstrated that radiolabeled anti-carcinoembryonic antigen (CEA) monoclonal antibody (M5A) can target CEA-expressing cancers. This ongoing pilot study (NCT05245786) evaluates the ability of Cu-64-DOTA-M5A PET imaging to define disease extent before and after neoadjuvant radiotherapy in patients with locally advanced rectal cancer. Patients with biopsy proven cT3-4, N0 or N+ rectal cancer who were scheduled for neoadjuvant chemoradiation prior to TME or total neoadjuvant therapy underwent PET imaging with Cu-64-M5A within 4 weeks prior to start of neoadjuvant RT and 6-8 weeks after end of all neoadjuvant therapy and prior to planned surgery. Cu-64-M5A PET scans were read by the same nuclear medicine physician. A regional analysis (primary, pelvic nodes, and extra-pelvic) later compared CEA scans to standard of care (SOC) CT and MRI imaging, FDG PET if available, biopsies and surgical findings. Nine patients have been imaged to date with Cu-64-M5A PET (ages 46-70 years old). CEA PET imaging prior to RT identified the primary tumor in all 9 patients. For disease involving pelvic nodes, CEA PET imaging was in concordance with SOC imaging in 6 of 9 patients. In 5 patients CEA scans identified suspicious lesions outside the pelvis, which in 2 patients were confirmed by SOC imaging and biopsy (lung metastases; and a single liver metastasis), while in 3 patients PET avid nodes detected (para-aortic, left supraclavicular, mediastinal, porta hepatis, and portacaval) were outside the regions imaged as part of SOC. 4 of 9 patients to date have also been imaged post RT and prior to surgery. 2 patients had radiologic complete response (CR) on CEA scans which correlated with pathologic CR at surgery and with clinical CR on follow-up sigmoidoscopy. Two patients had positive scans; 1 patient at the primary site confirmed as residual disease at surgery; and 1 patient at the primary site, in mediastinal, para-aortic, and pelvic lymph nodes, and a new focus near the hepatic surface with biopsy confirmation of disease at the primary site and liver. Results demonstrate that Cu-64-M5A anti-CEA M5A PET imaging in patients with advanced rectal cancer shows promise in identifying known sites of disease at the primary site and regional lymph nodes, as well as identifying extra pelvic sites of disease. In addition, it shows promise for assessing response to neoadjuvant therapy. Cu-64-M5A imaging warrants further evaluation as a way to complement SOC imaging at initial staging, to select patients for local regional therapy and to select patients for non-operative management after neoadjuvant therapy. Given its targeting capabilities, M5A is also being evaluated radiolabeled with Ac-225 as a therapeutic radiopharmaceutical (NCT05204147) and as an anti-CEA-IL2 immunotherapy fusion agent (NCT06130826) in phase 1 trials. [ABSTRACT FROM AUTHOR]

As a cladding material used to encapsulate nuclear fuel pellets, zirconium alloys are the primary barrier separating the fuel and a pressurised steam or lithiated water environment. Degradation mechanisms such as oxidation can be the limiting factor in the life-time of the fuel assembly. Key to controlling oxidation, and therefore allowing increased burn-up of fuel, is the development of a mechanistic understanding of the corrosion process. In an autoclave, the oxidation kinetics for zirconium alloys are typically cyclical, with periods of accelerated kinetics being observed in steps of ∼2 μm oxide growth. These periods of accelerated oxidation are immediately preceded by the development of a layer of lateral cracks near the metal-oxide interface, which may be associated with the development of interface roughness. The present work uses scanning electron microscopy to carry out a statistical analysis of changes in the metal-oxide interface roughness between three different alloys at different stages of autoclave oxidation. The first two alloys are Zircaloy-4 and ZIRLO ™ for which analysis is carried out at stages before, during and after first transition. The third alloy is an experimental low tin alloy, which under the same oxidation conditions and during the same time period does not appear to go through transition. Assessment of the metal-oxide interface roughness is primarily carried out based on the root mean square of the interface slope known as the R dq parameter. Results show clear trends with relation to transition points in the corrosion kinetics. Discussion is given to how this relates to the existing mechanistic understanding of the corrosion process, and the components required for possible future modelling approaches. [ABSTRACT FROM AUTHOR]

