Five percent of all patients with breast cancer have distant metastatic disease at initial presentation. Because metastatic breast cancer is considered to be an incurable disease, it is generally treated with a palliative intent. Recent non-randomized studies have demonstrated that (complete) resection of the primary tumor is associated with a significant improvement of the survival of patients with primary metastatic breast cancer. However, other studies have suggested that the claimed survival benefit by surgery may be caused by selection bias. Therefore, a randomized controlled trial will be performed to assess whether breast surgery in patients with primary distant metastatic breast cancer will improve the prognosis.

Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response.

Joint replacement surgery of the lower extremities are common procedures in elderly persons who are at increased risk of postoperative falls. The use of mental state altering medications, such as opioids, antidepressants or benzodiazepines, can further contribute to impaired balance and risk of falls. The objective of the current systematic review was to evaluate the risk of the use of mental state altering medications on postoperative falls in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA).

Antibiotic exposure in intensive care patients with sepsis is frequently inadequate and is associated with poorer outcomes. Antibiotic dosing is challenging in the intensive care, as critically ill patients have altered and fluctuating antibiotic pharmacokinetics that make current one-size-fits-all regimens unsatisfactory. Real-time bedside dosing software is not available yet, and therapeutic drug monitoring is typically used for few antibiotic classes and only allows for delayed dosing adaptation. Thus, adequate and timely antibiotic dosing continues to rely largely on the level of pharmacokinetic expertise in the ICU. Therefore, we set out to assess the level of knowledge on antibiotic pharmacokinetics among these intensive care professionals.

VEGFR1 rs9582036 and rs9554320 were previously reported the association with sunitinib progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Hereafter, the association of both single nucleotide polymorphisms (SNPs) with PFS/OS was confirmed in two independent mRCC cohorts. The aim of the current study was to validate the associations of both SNPs with sunitinib outcome in three independent well-characterized cohorts (SUTOX, CCF and SOGUG) including 286 sunitinib-treated mRCC patients, as well as to perform a meta-analysis of current and published data combined. We found that rs9582036 and rs9554320 showed a significant association with sunitinib PFS in the CCF cohort (HR: 0.254, 95%CI: 0.092-0.703; P=0.008 and HR: 0.430, 95%CI: 0.200-0.927; P=0.031, respectively). Patients with the variant genotype of rs9582036 and rs9554320 had a shorter median PFS. No significant association of both SNPs with sunitinib PFS or OS was detected in either the SUTOX or SOGUG cohort. After the combination of all available data into a meta-analysis, the association of both SNPs with sunitinib PFS or OS did not achieve the threshold for statistical significance. Our findings suggest that, although VEGFR1 rs9582036 and rs9554320 are involved in sunitinib therapy outcome, its clinical use as biomarkers for prediction of sunitinib outcome in mRCC patients is limited, due to inconsistent findings when analyzing all existing studies together.

This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes.

We determined whether progression-free survival (PFS) in metastatic breast cancer (MBC) patients receiving everolimus plus exemestane (EVE/EXE) varies depending on circulating tumour DNA (ctDNA) characteristics. Baseline plasma cell-free DNA (cfDNA) from 164 postmenopausal women with ER-positive, HER2-negative MBC refractory to a nonsteroidal aromatase inhibitor and treated with standard EVE/EXE (Everolimus Biomarker Study, Eudract 2013-004120-11) was characterised for 10 relevant breast cancer genes by next-generation sequencing with molecular barcoding. ctDNA molecule numbers, number of mutations and specific variants were related with PFS and overall survival (OS). Missense hotspot mutations in cfDNA were detected in 125 patients. The median of 54 ctDNA molecules per mL plasma distinguished patients with high and low/no ctDNA load. Patients with low/no ctDNA load (N = 102) showed longer median PFS of 5.7 months (P = 0.006) and OS of 124.8 months (P = 0.008) than patients with high ctDNA load (N = 62; 4.4 months and 107.7 months, respectively) in multivariate analyses. Patients with < 3 specific mutations (N = 135) had longer median PFS of 5.4 months compared to those with ≥ 3 mutations (3.4 months; P < 0.001). In conclusion, MBC patients with low/no ctDNA load or < 3 hotspot mutations experience longer PFS while treated with EVE/EXE.

Breast cancer arising in female BRCA1 mutation carriers is characterized by an aggressive phenotype and early age of onset. We performed tandem mass spectrometry-based proteomics of secretomes and exosome-like extracellular vesicles from BRCA1-deficient and BRCA1-proficient murine breast tumor models to identify extracellular protein biomarkers, which can be used as an adjunct to current diagnostic modalities in patients with BRCA1-deficient breast cancer. We identified 2,107 proteins, of which 215 were highly enriched in the BRCA1-deficient secretome. We demonstrated that BRCA1-deficient secretome proteins could cluster most human BRCA1- and BRCA2-related breast carcinomas at the transcriptome level. Topoisomerase I (TOP1) and P-cadherin (CDH3) expression was investigated by immunohistochemistry on tissue microarrays of a large panel of 253 human breast carcinomas with and without BRCA1/2 mutations. We showed that expression of TOP1 and CDH3 was significantly increased in human BRCA1-related breast carcinomas relative to sporadic cases (p = 0.002 and p < 0.001, respectively). Multiple logistic regression showed that TOP1 (adjusted odds ratio [OR] 3.75; 95% confidence interval [95% CI], 1.85 - 7.71, p < 0.001) as well as CDH3 positivity (adjusted OR 2.45; 95% CI, 1.08 - 5.49, p = 0.032) were associated with BRCA1/2-related breast carcinomas after adjustment for triple-negative phenotype and age. In conclusion, proteome profiling of secretome using murine breast tumor models is a powerful strategy to identify non-invasive candidate biomarkers of BRCA1-deficient breast cancer. We demonstrate that TOP1 and CDH3 are closely associated to BRCA1-deficient breast cancer. These data merit further investigation for early detection of tumors arising in BRCA1 mutation carriers.

The spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931.

Introduction: Capecitabine is a widely prescribed oral anticancer agent. We studied medication adherence and explored its use in daily practice from a patients' perspective. Patients and Methods: Patients (n = 92) starting capecitabine were followed up to five 3-week cycles. Adherence was assessed using a pill count, pharmacy data and dosing information from the patients' medical file. Self-reported adherence was measured using the Medication Adherence Report Scale (MARS). At baseline and during week 2 of cycles 1, 3, and 5, patients filled out questionnaires about quality of life, symptoms, attitude toward medicines and disease and use in daily practice. Simultaneously, blood samples were taken to determine the area under the curve (AUC) of 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL) by a population pharmacokinetic model. Associations between AUCs and patient-reported symptoms were tested for cycles 3 and 5. Results: Most patients (84/92; 91%) had an adherence rate of ≥95 and ≤ 105%. The percentage of patients reporting any non-adherence behavior measured with MARS increased from 16% at cycle 1 to 29% at cycle 5. Symptoms were reported frequently and the dosing regimen was adjusted by the physician at least once in 62% of patients. In multivariate analysis the probability of an adjustment increased with the number of co-medication (OR 1.19, 95% CI: 1.03-1.39) and a stronger emotional response to the disease (OR 1.32, 95% CI: 1.10-1.59). The AUC of 5'-DFUR was associated with weight loss (OR 1.10, 95% CI: 1.01-1.19), AUC of FBAL with hand-foot syndrome (OR 0.90, 95% CI: 0.83-0.99), rhinorrhea (OR 1.21, 95% CI: 1.03-1.42 weight loss (OR 1.09, 95% CI: 1.00-1.20) and depression (OR 0.90, 95% CI: 0.82-0.99). Side effects were reported by one third of patients as the reason to discontinue treatment. Conclusion: Adherence to capecitabine was generally high. Nevertheless, adherence measured with MARS decreased over time Adherence management to support implementation of correct capecitabine use is specifically relevant in longer term treatment. In addition, it appears that adverse event management is important to support persistence. With the extending armamentarium of oral targeted anticancer agents and prolonged treatment duration, we expect the issue of medication adherence of increasing importance in oncology.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

The phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are frequently activated in breast cancer. We recently demonstrated the importance of analyzing multiple proteins as read-out for pathway activation in ER+/HER2- breast cancer, since single proteins are known to provide insufficient information. Here, we determined pathway activation in other primary breast cancer intrinsic subtypes derived from postmenopausal patients. Tumor blocks were recollected, and immunohistochemistry was performed using antibodies against PTEN, p-AKT(Thr308), p-AKT(Ser473), p-p70S6K, p-4EBP1, p-S6RP(Ser235/236) and p-ERK1/2, followed by unsupervised hierarchical clustering. In 32 ER+/HER2+, 37 ER-/HER2+ and 74 triple-negative breast cancer patients, subgroups were identified with preferentially activated (A) and preferentially not activated (N) proteins. These subgroups likely reflect tumors with differences in biological behavior as well as treatment outcome.

Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.

Colorectal cancer (CRC) is a major health problem. Biomarkers associated with molecular changes in cancer cells can aid early detection, diagnosis, prognosis, therapy selection, and disease monitoring. Tumor tissue secretomes are a rich source of candidate biomarkers. To identify CRC protein biomarkers, secretomes of four pairs of human CRC tissue and patient-matched normal colon tissue samples, and secretomes of five CRC cell lines were analyzed by GeLC-MS/MS. Subsequent data analysis was based on label-free spectral counting, Ingenuity Pathway Analysis, Secretome/SignalP, STRING and Cytoscape, resulting in 2703 protein identifications in the tissue secretomes, of which 409 proteins were significantly more present in CRC samples than in controls. Biomarker selection of 76 candidates was based on consistent and abundant over-representation in cancer- compared to control-secretomes, and presumed neoplastic origin. Overlap analysis with previously obtained datasets revealed 21 biomarkers suited for early detection of CRC. Immunohistochemistry confirmed overexpression in CRC of one candidate marker (MCM5). In conclusion, a human reference dataset of 76 candidate biomarkers was identified for which we illustrate that combination with existing pre-clinical datasets allows pre-selection of biomarkers for blood- or stool-based assays to support clinical management of CRC. Further dedicated validation studies are required to demonstrate their clinical applicability.

The antitumor drug nilotinib has a large inter- and intra individual variability in pharmacokinetics. Adherence to treatment may substantially influence plasma levels and has been recognized as the most important determinant of treatment failure in chronic myeloid leukemia (CML). A better understanding of the various factors contributing to the efficacy of treatment is essential for the development of interventions to optimize the treatment of chronic phase CML (CP-CML) with a protein kinase inhibitor like nilotinib.

Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib.

Correct identification of tumour receptor status is important for treatment decisions in breast cancer. [18F]FES PET and [18F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [18F]FES PET and [18F]FDHT PET interpretation in patients with metastatic breast cancer.

Adherence to pharmacological therapy is a complex and multifactorial issue that can substantially alter the outcome of treatment. Especially when using long-term medication, cancer patients have adherence rates similar to those of patients with other diseases. The consequences of poor adherence are poor health outcomes and increased health care costs. Only few studies have focused on the use of oral anticancer agents in daily practice. Information about the reasons for nonadherence is essential for the development of interventions that may improve adherence. This report presents the CAPER-capecitabine protocol, which is designed to study the adherence to capecitabine and the influence of patient attitudes towards medication and self-reported side effects. Furthermore, the relationships between patient characteristics, disease characteristics, side effects, quality of life, patient beliefs and attitudes towards disease and medication, dose adjustments, reasons for discontinuation, and plasma concentration of three of the main metabolites, including the active compound 5-fluorouracil, will be explored.

Early clinical recognition of sepsis can be challenging. With the advancement of machine learning, promising real-time models to predict sepsis have emerged. We assessed their performance by carrying out a systematic review and meta-analysis.