Summary Until 2010, docetaxel was the only agent with proven survival benefit for castration-resistant prostate cancer. The development of cabazitaxel, abiraterone acetate, enzalutamide, radium-223, ...and sipuleucel-T has increased the number of treatment options. Because these agents were developed concurrently within a short period of time, prospective data on their sequential use efficacy are scarce. The challenge now is to reach a consensus on the best way to sequence effective treatments, ideally by the use of an approach specific to patient subgroups. However, the absence of robust surrogates of survival and the lack of predictive biomarkers makes data for the sequential use of these agents difficult to obtain and interpret.
Purpose
Relationships between diffusion‐weighted MRI signals and hepatocyte microstructure were investigated to inform liver diffusion MRI modeling, focusing on the following question: Can cell size ...and diffusivity be estimated at fixed diffusion time, realistic SNR, and negligible contribution from extracellular/extravascular water and exchange?
Methods
Monte Carlo simulations were performed within synthetic hepatocytes for varying cell size/diffusivity L/D0, and clinical protocols (single diffusion encoding; maximum b‐value: {1000, 1500, 2000} s/mm2; 5 unique gradient duration/separation pairs; SNR = {∞, 100, 80, 40, 20}), accounting for heterogeneity in (D0,L) and perfusion contamination. Diffusion (D) and kurtosis (K) coefficients were calculated, and relationships between (D0,L) and (D,K) were visualized. Functions mapping (D,K) to (D0,L) were computed to predict unseen (D0,L) values, tested for their ability to classify discrete cell‐size contrasts, and deployed on 9.4T ex vivo MRI‐histology data of fixed mouse livers
Results
Relationships between (D,K) and (D0,L) are complex and depend on the diffusion encoding. Functions mapping D,K to (D0,L) captures salient characteristics of D0(D,K) and L(D,K) dependencies. Mappings are not always accurate, but they enable just under 70% accuracy in a three‐class cell‐size classification task (for SNR = 20, bmax = 1500 s/mm2, δ = 20 ms, and Δ = 75 ms). MRI detects cell‐size contrasts in the mouse livers that are confirmed by histology, but overestimates the largest cell sizes.
Conclusion
Salient information about liver cell size and diffusivity may be retrieved from minimal diffusion encodings at fixed diffusion time, in experimental conditions and pathological scenarios for which extracellular, extravascular water and exchange are negligible.
Abstract Background Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) occurs frequently in prostate cancers. Preclinical evidence suggests that activation of PI3K/AKT signaling ...through loss of PTEN can result in resistance to hormonal treatment in prostate cancer. Objective To explore the antitumor activity of abiraterone acetate (abiraterone) in castration-resistant prostate cancer (CRPC) patients with and without loss of PTEN protein expression. Design, setting, and participants We retrospectively identified patients who had received abiraterone and had hormone-sensitive prostate cancer (HSPC) and/or CRPC tissue available for PTEN immunohistochemical analysis. Outcome measurements and statistical analysis The primary end point was overall survival from initiation of abiraterone treatment. Relationship with outcome was analyzed using multivariate Cox regression and log-rank analyses. Results and limitations A total of 144 patients were identified who had received abiraterone post-docetaxel and had available tumor tissue. Overall, loss of PTEN expression was observed in 40% of patients. Matched HSPC and CRPC tumor biopsies were available for 41 patients. PTEN status in CRPC correlated with HSPC in 86% of cases. Loss of PTEN expression was associated with shorter median overall survival (14 vs 21 mo; hazard ratio HR: 1.75; 95% confidence interval CI, 1.19–2.55; p = 0.004) and shorter median duration of abiraterone treatment (24 vs 28 wk; HR: 1.6; 95% CI, 1.12–2.28; p = 0.009). PTEN protein loss, high lactate dehydrogenase, and the presence of visceral metastases were identified as independent prognostic factors in multivariate analysis. Conclusions Our results indicate that loss of PTEN expression was associated with worse survival and shorter time on abiraterone treatment. Further studies in larger and prospective cohorts are warranted. Patient summary PTEN is a protein often lost in prostate cancer cells. In this study we evaluated if prostate cancers that lack this protein respond differently to treatment with abiraterone acetate. We demonstrated that the survival of patients with loss of PTEN is shorter than patients with normal PTEN expression.