Pressurised and boiling water reactors contain zirconium alloys, which are used as nuclear fuel cladding. Oxidation of these alloys, and the associated hydrogen pick-up, is a limiting factor in the lifetime of the fuel. To extend the burn-up of nuclear fuel requires control of the oxidation, and therefore development of a mechanistic understanding of the cladding corrosion process. Synchrotron X-ray diffraction (S-XRD) has been used to analyse oxide layers formed during in-situ air oxidation of Zircaloy-4 and ZIRLO™. Analysis shows that as the oxide thickness increases over time there is a relaxation of the stresses present in both the monoclinic and meta-stable tetragonal phases, and a reduction in the tetragonal phase fraction. To better understand the mechanisms behind stress relaxation in the oxide layer, finite element analysis has been used to simulate mechanical aspects of the oxidation process. This simulation was first developed based on stress relaxation in oxides formed in autoclave, and analysed ex-situ using S-XRD. Relaxation mechanisms include creep and hydrogen-induced lattice strain in the metal substrate and creep in the oxide layer. Subsequently the finite element analysis has been extended to stress relaxation observed by in-situ S-XRD oxidation experiments. Finite element analysis indicates that the impact of creep in the oxide is negligible, and the impact of both creep and hydrogen-induced lattice strain in the metal substrate metal is small. The implication is that stress relaxation must result from another source such as the development of roughness at the metal–oxide interface, or fracture in the oxide layer. [ABSTRACT FROM AUTHOR]

A detailed characterization of nanostructured thin zirconium oxide films formed during aqueous corrosion of a nuclear-grade zirconium alloy (Zircaloy-4) has been carried out by means of two novel, ultra-high-spatial-resolution grain mapping techniques, namely automated crystal orientation mapping in the transmission electron microscope (TEM) and transmission electron backscatter diffraction (t-EBSD). While the former provided excellent spatial resolution with the ability to identify tetragonal ZrO 2 grains as small as ∼5 nm, the superior angular resolution and unambiguous indexing with t-EBSD enabled verification of the TEM observations. Both techniques revealed that in a stress-free condition (TEM foil prepared by focused ion beam milling), the oxide consists mainly of well-oriented columnar monoclinic grains with a high fraction of transformation twin boundaries, which indicates that the transformation from tetragonal to monoclinic ZrO 2 is a continuous process, and that a significant fraction of the columnar grains transformed from stress-stabilized tetragonal grains with (0 0 1) planes parallel to the metal–oxide interface. The TEM analysis also revealed a small fraction of size-stabilized, equiaxed tetragonal grains throughout the oxide. Those grains were found to show significant misalignment from the expected (0 0 1) growth direction, which explains the limited growth of those grains. The observations are discussed in the context of providing new insights into corrosion mechanisms of zirconium alloys, which is of particular importance for improving service life of fuel assemblies used in water-cooled reactors. [ABSTRACT FROM AUTHOR]

Zirconium alloys used as cladding materials in nuclear reactors can exhibit accelerated irradiation induced growth, often termed linear growth, after sustained neutron irradiation. This phenomenon has been linked to the formation of < c >-component dislocation loops and to the concentration of interstitial solute atoms. It is well documented for the Zircaloys that Fe dissolves from second phase particles (SPPs) during irradiation thus increasing the interstitial solute concentration in the matrix. However, no progress has yet been made into understanding whether a similar process occurs for the newer ZIRLO™ alloys. We aim to overcome this shortcoming here by studying compositional changes in second phase particles in Low Tin ZIRLO™ after neutron and proton irradiation using energy dispersive X-ray (EDX) spectroscopy. Material irradiated to 18 dpa (displacements per atom) using neutrons and to 2.3 and 7 dpa by protons was investigated. The results show that Fe is lost from Zr–Nb–Fe-SPPs during both neutron and proton irradiation. Prior to irradiation, Fe was detected at the interface of β-Nb-SPPs. This Fe enrichment is also dispersed during irradiation. Qualitatively, excellent agreement was found regarding the elemental redistribution processes observed after proton and neutron irradiation. [ABSTRACT FROM AUTHOR]

