Candidate biomarkers for treatment benefit from sunitinib in patients with advanced renal cell carcinoma using mass spectrometry-based (phospho)proteomics

The tyrosine kinase inhibitor sunitinib is an effective first-line treatment for patients with advanced renal cell carcinoma (RCC). Hypothesizing that a functional read-out by mass spectrometry-based (phospho, p-)proteomics will identify predictive biomarkers for treatment outcome of sunitinib, tumor tissues of 26 RCC patients were analyzed. Eight patients had primary resistant (RES) and 18 sensitive (SENS) RCC. A 78 phosphosite signature (p &lt; 0.05, fold-change &gt; 2) was identified; 22 p-sites were upregulated in RES (unique in RES: BCAR3, NOP58, EIF4A2, GDI1) and 56 in SENS (35 unique). EIF4A1/EIF4A2 were differentially expressed in RES at the (p-)proteome and, in an independent cohort, transcriptome level. Inferred kinase activity of MAPK3 (p = 0.026) and EGFR (p = 0.045) as determined by INKA was higher in SENS. Posttranslational modifications signature enrichment analysis showed that different p-site-centric signatures were enriched (p &lt; 0.05), of which FGF1 and prolactin pathways in RES and, in SENS, vanadate and thrombin treatment pathways, were most significant. In conclusion, the RCC (phospho)proteome revealed differential p-sites and kinase activities associated with sunitinib resistance and sensitivity. Independent validation is warranted to develop an assay for upfront identification of patients who are intrinsically resistant to sunitinib.</p

Albumin determined by bromocresol green leads to erroneous results in routine evaluation of patients with chronic kidney disease

Objectives: Measurement of plasma albumin is pivotal for clinical decision-making in patients with chronic kidney disease (CKD). Routinely used methods as bromocresol green (BCG) and bromocresol purple (BCP) can suffer from aselectivity, but the impact of aselectivity on the accuracy of plasma albumin results of CKD-patients is still unknown. Therefore, we evaluated the performance of BCG-, BCP- and JCTLM-endorsed immunological methods in patients with various stages of CKD. Methods:We evaluated the performance of commonly used albumin methods in patients with CKD stages G1 through G5, the latter divided in two groups based on whether they received hemodialysis treatment. In total, 163 patient plasma samples were measured at 14 laboratories, on six different BCG and BCP-platforms, and four different immunological platforms. The results were compared with an ERM-DA-470k-corrected nephelometric assay. The implications on outcome is evaluated by the proportion of patient results &lt;38g/L for the diagnosis of protein energy wasting. Results:Albumin results determined with BCP- and immunological methods showed the best agreement with the target value (92.7 and 86.2%, respectively vs. 66.7% for BCG, namely due to overestimation). The relative agreement of each method with the target value was platform-dependent, with larger variability in agreement between platforms noted for BCG and immunological methods (3.2-4.6 and 2.6-5.3%) as opposed to BCP (0.7-1.5%). The stage of CKD had similar effects on the variability in agreement for the three method-groups (0.6-1.8% vs. 0.7-1.5% vs. 0.4-1.6%). The differences between methods cause discrepancies in clinical decision-making, as structurally fewer patients were diagnosed with protein energy wasting upon using BCG-based albumin results. Conclusions: Our study shows that BCP is fit for the intended use to measure plasma albumin levels in CKD patients from all stages, including patients on hemodialysis. In contrast, most BCG-based platforms falsely overestimate the plasma albumin concentration.</p

Perspectief natuurlijke keringen: een eerste verkenning ten behoeve van het Deltaprogramma

In het Deltaprogramma staan de waterveiligheid en de watervoorziening van Nederland nu en voor de lange termijn centraal. In de aanpak wordt actief gezocht naar de koppeling met andere ambities van rijk, provincies, waterschappen, gemeenten, maar ook van maatschappelijke organisaties en bedrijven op andere beleidsterreinen, zoals economie, natuur en ruimte. De Deltacommissaris heeft de Stichting Ecoshape gevraagd de mogelijkheden te verkennen voor het toepassen van natuurlijke keringen in het IJsselmeergebied, de Wadden en estuaria en het rivierengebie

Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Substance-Related Health Problems during Rave Parties in the Netherlands (1997–2008)