Handwriting is a complex activity that involves continuous interaction between lower-level handwriting and motor skills and higher-order cognitive processes. It is important to allocate mental ...resources to these high-order processes since these processes place a great demand on cognitive capacity. This is possible when lower-level skills such as transcription are effortlessness and fluent. Given that fluency is a value in virtually all areas of academic learning, schools should provide instructional activities to promote writing fluency from the first stages of learning to write. In an effort to determine if teaching handwriting enhances writing fluency, we conducted a systematic and meta-analytic review of the writing fluency intervention literature. We selected 31 studies: 21 true and quasi-experimental studies, 4 single-group design, 3 single-subject design, and 3 non-experimental studies, conducted with K-6 students in a regular school setting. A total of 2,030 students participated in these studies. When compared to no instruction or non-handwriting instructional conditions, teaching different handwriting intervention programs resulted in statistically significant greater writing fluency (ES = 0.64). Moreover, three specific handwriting interventions yielded statistically significant results in improving writing fluency, when compared to other handwriting interventions or to typical handwriting instruction conditions: handwriting focused on training timed transcription skills (ES = 0.49), multicomponent handwriting treatments (ES = 0.40), and performance feedback (ES = 0.36). There were not enough data to calculate the impact of sensory-motor and self-regulated strategy handwriting interventions on writing fluency. The significance of these findings for implementing and differentiating handwriting fluency instruction and guiding future research will be discussed.
Research Findings: The COVID-19 pandemic is leading to an unprecedented crisis worldwide. With schools closed, the frequency with which Spanish parents engage in home literacy activities with their ...children between the ages of 2 and 8 and the sociodemographic variables that influence this collaboration are unknown. The present research aimed to understand interactions among parents and children in the context of literacy activities at home. A total of 337 Spanish parents completed the Home Literacy Activities Questionnaire (HLAQ). Results from the reliability test showed a good adequacy and consistency (Cronbach's alpha .85), and a factorial analysis indicated all items could be grouped into four factors: reading activities, writing activities, digital literacy activities, and dialogic-creative literacy activities. A latent class cluster analysis, based on parents' factorial scores in the HLAQ and their sociodemographic data, suggested four discrete parental clusters: parents prioritizing writing activities, interested in practicing all type of literacy activities, willing to do digital activities, or ready to practice dialogic-creative literacy activities. All indicators and sociodemographic characteristics - the children's age, the number of children in the family, and the parents' educational level - were significant and discriminated among the parental clusters. The activities carried out with least frequency were dialogic-creative literacy activities and digital literacy activities. Practice or Policy: Schools, as well as researchers, must be intentional about engaging families who may not be aware of certain activities to support their young children's literacy skills, in times of crisis, for all children and families, for specific groups of families and children, and at varying grade levels.
Diffusion‐weighted magnetic resonance imaging (DW‐MRI) aims to disentangle multiple biological signal sources in each imaging voxel, enabling the computation of innovative maps of tissue ...microstructure. DW‐MRI model development has been dominated by brain applications. More recently, advanced methods with high fidelity to histology are gaining momentum in other contexts, for example, in oncological applications of body imaging, where new biomarkers are urgently needed. The objective of this article is to review the state‐of‐the‐art of DW‐MRI in body imaging (ie, not including the nervous system) in oncology, and to analyze its value as compared to reference colocalized histology measurements, given that demonstrating the histological validity of any new DW‐MRI method is essential. In this article, we review the current landscape of DW‐MRI techniques that extend standard apparent diffusion coefficient (ADC), describing their acquisition protocols, signal models, fitting settings, microstructural parameters, and relationship with histology. Preclinical, clinical, and in/ex vivo studies were included. The most used techniques were intravoxel incoherent motion (IVIM; 36.3% of used techniques), diffusion kurtosis imaging (DKI; 16.7%), vascular, extracellular, and restricted diffusion for cytometry in tumors (VERDICT; 13.3%), and imaging microstructural parameters using limited spectrally edited diffusion (IMPULSED; 11.7%). Another notable category of techniques relates to innovative
b
‐tensor diffusion encoding or joint diffusion‐relaxometry. The reviewed approaches provide histologically meaningful indices of cancer microstructure (eg, vascularization/cellularity) which, while not necessarily accurate numerically, may still provide useful sensitivity to microscopic pathological processes. Future work of the community should focus on improving the inter‐/intra‐scanner robustness, and on assessing histological validity in broader contexts.
Level of Evidence
NA
Technical Efficacy
Stage 2
Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair ...defects would respond to poly(adenosine diphosphate ADP-ribose) polymerase (PARP) inhibition with olaparib.
We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies.
Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients 20%) and fatigue (in 6 12%) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib.
Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
Objective
Previously, only the HLA–DRB1 alleles have been assessed in rheumatoid arthritis (RA). The aim of the present study was to identify the key major histocompatibility complex (MHC) ...susceptibility factors showing a significant association with anti–carbamylated protein antibody–positive (anti‐CarP+) RA.
Methods
Analyses were restricted to RA patients who were anti–cyclic citrullinated peptide antibody negative (anti‐CCP−), because the anti‐CCP status dominated the results otherwise. Therefore, we studied samples from 1,821 anti‐CCP− RA patients and 6,821 population controls from Spain, Sweden, and the Netherlands. The genotypes for ~8,000 MHC biallelic variants were assessed by dense genotyping and imputation. Their association with the anti‐CarP status in RA patients was tested with logistic regression and combined with inverse‐variance meta‐analysis. Significance of the associations was assessed according to a study‐specific threshold of P < 2.0 × 10−5.
Results
The HLA–B*08 allele and its correlated amino acid variant Asp‐9 showed a significant association with anti‐CarP+/anti‐CCP− RA (P < 3.78 × 10−7; I2 = 0). This association was specific when assessed relative to 3 comparator groups: population controls, anti‐CarP−/anti‐CCP− RA patients, and anti‐CCP− RA patients who were positive for other anti–citrullinated protein antibodies. Based on these findings, anti‐CarP+/anti‐CCP− RA patients could be separated from other antibody‐defined subsets of RA patients in whom an association with the HLA–B*08 allele has been previously demonstrated. No other MHC variant remained associated with anti‐CarP+/anti‐CCP− RA after accounting for the presence of the HLA–B*08 allele. Specifically, the reported association of HLA–DRB1*03 was observed at a level comparable to that reported previously, but it was attributable to linkage disequilibrium.
Conclusion
These results identify HLA–B*08 carrying Asp‐9 as the MHC locus showing the strongest association with anti‐CarP+/anti‐CCP− RA. This knowledge may help clarify the role of the HLA in susceptibility to specific subsets of RA, by shaping the spectrum of RA autoantibodies.
This study aimed to: 1) analyze the inflammatory profile of Rheumatoid Arthritis (RA) patients, identifying clinical phenotypes associated with cardiovascular (CV) risk; 2) evaluate biologic and ...targeted-synthetic disease-modifying antirheumatic drugs (b-DMARDs and ts-DMARDs’: TNFi, IL6Ri, JAKinibs) effects; and 3) characterize molecular mechanisms in immune-cell activation and endothelial dysfunction.
A total of 387 RA patients and 45 healthy donors were recruited, forming three cohorts: i) 208 RA patients with established disease but without previous CV events; ii) RA-CVD: 96 RA patients with CV events, and iii) 83 RA patients treated with b-DMARDs/ts-DMARDs for 6 months. Serum inflammatory profiles (cytokines/chemokines/growth factors) and NETosis/oxidative stress-linked biomolecules were evaluated. Mechanistic in vitro studies were performed on monocytes, neutrophils and endothelial cells (EC).
In the first RA-cohort, unsupervised clustering unveiled three distinct groups: cluster 3 (C3) displayed the highest inflammatory profile, significant CV-risk score, and greater atheroma plaques prevalence. In contrast, cluster 1 (C1) exhibited the lowest inflammatory profile and CV risk score, while cluster 2 (C2) displayed an intermediate phenotype. Notably, 2nd cohort RA-CVD patients mirrored C3's inflammation.
Treatment with b-DMARDs or ts-DMARDs effectively reduced disease-activity scores (DAS28) and restored normal biomolecules levels, controlling CV risk. In vitro, serum from C3-RA or RA-CVD patients increased neutrophils activity and CV-related protein levels in cultured monocytes and EC, which were partially prevented by pre-incubation with TNFi, IL6Ri, and JAKinibs.
Overall, analyzing circulating molecular profiles in RA patients holds potential for personalized clinical management, addressing CV risk and assisting healthcare professionals in tailoring treatment, ultimately improving outcomes.
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•Unsupervised clustering of RA profiles revealed 3 groups with diverse inflammatory, oxidative, and netotic profiles.•RA patients without CV events but highest CV-risk showed inflammatory profiles akin to those with prior CV events.•TNFi, IL6Ri, and JAKi treatment for six months restores normal inflammatory biomolecule levels, cutting-RA-related CV-risk.•High CV risk RA serum activates neutrophils, modulates monocytes, and disrupts endothelial cells, reversed by b/ts-DMARDS.•Analyzing RA patients' molecular profiles enhances personalized management, addressing their cardiovascular risk.
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