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor–positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials. [ABSTRACT FROM AUTHOR]

Abstract: Let be real Hilbert spaces, let , be closed convex functions and let , be linear continuous operators. Let us consider the constrained minimization problem Given a sequence which tends toward as , we study the following alternating proximal algorithm where and are positive parameters. It is shown that if the sequence tends moderately slowly toward , then the iterates of weakly converge toward a solution of . The study is extended to the setting of maximal monotone operators, for which a general ergodic convergence result is obtained. Applications are given in the area of domain decomposition for PDE’s. [Copyright &y& Elsevier]

We report on a predictive model of long-term outcome in 114 high-risk breast cancer patients treated with high-dose chemotherapy between 1989 and 1994. Paraffin-blocks from 90 of the 114 primaries were assessed for the presence of five risk factors: grade, mitotic index, protein expression of p53, HER2/neu, and oestrogen/progesterone receptor status; we could analyse the effect of risk factors in 84 of these 90 tumours. Seven-year relapse-free and overall survival was 58% (95% confidence interval 44-74%) and 82% (95% confidence interval 71-94%) vs 33% (95% confidence interval 21-52%) and 41% (95% confidence interval 28-60%) for patients whose primary tumours displayed > or =3 risk factors vs patients with < or =2 risk factors. For the entire group of 168 high-risk breast cancer patients, inflammatory stage IIIB disease and involved post-mastectomy margins were associated with decreased relapse-free survival and overall survival; patients treated with non-doxorubicin containing standard adjuvant therapy experienced worse overall survival (RR, 2.08; 95% confidence interval 1.04 to 4.16; P=0.04), while adjuvant tamoxifen improved overall survival (RR, 0.65; 95% confidence interval 0.41-1.01; P=0.054). Future trial designs and patient selection for studies specific for high-risk breast cancer patients should include appropriate prognostic models. Validation of such models could come from recently completed randomised, prospective trials. [ABSTRACT FROM AUTHOR]

Proton irradiation is increasingly used as a surrogate for neutron irradiation, providing similar damage structures at significantly lower costs and less time compared to neutron irradiation. However, in contrast to neutrons, protons produce a depth dependent damage profile that incorporates a plateau region and a Bragg peak in the tens of microns region depending on the material and proton energy. Here we demonstrate that this depth dependent damage can be utilised to obtain new understanding about irradiation induced damage at different dose levels from a single sample by combining spatially resolved micro-beam synchrotron X-ray diffraction-based dislocation analysis and nanoindentation. For this purpose, and to study the damage evolution starting from very early stages, we have investigated microstructure evolution and hardening behaviour of Zircaloy-2 and Zircaloy-4 proton irradiated samples between 0.01 dpa and 17 dpa at 350 °C. The results highlight good agreements of SRIM-based damage depth predictions with irradiation-induced dislocation appearance and nanohardness. However, at even relatively low damage levels within the plateau region, dislocation line density and nanohardness profiles appear saturated across the entire irradiated region, even when the dpa levels differed significantly. When relating dislocation loop line densities to nanohardness, it was found that from a certain point hardness increased only very slightly with increasing line densities. This apparent discrepancy can be explained by a decreasing loop size for the highest line densities identified by from the diffraction line profile analysis and the application of a Dispersed Barrier Hardening model that relates obstacle strength to dislocation loop size. [Display omitted] [ABSTRACT FROM AUTHOR]

