Additive Manufacturing of Binary Ni–Ti Shape Memory Alloys Using Electron Beam Powder Bed Fusion: Functional Reversibility Through Minor Alloy Modification and Carbide Formation

Shape memory alloys (SMAs), such as Ni–Ti, are promising candidates for actuation and damping applications. Although processing of Ni–Ti bulk materials is challenging, well-established processing routes (i.e. casting, forging, wire drawing, laser cutting) enabled application in several niche applications, e.g. in the medical sector. Additive manufacturing, also referred to as 4D-printing in this case, is known to be highly interesting for the fabrication of SMAs in order to produce near-net-shaped actuators and dampers. The present study investigated the impact of electron beam powder bed fusion (PBF-EB/M) on the functional properties of C-rich Ni50.9Ti49.1 alloy. The results revealed a significant loss of Ni during PBF-EB/M processing. Process microstructure property relationships are discussed in view of the applied master alloy and powder processing route, i.e. vacuum induction-melting inert gas atomization (VIGA). Relatively high amounts of TiC, being already present in the master alloy and powder feedstock, are finely dispersed in the matrix upon PBF-EB/M. This leads to a local change in the chemical composition (depletion of Ti) and a pronounced shift of the transformation temperatures. Despite the high TiC content, superelastic testing revealed a good shape recovery and, thus, a negligible degradation in both, the as-built and the heat-treated state

Phase II study of a triplet regimen in advanced colorectal cancer using methotrexate, oxaliplatin and 5-fluorouracil

Building upon the concept of schedule-specific biochemical modulation of 5-fluorouracil (FU), which alternates bolus and continuous infusion (CI) FU, we have incorporated oxaliplatin (l-OHP) following the bolus part of the regimen to explore the activity of this new combination. Patients with advanced, untreated, measurable colorectal cancer received sequential methotrexate (MTX) (days 1 and 15)-->l-OHP+FU (days 2 and 16) (200, 85 and 600 mg m(-2), respectively) followed by 3 weeks of CI FU (200 mg m(-2) day(-1)) given from day 29 to 50, modulated by weekly leucovorin (LV) (20 mg m(-2)). After 1 week of rest, the second cycle was started. The treatment was continued until progression or patient's refusal. According to the intention-to-treat analysis on all 46 patients accrued, the response rate was 42% (95% CL=28-55%), with three complete responses and 16 partial responses. The median overall survival was 15.9 months and the median progression-free survival 6.9 months. Toxicity was very mild, with the bolus part of the regimen more toxic than the infusional part (24 vs 7% of grade III-IV, respectively). This new combination of MTX -->l-OHP-FU followed by FU CI is well tolerated, feasible and produces activity results similar to other more simple, but more toxic, regimens. Pros and cons of the different fluoropyrimidines-l-OHP combinations are discussed

Subgroup analysis of patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG) in the CORRECT trial who had progression-free survival (PFS) longer than 4 months

No abstract availabl

Toxicity associated with combination oxaliplatin plus fluoropyrimidine with or without cetuximab in the MRC COIN trial experience

We present the preliminary toxicity data from the MRC COIN trial, a phase III randomised controlled trial of first-line therapy in advanced colorectal cancer, with particular reference to the addition of cetuximab to an oxaliplatin–fluoropyrimidine combination. A total of 804 patients were randomised between March 2005 and July 2006 from 78 centres throughout the United Kingdom. Patients were allocated to oxaliplatin plus fluoropyrimidine chemotherapy with or without the addition of weekly cetuximab. The choice of fluoropyrimidine (either 5-fluorouracil (5FU) or capecitabine) was decided by the treating physician and patient before randomisation. Toxicity data were collected from all patients. Two hundred and three patients received 5FU plus oxaliplatin (OxMdG, 25%), 333 oxaliplatin+capecitabine (Xelox, 41%), 102 received OxMdG+cetuximab (OxMdG+C, 13%) and 166 Xelox+cetuximab (21%). Percent grade 3/4 toxicities included diarrhoea 6, 15, 13 and 25%, nausea/vomiting 3, 7, 7 and 14% for OxMdG, Xelox, OxMdG+C and Xelox+C, respectively. Sixty-day all-cause mortality was 6, 5, 5 and 7%. Statistically significant differences were evident for patients receiving Xelox+cetuximab vs Xelox alone: diarrhoea relative risk (RR) 1.69 (1.17, 2.43, P=0.005) and nausea/vomiting RR 2.01 (1.16, 3.47, P=0.012). The excess toxicity observed in the oxaliplatin-, capecitabine-, cetuximab-treated patients led the trial management group to conclude that a capecitabine dose adjustment was required to maintain safety levels when using this regimen

