Neutrophil-guided dosing of anthracycline–cyclophosphamide-containing chemotherapy in patients with breast cancer: a feasibility study

The aim of this study was to investigate whether neutrophil-guided dose escalation of anthracycline–cyclophosphamide-containing chemotherapy (ACC) for breast cancer is feasible, in order to optimize outcome. Breast cancer patients planned for 3-weekly ACC were enrolled in this study. The first treatment cycle was administered in a standard BSA-adjusted dose. The absolute neutrophil count was measured at baseline and at day 8, 11 and 15 after administration of ACC. For patients with none or mild (CTC grade 0–2) neutropenia and no other dose-limiting toxicity, we performed a 10–25 % dose escalation of the second cycle with the opportunity to a further 10–25 % dose escalation of the third cycle. Thirty patients were treated in the adjuvant setting with either FE100C (n = 23) or AC (n = 4), or in the palliative setting with FAC (n = 3). Two out of 23 patients (9 %) treated with FEC did not develop grade 3–4 neutropenia after the first treatment cycle. Dose escalation was performed in these two patients (30 % in one and 15 % in the other patient). During dose escalation, there were no complications like febrile neutropenia. No patients treated with FAC or AC could be escalated, since all of them developed grade 3–4 neutropenia. We conclude that asymptomatic grade 3–4 neutropenia is likely to be achieved in the majority of patients with breast cancer treated with ACC according to presently advocated BSA-based dose levels. Escalation of currently advocated ACC doses without G-CSF, with a target of grade 3–4 neutropenia, is feasible, but only possible in a small proportion of patients. EudraCT 2010-020309-33

Unlocking Synergy in Bimetallic Catalysts by Core-Shell Design

Extending the toolbox from mono- to bimetallic catalysts is key in realizing efficient chemical processes. Traditionally, the performance of bimetallic catalysts featuring one active and one selective metal is optimized by varying the metal composition, often resulting in a compromise between the catalytic properties of the two metals. Here we show that by designing the atomic distribution of bimetallic Au-Pd nanocatalysts, we obtain a synergistic catalytic performance in the industrially relevant selective hydrogenation of butadiene. Our single crystalline Au-core Pd-shell nanorods were up to 50 times more active than their alloyed and monometallic counterparts, while retaining high selectivity. We find a shell thickness dependent catalytic activity, indicating that not only the nature of the surface but also several sub-surface layers play a crucial role in the catalytic performance, and rationalize this finding using density-functional-theory calculations. Our results open up a novel avenue for the structural design of bimetallic catalysts.</div

Unlocking synergy in bimetallic catalysts by core–shell design

Extending the toolbox from mono- to bimetallic catalysts is key in realizing efficient chemical processes1. Traditionally, the performance of bimetallic catalysts featuring one active and one selective metal is optimized by varying the metal composition1–3, often resulting in a compromise between the catalytic properties of the two metals4–6. Here we show that by designing the atomic distribution of bimetallic Au–Pd nanocatalysts, we obtain a synergistic catalytic performance in the industrially relevant selective hydrogenation of butadiene. Our single-crystalline Au-core Pd-shell nanorods were up to 50 times more active than their alloyed and monometallic counterparts, while retaining high selectivity. We find a shell-thickness-dependent catalytic activity, indicating that not only the nature of the surface but also several subsurface layers play a crucial role in the catalytic performance, and rationalize this finding using density functional theory calculations. Our results open up an alternative avenue for the structural design of bimetallic catalysts

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment

Purpose: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. Methods: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. Results: A strong and highly significant correlation (r=-0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Conclusion: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies

Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment

Item does not contain fulltextPURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. METHODS: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. RESULTS: A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. CONCLUSION: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies

Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer : Updated results and molecular subgroup analyses of the phase 3 CAIRO3 study

Background: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy. Patients and methods: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n=279) or observation (n=279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status. Results: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RASmutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment. Conclusions: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours

Unlocking synergy in bimetallic catalysts by core–shell design

Extending the toolbox from mono- to bimetallic catalysts is key in realizing efficient chemical processes1. Traditionally, the performance of bimetallic catalysts featuring one active and one selective metal is optimized by varying the metal composition1–3, often resulting in a compromise between the catalytic properties of the two metals4–6. Here we show that by designing the atomic distribution of bimetallic Au–Pd nanocatalysts, we obtain a synergistic catalytic performance in the industrially relevant selective hydrogenation of butadiene. Our single-crystalline Au-core Pd-shell nanorods were up to 50 times more active than their alloyed and monometallic counterparts, while retaining high selectivity. We find a shell-thickness-dependent catalytic activity, indicating that not only the nature of the surface but also several subsurface layers play a crucial role in the catalytic performance, and rationalize this finding using density functional theory calculations. Our results open up an alternative avenue for the structural design of bimetallic catalysts