This work is a first assessment of the radiation tolerance of the nanolayered ternary carbides (MAX phases), Zr 3 AlC 2 , Nb 4 AlC 3 and (Zr 0.5 ,Ti 0.5) 3 AlC 2 , using proton irradiation followed by post-irradiation examination based primarily on x-ray diffraction analysis. These specific MAX phase compounds are being evaluated as candidate coating materials for fuel cladding applications in advanced nuclear reactor systems. The aim of using a MAX phase coating is to protect the substrate fuel cladding material from corrosion damage during its exposure to the primary coolant. Proton irradiation was used in this study as a surrogate for neutron irradiation in order to introduce radiation damage into these ceramics at reactor-relevant temperatures. The post-irradiation examination of these materials revealed that the Zr-based 312-MAX phases, Zr 3 AlC 2 and (Zr 0.5 ,Ti 0.5) 3 AlC 2 have a superior ability for defect-recovery above 400 °C, whilst the Nb 4 AlC 3 does not demonstrate any appreciable defect recovery below 600 °C. Density functional theory calculations have demonstrated that the structural differences between the 312 and 413-MAX phase structures govern the variation of the irradiation tolerance of these materials. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Abstract Detailed analysis was carried out on proton and a neutron irradiated Nb-containing Zr-alloy to study the evolution of dislocation loop size and densities as well as the formation and evolution of irradiation-induced precipitation/clustering. The results obtained here have been contrasted against previously published work on a Nb-free Zr-alloy [1, 2] to investigate the mechanistic reason for the improved resistance to irradiation-induced growth of Nb-containing Zr alloys. The combined use of bright field scanning transmission electron microscopy, ultra-high-resolution energy dispersive spectroscopy and atom probe tomography analysis provides evidence of evenly distributed radiation-induced Nb clusters that have formed during the early stage of proton irradiation and Fe-rich nano-rods near Fe-containing second phase particles. The former seems to have a profound effect on loop and subsequent loop formation, keeping loop size small but number density high while loops seem to initially form at similar dose levels compared to a Nb-free alloy but loop line density does not increase during further irradiation. It is hypothesized that the formation of the Nb nano-precipitates/clusters significantly hinders mobility and growth of loops, resulting in a small size, high number density and limited ability of loops to arrange along basal traces compared to Nb-free Zr-alloys. It is suggested that it is the limited loop arrangement that slows down loop formation and the root cause for the high resistance of Nb-containing Zr-alloys to irradiation-induced growth. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract A study into the effects of irradiation temperature on the damage structures that form during proton-irradiation has been carried out on two commercial Zr alloys in order to develop a more mechanistic understanding of the effect of niobium on dislocation loop evolution. The two Zr alloys (Zircaloy-2 and Low-Sn ZIRLO™) were proton irradiated to a damage level of ∼2 dpa at 280 °C, 350 °C and 450 °C. Detailed dislocation analysis was carried out using on-axis bright-field scanning transmission electron microscopy combined with spectral imaging and synchrotron x-ray line profile analysis. The analysis revealed a significant difference in the effect of irradiation temperature on loop size between the two alloys. In the case of the Nb-free Zr-alloy (Zircaloy-2), an increase in irradiation temperature results in a marked increase in a-loop diameter, by a factor of ∼7.5 from 280 to 450 °C, and a stark decrease in the dislocation line density. In contrast, the Nb-containing Zr-alloy (Low-Sn ZIRLO™) showed very little variation of loop size and line density over the same radiation temperature range. The STEM-based spectral imaging revealed irradiation-induced nano-clustering found throughout the matrix in Low-Sn ZIRLO™, which is not present in the case of Zircaloy-2. Therefore, it is proposed that Nb plays a crucial role in the evolution of dislocation loops in Zr through the formation of irradiation precipitation throughout the matrix. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