Adaptive remodeling of the bacterial proteome by specific ribosomal modification regulates Pseudomonas infection and niche colonisation

Post-transcriptional control of protein abundance is a highly important, underexplored regulatory process by which organisms respond to their environments. Here we describe an important and previously unidentified regulatory pathway involving the ribosomal modification protein RimK, its regulator proteins RimA and RimB, and the widespread bacterial second messenger cyclic-di-GMP (cdG). Disruption of rimK affects motility and surface attachment in pathogenic and commensal Pseudomonas species, with rimK deletion significantly compromising rhizosphere colonisation by the commensal soil bacterium P. fluorescens, and plant infection by the pathogens P. syringae and P. aeruginosa. RimK functions as an ATP-dependent glutamyl ligase, adding glutamate residues to the C-terminus of ribosomal protein RpsF and inducing specific effects on both ribosome protein complement and function. Deletion of rimK in P. fluorescens leads to markedly reduced levels of multiple ribosomal proteins, and also of the key translational regulator Hfq. In turn, reduced Hfq levels induce specific downstream proteomic changes, with significant increases in multiple ABC transporters, stress response proteins and non-ribosomal peptide synthetases seen for both ΔrimK and Δhfq mutants. The activity of RimK is itself controlled by interactions with RimA, RimB and cdG. We propose that control of RimK activity represents a novel regulatory mechanism that dynamically influences interactions between bacteria and their hosts; translating environmental pressures into dynamic ribosomal changes, and consequently to an adaptive remodeling of the bacterial proteome

regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial.

Summary Background No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. Methods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Findings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Interpretation Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population

Biological predictive factors in rectal cancer treated with preoperative radiotherapy or radiochemotherapy

We analysed the expression of microsatellite instability, p53, p21, vascular endothelial growth factor and thymidylate synthase (TS) in pretreatment biopsy specimens from 57 locally advanced rectal cancers. The aim of the study was to correlate the expression of these markers with pathological response. Nineteen patients were treated with preoperative concomitant radiotherapy (RT) and fluorouracil/oxaliplatin-based chemotherapy (RCT), while 38 had RT alone. Pathological complete remission (pCR) and microfoci residual tumour (micR) occurred more frequently in patients treated with RCT (P=0.002) and in N0 tumours (P=0.004). Among patients treated with RCT, high TS levels were associated with a higher response rate (pCR+micR; P=0.015). No such correlation was found in the RT group. The other molecular factors were of no predictive value. Multivariate analysis confirmed a significant interaction between nodal status and the probability of achieving a pathological response (P=0.023) and between TS expression and treatment, indicating that a high TS level is predictive of a higher pathological response in the RCT subset (P=0.007). This study shows that lymph node status is the most important predictive factor of tumour response to preoperative treatment. Thymidylate synthase expression assessed immunohistochemically from pretreatment tumour biopsies may be a useful predictive marker of rectal tumour response to preoperative RCT

Relation between outcomes and localisation of p-mTOR expression in gastric cancer

The mammalian target of rapamycin (mTOR), a Ser/Thr protein kinase that mediates intracellular signalling related to cell growth, proliferation, and differentiation, has received considerable interest as a possible target for cancer treatment. We evaluated the correlation of mTOR expression with clinicopathological features, outcomes, and the expression of Akt, an upstream regulator of mTOR, in gastric cancer. Tumour samples were obtained from 109 patients with gastric adenocarcinomas who underwent a radical gastrectomy. The expressions of phosphorylated mTOR (p-mTOR) and phosphorylated Akt (p-Akt) in the cytoplasm and in the nucleus were analysed by immunohistochemical staining. Cytoplasmic p-mTOR expression positively correlated with the depth of tumour invasion (T1 vs T2–4, P=0.003), involved lymph nodes (P=0.010), and tumour stage (I vs II–IV, P=0.002). In contrast, nuclear p-mTOR expression negatively correlated with these variables (P<0.001,=0.035, and <0.001). Cytoplasmic p-mTOR expression was associated with significantly poorer relapse-free survival (RFS, P=0.037) and overall survival (OS, P=0.024), whereas nuclear p-mTOR expression was associated with better RFS and OS (P=0.029, 0.059). Neither cytoplasmic nor nuclear p-Akt expression was associated with any clinicopathological factor or with survival. Localisation of p-mTOR may play an important role in tumour progression and outcomes in patients with gastric cancer

Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database

Background KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. Methods Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. Results 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84–0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68–0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68–0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86–1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). Conclusion The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases