The majority of high-risk neuroblastoma patients are refractory to, or relapse on, current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to ...identify novel therapeutic targets. Here, we report that high
kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild-type xenografts, while NF1 knockout cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild-type neuroblastoma.
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Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune ...homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured
showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell-inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ
, granzyme B
cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity.
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Transcatheter aortic valve replacement (TAVR) is associated with procedural-related neurological events and acute cognitive decline. However, data on the effect of TAVR on mid-term cognitive outcome ...are scarce. Therefore, we aimed to assess the impact of TAVR on mid-term cognitive outcome using different neurocognitive test batteries.
Patients with severe aortic valve stenosis scheduled for TAVR were enrolled. Cognitive assessment was performed at baseline and 4 months post-TAVR using an eight-word verbal-learning test (“Immediate Recall Memory Test” IRMT, “Delayed Recall Memory Test” DRMT, “Recognition of Verbal Information Test” RVIT), global cognitive function (“Mini Mental State Examination” MMSE), and executive function (“Trail Making Test” TMT, “Clock-Drawing Test” CDT).
A total of 30 patients (age: 81±6years, logistic EuroSCORE: 19±10%) completed the follow-up cognitive assessments. Postoperatively, 17% (n=5) developed delirium, 13% (n=4) received permanent pacemaker, and there were no cerebrovascular events. Mean hospital duration time was 5±2 days. Patients (n=22) who did not complete the follow-up cognitive assessments had comparable baseline, procedural and hospital outcome. At follow-up there was a significant improvement in IRMT (27±5 vs. 30±4, p=0.016), with a trend toward improved DRMT (4±2 vs. 5±2, p=0.079). Moreover, patients with lower baseline MMSE and IRMT improved significantly during the follow-up.
Transcatheter aortic valve replacement was associated with an improved IRMT during follow-up. Both MMSE and IRMT were significantly improved among those with lower baseline scores.
Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory ...syndrome coronavirus 2 (SARS-CoV-2) replicates
. Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c
natural killer (NK) cells and CD4
T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DR
monocytes, CD38
PD1
CD4
T effector (T
) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127
granulocytes and CD38
CD8
tissue-resident memory T cells (T
). SARS-CoV-2-specific CD8
T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.
Suboptimal nutrition in pregnancy is associated with worse offspring cardiometabolic health. DNA methylation may be an underlying mechanism. We meta-analyzed epigenome-wide association studies (EWAS) ...of maternal dietary glycemic index and load with cord blood DNA methylation.
We calculated maternal glycemic index and load from food frequency questionnaires and ran EWAS on cord blood DNA methylation in 2,003 mother-offspring pairs from three cohorts. Analyses were additionally stratified by maternal BMI categories. We looked-up the findings in EWAS of maternal glycemic traits and BMI as well as in EWAS of birth weight and child BMI. We examined associations with gene expression in child blood in the online Human Early Life Exposome eQTM catalog and in 223 adipose tissue samples.
Maternal glycemic index and load were associated with cord blood DNA methylation at 41 cytosine-phosphate-guanine sites (CpGs, P < 1.17 × 10-7), mostly in mothers with overweight/obesity. We did not observe overlap with CpGs associated with maternal glycemic traits, BMI, or child birth weight or BMI. Only DNA methylation at cg24458009 and cg23347399 was associated with expression of PCED1B and PCDHG, respectively, in child blood, and DNA methylation at cg27193519 was associated with expression of TFAP4, ZNF500, PPL, and ANKS3 in child subcutaneous adipose tissue.
We observed multiple associations of maternal glycemic index and load during pregnancy with cord blood DNA methylation, mostly in mothers with overweight/obesity; some of these CpGs were associated with gene expression. Additional studies are required to further explore functionality, uncover causality, and study pathways to offspring health.
Objectives
To evaluate the effectiveness of a web‐based decision aid (DA), with values clarification exercises compared with usual care, for men with lower urinary tract symptoms due to benign ...prostatic hyperplasia (LUTS/BPH).
Patients and Methods
Between July 2016 and January 2017, all new patients with LUTS/BPH who consulted the urologist were invited to use the DA and participate in this prospective questionnaire study. Patients who consulted the urologist between December 2015 and February 2016 served as controls. The DA was designed to support patients in making a well‐informed treatment decision, corresponding with their personal preferences and values. Well‐informed decision was measured by using a knowledge questionnaire. Value congruent decision was measured by the correspondence between responses on nine value statements and chosen treatment. The primary outcome, decision quality, was defined as the combination of well‐informed decision and value congruent decision. Secondary outcomes were decisional conflict, involvement and received role in shared decision‐making, decisional regret, and treatment choice.
Results
A total of 109 DA‐users and 108 controls were included. DA‐users were younger (68.4 vs 71.5 years; P = 0.003) and their education level was higher (P = 0.047) compared with the controls. Patients who used the DA made a well‐informed and value congruent decision more often than the control group (43% vs 21%; P = 0.028). DA‐users had less decisional conflict (score 33.2 vs 46.6; P = 0.003), experienced a less passive role in decision‐making (22% vs 41%; P = 0.038), and reported less process regret (score 2.4 vs 2.8; P = 0.034). Furthermore, DA‐users who had not used prior medication chose lifestyle advices more often than the control group (43% vs 11%; P = 0.002). Outcomes were adjusted for significantly different baseline characteristics.
Conclusion
The LUTS/BPH DA seems to improve the decision quality by supporting patients in making more well‐informed and value congruent treatment decisions. Therefore, further implementation of this DA into routine care is suggested.
Eculizumab is a lifesaving yet expensive drug for atypical haemolytic uraemic syndrome (aHUS). Current guidelines advise a fixed-dosing schedule, which can be suboptimal and inflexible in the ...individual patient.
We evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) classical pathway (CP) activity levels of eculizumab in 48 patients, consisting of 849 time-concentration data and 569 CP activity levels. PK-PD modelling was performed with non-linear mixed-effects modelling. The final model was used to develop improved dosing strategies.
A PK model with parallel linear and non-linear elimination rates best described the data with the parameter estimates clearance 0.163 L/day, volume of distribution 6.42 L, maximal rate 29.6 mg/day and concentration for 50% of maximum rate 37.9 mg/L. The PK-PD relation between eculizumab concentration and CP activity was described using an inhibitory Emax model with the parameter estimates baseline 101%, maximal inhibitory effect 95.9%, concentration for 50% inhibition 22.0 mg/L and Hill coefficient 5.42. A weight-based loading dose, followed by PK-guided dosing was found to improve treatment. On day 7, we predict 99.95% of the patients to reach the efficacy target (CP activity <10%), compared with 94.75% with standard dosing. Comparable efficacy was predicted during the maintenance phase, while the dosing interval could be prolonged in ∼33% of the population by means of individualized dosing. With a fixed-dose 4-week dosing interval to allow for holidays, treatment costs will increase by 7.1% and we predict 91% of the patients will reach the efficacy target.
A patient-friendly individualized dosing strategy of eculizumab has the potential to improve treatment response at reduced costs.
The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the ...CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy.
All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted.
A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1–43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks 0.0–236.9), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3–53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight.
It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.
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To evaluate treatment preferences of patients with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) before and after using a web-based decision aid (DA).
Between ...July 2016 and January 2017 patients were invited to use a web-based LUTS/BPH DA. Treatment preferences (for lifestyle advices, medication or surgery) before and after DA use and responses on values clarification exercises were extracted from the DA.
In total, 126 patients were included in the analysis. Thirty-four percent (43/126) had not received any previous treatment and were eligible for (continuation of) lifestyle advices or to start medication, as initial treatment. The other 66% (83/126) did use medication and were eligible, either for continuing medication or to undergo surgery. Before being exposed to the DA, 67 patients (53%) were undecided and 59 patients (47%) indicated an initial treatment preference. Half of the patients who were initially undecided were able to indicate a preference after DA use (34/67, 51%). Of those with an initial preference, 80% (47/59) confirmed their initial preference after DA use. Five out of 7 values clarification exercises used in the DA were discriminative between final treatment preferences. In 79%, the treatment preferred after DA use matched the received treatment. Overall, healthcare providers were positive about DA feasibility.
Our findings suggest that a LUTS/BPH DA may help patients to confirm their initial treatment preference and support them in forming a treatment preference if they did not have an initial preference.
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