In service, zirconium alloys undergo aqueous corrosion and hydrogen is absorbed, which can lead to the formation of hydrides. Hydrides, as well as the precipitates in zirconium alloys, affect the mechanical performance, though their contribution to plasticity is not yet well understood. This study uses a combination of high-resolution digital image correlation and electron backscatter diffraction to quantify the strain partitioning between the different phases. Following uniaxial tensile deformation, it was found that the average strain within the δ-ZrH and Zr(Fe,Cr) 2 was lower than in the α-Zr. Shear bands in the α-Zr matrix were observed to interact with small and medium sized hydride in multiple ways, such as terminating at the interface, cracking and shear around the interface or causing plastic slip in the hydride. Large hydrides showed a particularly detrimental effect on deformation behavior, with large strain localizations and cracking observed at interfaces, which are typically precursors to failure. In contrast, the Zr(Fe,Cr) 2 precipitates remained undeformed and forced the expected metal-matrix lattice rotation. The importance of these observations in context of fuel cladding integrity is discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract We investigate nano-scale irradiation-induced precipitation in a Zr Sn Fe Cr Ni-alloy (Zircaloy-2) by combining atom probe tomography (APT) for chemical detail with scanning transmission electron microscopy (STEM) and high resolution energy dispersive X-ray (EDX) spectroscopy for wider context and complimentary and correlative TEM diffraction techniques for crystallographic relationships. We find that Fe and Cr-rich nano-rods precipitate in Zircaloy-2 following proton irradiation at 350 °C to a low dose of ∼2 dpa. The long-axis of the nano-rods are aligned in a direction 12–15° from the Zr matrix 〈 0001 〉 , align in the basal plane and are of width 1.5–5 nm. Smaller rods are of APT-determined composition Zr 4 (Fe 0.67 Cr 0.33), tending towards Zr 3 (Fe 0.69 Cr 0.31) as the rod volume increases to > ∼400 nm3, in agreement with STEM-EDX determination of composition resembling that of Zr 3 Fe with Cr replacing some of the Fe. The Fe/Cr ratio has been shown to increase with distance from the nearest partially-dissolved Zr(Fe,Cr) 2 phase particle. The nucleation of nano rods has implications for macroscopic irradiation-induced deformation phenomena, irradiation-induced hardening and the evolution of dislocation loops and other defects. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

High Resolution Digital Image Correlation (HRDIC) has been established recently as a novel displacement mapping technique during mechanical loading experiments to quantify strain localisation down to the level of individual slip traces. This is achieved by the creation of a nano-scale gold pattern naturally formed during remodelling of a thin gold layer that was sputtered onto the region of interest. To date, the gold remodelling is carried out in a water vapourisation environment, which excludes the technique to be applied to materials that readily form noticeable oxide layers in such environments. The current paper describes a recently developed gold remodelling technique using a styrene-argon environment at substantially lower temperatures than the water-vapour based technique. The material used in the present work is a zirconium alloy where we first demonstrate the problem of oxide formation during remodelling in water vapour and the benefit of the modified remodelling procedure. The error associated with the spatial drift was assessed for different interrogation window sizes followed by detailed analysis of the subsequent strain maps produced using the styrene remodelled patterns after tensile deformation to nominal applied strains of ~3.5% and ~7.0%. The level of detail captured demonstrate the suitability of styrene-argon-based remodelling for materials like Zr alloys with the strain maps showing clear strain patterning on both a transgranular and single grain scale with the possibility of quantifying strain across a single slip trace. [ABSTRACT FROM AUTHOR]

