Citations

AbstractBackgroundEndobronchial ultrasound‐guided transbronchial lung biopsy (EBUS‐TBLB) and fluorodeoxyglucose positron emission tomography (FDG‐PET) have been widely used in the diagnosis of peripheral pulmonary lesions (PPLs). This study was conducted to determine the diagnostic value of EBUS‐TBLB combined with FDG‐PET in the assessment of PPLs.MethodsThe clinical data of 76 patients with PPLs who received both FDG‐PET and EBUS‐TBLB from January 2016 to February 2018 were retrospectively evaluated. Further subgroup analysis was performed according to lesion diameter (≤20 mm or >20 mm). Related diagnostic indices were calculated and compared between groups.ResultsWhen combining EBUS‐TBLB with FDG‐PET, the diagnostic accuracy rate, sensitivity, specificity, Youden's index, positive predictive value, and negative predictive value for PPLs were 86.8%, 90.2%, 73.3%, 63.5%, 93.2%, and 64.7%, respectively. In addition, the diagnostic accuracy rate of the combined approach was significantly higher than the single EBUS‐TBLB and FDG‐PET (P < 0.01 and P < 0.05, respectively), and its Youden's index was also at a higher level. When stratified by lesion diameter, the combined approach showed a significantly higher diagnostic accuracy rate (P < 0.05) and a higher Youden's index for PPLs >20 mm than PPLs ≤20 mm. In addition, we found that positive bronchus sign and probe within the probe were two important factors conducing to enhancing the diagnostic accuracy rate for EBUS‐TBLB.ConclusionsAn integrated approach combining EBUS‐TBLB with FDG‐PET is particularly useful for diagnosing PPLs, and the improved diagnostic yields were especially evident for PPLs >20 mm.

Epilepsy is a major neurological condition that affects millions of people globally. While a number of interventions have been developed to mitigate this condition, a significant number of patients are refractory to these treatments. Consequently, other avenues of research are needed. One such avenue is modulation of the immune system response to this condition, which has mostly focused on microglia, the resident immune cells of the central nervous system (CNS). However, other immune cells can impact neurological conditions, principally blood‐borne monocytes that can infiltrate into brain parenchyma after seizures. As such, this review will first discuss how monocytes can be recruited to the CNS and how they can be distinguished from there immunological cousins, microglia. Then, we will explore what is known about the role monocytes have within seizure pathogenesis and epilepsy. Considering how little is known about monocyte function in seizure‐ and epilepsy‐related pathologies, further studies are warranted that investigate infiltrated blood‐borne monocytes as a potential therapeutic target for epilepsy treatment.

Abstract We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

Background: Patients with bicuspid aortic valve (AV) stenosis were excluded from the pivotal evaluations of transcatheter AV replacement (TAVR) devices. We sought to evaluate the outcomes of TAVR in patients with bicuspid AV stenosis in comparison with those with tricuspid AV stenosis. Methods: We used data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry (November 2011 through November 2018) to determine device success, procedural outcomes, post-TAVR valve performance, and in-hospital clinical outcomes (mortality, stroke, and major bleeding) according to valve morphology (bicuspid versus tricuspid). Results were stratified by older and current (Sapien 3 and Evolut R) generation valve prostheses. Medicare administrative claims were used to evaluate mortality and stroke to 1 year among eligible individuals (≥65 years). Results: After exclusions, there were 170 959 eligible procedures at 593 sites during the specified interval. Of these, 5412 TAVR procedures (3.2%) were performed in patients with bicuspid AV, including 3705 with current-generation devices. In comparison with patients with tricuspid valves, patients with bicuspid AV were younger and had a lower Society of Thoracic Surgeons Predicted Risk of Operative Mortality score. When current-generation devices were used to treat patients with bicuspid AV, device success increased (93.5 versus 96.3; P =0.001) and the incidence of 2+ aortic insufficiency declined (14.0% versus 2.7%; P <0.001) in comparison with older-generation devices. With current-generation devices, device success was slightly lower in the bicuspid (versus tricuspid) AV group (96.3% in bicuspid versus 97.4% in tricuspid, P =0.07), with a slightly higher incidence of residual moderate or severe aortic insufficiency among patients with bicuspid AV (2.7% versus 2.1%; P <0.001). A lower 1-year adjusted risk of mortality (hazard ratio, 0.88 [95% CI, 0.78–0.99]) was observed for patients with bicuspid AV versus patients with tricuspid AV in the Medicare-linked cohort, whereas no difference was observed in the 1-year adjusted risk of stroke (hazard ratio, 1.14 [95% CI, 0.94–1.39]). Conclusions: Using current-generation devices, procedural, postprocedural, and 1-year outcomes were comparable following TAVR for bicuspid AV versus tricuspid AV disease. With newer-generation devices, TAVR is a viable treatment option for patients with bicuspid AV disease.