The objective of this study was to describe a 12-year (1997–2008) observation of substance-related incidents occurring at rave parties in the Netherlands, including length of visits to first-aid stations, substances used, and severity of the incidents. During rave parties, specifically trained medical and paramedical personnel staffed first aid stations. Visitors were diagnosed and treated, and their data were recorded using standardized methods. During the 12-year period with 249 rave parties involving about 3,800,000 visitors, 27,897 people visited a first aid station, of whom 10,100 reported having a substance-related problem. The mean age of these people was 22.3+/−5.4 years; 52.4% of them were male. Most (66.7%) substance-related problems were associated with ecstasy or alcohol use or both. Among 10,100 substance-related cases, 515 required professional medical care, and 16 of these cases were life threatening. People with a substance-related problem stayed 20 min at the first aid station, which was significantly longer than the 5 min that those without a substance-related health problem stayed. These unique data from the Netherlands identify a variety of acute health problems related to the use of alcohol, amphetamines, cannabis, cocaine, ecstasy, and GHB. Although most problems were minor, people using GHB more often required professional medical care those using the other substances. We recommended adherence to harm and risk reduction policy, and the use of first aid stations with specially trained staff for both minor and serious incidents

Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency–approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer

Variable loss of functional activities of androgen receptor mutants in patients with androgen insensitivity syndrome

Androgen receptor (AR) mutations in androgen insensitivity syndrome (AIS) are associated with a variety of clinical phenotypes. The aim of the present study was to compare the molecular properties and potential pathogenic nature of 8 novel and 3 recurrent AR variants with a broad variety of functional assays. Eleven AR variants (p.Cys177Gly, p.Arg609Met, p.Asp691del, p.Leu701Phe, p.Leu723Phe, p.Ser741Tyr, p.Ala766Ser, p.Arg775Leu, p.Phe814Cys, p.Lys913X, p.Ile915Thr) were analyzed for hormone binding, transcriptional activation, cofactor binding, translocation to the nucleus, nuclear dynamics, and structural conformation. Ligand-binding domain variants with low to intermediate transcriptional activation displayed aberrant Kd values for hormone binding and decreased nuclear translocation. Transcriptional activation data, FxxFF-like peptide binding and DNA binding correlated well for all variants, except for p.Arg609Met, p.Leu723Phe and p.Arg775Leu, which displayed a relatively higher peptide binding activity. Variants p.Cys177Gly, p.Asp691del, p.Ala766Ser, p.Phe814Cys, and p.Ile915Thr had intermediate or wild type values in all assays and showed a predominantly nuclear localization in living cells. All transcriptionally inactive variants (p.Arg609Met, p.Leu701Phe, p.Ser741Tyr, p.Arg775Leu, p.Lys913X) were unable to bind to DNA and were associated with complete AIS. Three variants (p.Asp691del, p.Arg775Leu, p.Ile915Thr) still displayed significant functional activities in in vitro assays, although the clinical phenotype was associated with complete AIS. The data show that molecular phenotyping based on 5 different functional assays matched in most (70%) but not all cases. Copyrigh

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.Experimentele farmacotherapi

Drug use and nightlife: more than just dance music

<p>Abstract</p> <p>Background</p> <p>Research over the last decade has focused almost exclusively on the association between electronic music and MDMA (3,4-Methylenedioxymethamphetamine or "ecstasy") or other stimulant drug use in clubs. Less attention has been given to other nightlife venues and music preferences, such as rock music or southern/funky music. This study aims to examine a broader spectrum of nightlife, beyond dance music. It looks at whether certain factors influence the frequency of illegal drug and alcohol use: the frequency of going to certain nightlife venues in the previous month (such as, pubs, clubs or goa parties); listening to rock music, dance music or southern and funky music; or sampling venues (such as, clubs, dance events or rock festivals). The question of how these nightlife variables influence the use of popular drugs like alcohol, MDMA, cannabis, cocaine and amphetamines is addressed.</p> <p>Methods</p> <p>The study sample consisted of 775 visitors of dance events, clubs and rock festivals in Belgium. Study participants answered a survey on patterns of going out, music preferences and drug use. Odds ratios were used to determine whether the odds of being an illegal substance user are higher for certain nightlife-related variables. Furthermore, five separate ordinal regression analyses were used to investigate drug use in relation to music preference, venues visited during the last month and sampling venue.</p> <p>Results</p> <p>Respondents who used illegal drugs were 2.5 times more likely to report that they prefer dance music. Goa party visitors were nearly 5 times more likely to use illegal drugs. For those who reported visiting clubs, the odds of using illegal drugs were nearly 2 times higher. Having gone to a pub in the last month was associated with both more frequent alcohol use and more frequent illegal substance use. People who reported liking rock music and attendees of rock festivals used drugs less frequently.</p> <p>Conclusions</p> <p>It was concluded that a more extended recreational environment, beyond dance clubs, is associated with frequent drug use. This stresses the importance of targeted prevention in various recreational venues tailored to the specific needs of the setting and its visitors.</p