Zr alloys exhibit irradiation-induced growth and hardening which is associated with the defects and dislocation loops that form during irradiation. In this study, state-of-the-art in-situ synchrotron X-ray diffraction (SXRD) and transmission electron microscopy (TEM) techniques were used to investigate the stability of dislocation loops in two proton-irradiated Zr-Fe binary alloys in real time. Complementary data from both techniques show rapid annealing of a-loops occurs between 300 °C and 450 °C. Line profile analysis was performed on the SXRD patterns using the convoluted multiple whole profile analysis tool, to calculate the change in a-loop line density as a function of post-irradiation heat treatment temperature and time. At temperatures below 300 °C, no significant decrease in a-loop density was detected when held for 1 h at temperature. From this SXRD experiment, we calculate the effective activation energy for the annealing process as 0.46 eV. On-axis in-situ STEM imaging was used to directly observe a-loop mobility during heating cycles and confirm that a-loops begin to glide in the trace of the basal plane at ∼200 °C in a thin foil specimen. Such a-loop gliding events, leading to annihilation at the foil's surfaces, became more frequent between 300 and 450 °C. [ABSTRACT FROM AUTHOR]

• Novel methodology detects irradiation-induced strain localisation on the microscale • Novel methodology to be used in further understanding irradiation creep mechanisms • Speckle pattern stabilization for high-temperature proton irradiations • Strain localisation induced microcracking in MAX phases irradiated to ∼0.1 dpa Materials subjected to irradiation damage often undergo local microstructural changes that can affect their expected performance. To investigate such changes, this work proposes a novel approach to detect strain localisation caused by irradiation-induced damage in nuclear materials on the microstructural level, considering a statistically relevant number of grains. This approach determines local strains using high-resolution digital image correlation (HRDIC) and compares them with the underlying material microstructure. Sets of images captured before and after irradiation are compared to generate full-field displacement maps that can then be differentiated to yield high-resolution strain maps. These strain maps can subsequently be used to understand the effects of irradiation-induced dimensional change and cracking on the microscale. Here, the methodology and challenges involved in combining scanning electron microscopy (SEM) with HRDIC to generate strain maps associated with radiation-induced damage are presented. Furthermore, this work demonstrates the capabilities of this methodology by analysing three different materials subjected to proton irradiation: a zircaloy-4 (Zry-4) metal irradiated to 1 & 2 dpa, and two ceramics based on MAX phase compounds, i.e., the Nb 4 AlC 3 ternary compound and a novel (Ta,Ti) 3 AlC 2 solid solution, both irradiated to -0.1 dpa. These results demonstrated that all materials show measurable expansion, and the very high strains seen in the MAX phase ceramics can be easily attributed to their microstructure. Grain-to-grain variability was observed in Zry-4 with a macroscopic expansion along the rolling direction that increased with irradiation damage dose, the Nb 4 AlC 3 ceramic showed significant expansion within individual grains, leading to intergranular cracking, while the less phase-pure (Ta,Ti) 3 AlC 2 ceramic exhibited very high strains at phase boundaries, with limited expansion in the binary carbide phases. This ability to measure irradiation-induced dimensional changes at the microstructural scale is important for designing microstructures that are structurally resilient during irradiation. [Display omitted] [ABSTRACT FROM AUTHOR]

Advancements in transmission electron microscopy allow us to draw correlations between evolving matrix chemistry environments and the resulting dislocation structures that form. Such phenomena are essential in predicting the lifetime of neutron reactor components, but are not well understood at the fundamental level. We investigate the effect of nano-scale matrix chemical evolution in Zircaloy-2 on dislocation formation after emulating commercial reactor irradiation conditions on a proton beamline. Similarity in the dislocation type, morphology, density and evolution between the different irradiation types establishes proton irradiation in this regard. For the first time, we observe chemical segregation of Fe, Ni and Cr to a-loop positions in basal traces and the segregation of Sn in alternate rows, anticorrelated to the positions of the light transition elements. The resulting layered structure with a periodicity of ∼50 nm creates an even greater anisotropy than that usually associated with HCP materials. Concurrent analysis of chemical effects and dislocation spatial relationships provides evidence that may explain the delayed onset of c-loop nucleation and accelerated dimensional instability regimes in its dependence on the alignment of a-loops parallel to the trace of the basal plane. This demonstrates the applicability of chemical-structural correlations towards key research questions regarding deformation behaviour. [ABSTRACT FROM AUTHOR]

Zirconium alloys are widely used as the fuel cladding material in pressurized water reactors, accumulating a significant population of defects and dislocations from exposure to neutrons. We present and interpret synchrotron microbeam X-ray diffraction measurements of proton-irradiated Zircaloy-4, where we identify a transient peak and the subsequent saturation of dislocation density as a function of exposure. This is explained by direct atomistic simulations showing that the observed variation of dislocation density as a function of dose is a natural result of the evolution of the dense defect and dislocation microstructure driven by the concurrent generation of defects and their subsequent stress-driven relaxation. In the dynamic equilibrium state of the material developing in the high dose limit, the defect content distribution of the population of dislocation loops, coexisting with the dislocation network, follows a power law with exponent α ≈ 2. 2. This corresponds to the power law exponent of β ≈ 3. 4 for the distribution of loops as a function of their diameter that compares favourably with the experimentally measured values of β in the range 3 ≤ β ≤ 4. • Dislocation density evolution in irradiated Zr has been predicted and measured. • A transient peak and subsequent saturation in dislocation density has been observed. • Dislocation loop diameters in heavily irradiated Zr are power law distributed. [ABSTRACT FROM AUTHOR]

Zircaloy-4 oxide stress profiles and tetragonal:monoclinic oxide phase fraction distributions were studied using nano-beam transmission X-ray diffraction. Continuous stress relief and phase transformation during the first cycle of oxide growth was observed. The in-plane monoclinic stress was shown to relax strongly up to each transition, whereas in-plane tetragonal stress-relief (near the metal-oxide interface) was only observed post transition. The research demonstrates that plasticity in the metal and the development of a band of in-plane cracking both relax the monoclinic in-plane stress. The observations are consistent with a model of transition in which in-plane cracking becomes interlinked prior to transition. These cracks, combined with the development of cracks with a through-thickness component (driven primarily by plasticity in the metal) and/or a porous network of fine cracks (associated with phase transformation), form a percolation path through the oxide layer. The oxidising species can then percolate from the oxide surface to the metal/oxide interface, at which stage transition then ensues. [ABSTRACT FROM AUTHOR]

External beam radiation therapy (EBRT) to oligometastases may improve outcomes in patients (pts) with oligometastatic hormone-sensitive prostate cancer (oHSPC) who would traditionally receive androgen deprivation therapy (ADT) alone. To date, follow up (FU) on this cohort has been limited to ∼5 years. We reviewed the long-term outcomes of oHSPC pts treated with EBRT and ADT on an IRB approved prospective clinical trial (NCT00544830). From 2006 to 2011, oHSPC pts with 1-5 metastases (mts) detected by CT and bone scan received 36 weeks of ADT (LHRH agonist + bicalutamide) and consolidative EBRT up to 53 Gy to all visible mts. When indicated, the primary tumor or prostate bed was treated with EBRT up to 78 Gy or 66 Gy, respectively. Primary objectives were long-term progression free survival (PFS), overall survival (OS) and local control of treated mts. 29 pts (median age 66.9, range 49.5-79.3) were treated on this protocol. Median number of mts per patient was 1 (range 1-5) and EBRT was administered to 51 lesions (37 bone, 10 pelvic lymph nodes [LNs], 4 non-pelvic LNs) to a median biologically equivalent dose of 53 Gy (range 47-66). Median Gleason score was 8 (range 5-10) and median baseline PSA was 11.4 (range 1.0-74.5). 15 pts had de novo mts, and 14 pts had oligorecurrent mts. 22 pts (75.9%) had bone mts. 25 pts (86%) reached PSA nadir of <0.2 within 9 months of completing ADT. Median FU was 9.9 years (yrs, range 0.2-14.4) for all pts. Median OS was 9.7 yrs (95% Confidence Interval [CI]:5.8-Not Reached [NR]) and 48.3% (95%CI: 29.5-64.8) at 10 years. Of the 10 pts (34%) still alive at last FU, two remain progression-free. Median PFS for all pts was 1.9 yrs (95%CI: 1.6-2.2) and 12.4% (95%CI: 3.4-27.6) at 10 years. Pts who presented with de novo mts had significantly improved (p=0.04) median PFS (2.0 yrs, 95%CI: 1.3-6.0) compared to oligorecurrent pts (1.8 yrs, 95%CI: 1.0-2.0). Pts who presented with LN only mts had improved (p=0.13) median PFS (5.8 yrs, 95%CI: 1.2-NR) compared to pts with bony mts (1.8 yrs, 95%CI: 1.3-2.0). For pts still alive after 5 years, median number of lines of treatment was 6 (range 0-15). At the time of FU, 16 pts (55%) had local control of all EBRT treated mts. Across all pts, 70.6% (n=36) of all treated mts were controlled. The mts that locally progressed had previously been controlled for median 3.4 yrs (range 1.7-10.5), comprising 11 bony mts, 2 pelvic LNs, and 2 non-pelvic LNs. Our results compare favorably with other reported studies of oHSPC and provide new insights into their long-term outcomes. Metastasis-directed EBRT in this population of oHSPC pts resulted in longer than expected OS. The ongoing study adding radium-223 in addition to ADT and SBRT (NCT03361735) will seek to further delay recurrence in oHSPC with bone mts. [ABSTRACT FROM AUTHOR]

Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ⩽2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas. [ABSTRACT FROM AUTHOR]

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML. [ABSTRACT FROM AUTHOR]

Paclitaxel is commonly used in the treatment of breast cancer. Variability in paclitaxel clearance may contribute to the unpredictability of clinical outcomes. We assessed genomic DNA from the plasma of 93 patients with high-risk primary or stage IV breast cancer, who received dose-intense paclitaxel, doxorubicin and cyclophosphamide. Eight polymorphisms in six genes associated with metabolism and transport of paclitaxel were analyzed using Pyrosequencing. We found no association between ABCB1, ABCG2, CYP1B1, CYP3A4, CYP3A5 and CYP2C8 genotypes and paclitaxel clearance. However, patients homozygous for the CYP1B1*3 allele had a significantly longer progression-free survival than patients with at least one Valine allele (P=0.037). This finding could reflect altered paclitaxel metabolism, however, the finding was independent of paclitaxel clearance. Alternatively, the role of CYP1B1 in estrogen metabolism may influence the risk of invasive or paclitaxel resistant breast cancer in patients carrying the CYP1B1*3 allele.The Pharmacogenomics Journal (2007) 7, 362–365; doi:10.1038/sj.tpj.6500434; published online 16 January 2007 [ABSTRACT FROM AUTHOR]

Although autologous stem cell transplant is an effective therapy for patients with multiple myeloma and extends progression-free survival (PFS) and overall survival (OS), patients show a continued pattern of recurrent disease. Twenty-nine patients were enrolled in a phase II study investigating the tolerability and efficacy of maintenance thalidomide following single autologous peripheral blood stem cell transplant. Six to eight weeks after transplant, patients were started on maintenance thalidomide at 50 mg a day. The dose was gradually escalated to a target dose of 400 mg a day and continued until disease progression or 6 months after achieving complete remission (CR) for a maximum total duration of 18 months. At 6 months, 13 patients (45%) achieved CR or near complete remission (positive immunofixation without any evidence of disease). The estimated 2-year OS was 83% and PFS was 49%. Median tolerated dose of thalidomide was 200 mg a day. In conclusion, thalidomide as maintenance therapy is feasible and may improve outcome after single autologous stem cell transplant.Bone Marrow Transplantation (2006) 37, 825–829. doi:10.1038/sj.bmt.1705339; published online 27 March 2006 [ABSTRACT FROM AUTHOR]