176 Background: Multiple tumour tissue studies have demonstrated the prognostic utility of CNVs in mCRPC. However, accurate assessment of CNVs in plasma cfDNA remains challenging, and prognostic significance has not been well characterized. Using a large customized panel, we correlated plasma CNVs with clinical outcomes in a contemporary cohort of mCRPC patients. Methods: Deep targeted sequencing was performed using a 180-gene cfDNA panel (Predicine) in 56 patients commencing AR pathway inhibitors (enzalutamide or abiraterone; n = 34) or taxane chemotherapy (n = 22) at two Australian institutions. Kaplan-Meier estimates and Cox proportional-hazards models were used to correlate CNVs with progression-free survival (PFS) and overall survival (OS). Significant results were validated in an independent cohort (Mayo Clinic, n = 144). Results: Median follow-up was 19.4 months (mo; IQR 11.3-31.9). The most common CNVs in the Australian cohort are shown (Table). OS was significantly decreased in patients with PI3KCA gain (median 21.7 mo vs 6.6 mo, p < 0.0001), PTEN loss (24.8 mo vs 11.7 mo, p = 0.0019) and AR gain (21.7 mo vs 12.0 mo, p = 0.0083). Furthermore, all three alterations independently predicted for poor survival in multivariable analyses (MVA; Table). Findings in the independent cohort showed similar OS results in MVA: PIK3CA gain (HR 2.0, p = 0.07), PTEN loss (HR 1.7, p = 0.08) and AR gain (HR 1.7, p = 0.03). Conclusions: Sequencing of plasma cfDNA revealed that PTEN loss, and PIK3CA and AR gain are associated with inferior clinical outcomes in patients commencing contemporary systemic treatment. These data support therapeutic strategies co-targeting the PI3K and AR pathways in mCRPC.[Table: see text]

Introduction: Interferon regulatory factor 4 (IRF4) is a transcription factor involved in B cell activation and differentiation into plasma cells, as well as B-cell lineage neoplasia. Diverse genetic abnormalities and dysregulated expression of IRF4 have been documented in various hematologic malignancies, including multiple myeloma (MM). IRF4 is also identified as a major downstream target of CRBN/IKZF to regulate MYC expression, representing a primary mechanism underlying anti-MM action of IMiDs. However, it remains unclear how the expression and function of IRF4 are regulated in MM cells. Materials and Methods: DNAseq, whole exome RNAseq (WES), and label-free analyses of quantitative proteomics and post-translational modifications (PTMs) mapping were conducted to examine genetic aberrations, transcriptional dysregulation, or protein and PTM alterations in primary patient samples and drug-naive vs -resistant cell lines. Flow cytometry, qPCR, and Western blot analysis were utilized to monitor apoptosis or mRNA and protein levels of target genes. Stable transfection with wild-type or mutated IRF4 was carried out to evaluate its function. Analysis of the MM genome-wide GEP databases (R2: Genomics Analysis and Visualization Platform) was performed to validate the clinical significance of IRF4 and its target genes in MM patients. Results: MM cells that acquired bortezomib (btz) resistance (PS-R) exhibited a marked increase in protein levels of multiple key components of the canonical and non-canonical NF-κB signaling cascades, in association with increased NF-κB transcriptional activity. Pharmacological inhibition of NF-κB using several compounds (e.g., Bay 11-7082, parthenolide, triptolide) significantly increased btz sensitivity in PS-R cells and their parental U266 cells, as well as other MM cell lines. These events were accompanied by down-regulation of various genes, including NF-κB-dependent genes and those whose relationship with NF-κB remains uncertain. The latter included IRF4, MYC, MCL1, BIRC2/cIAP1, SQSTM1/p62, among others. Of note, overexpression of wild-type IRF4 sharply reduced sensitivity of drug-naive cells to btz alone or in combination with NF-κB inhibitors. However, IRF4 overexpression did not prevent inactivation of NF-κB and down-regulation of the NF-κB-dependent genes (e.g., Bcl-xL, TNFAIP3/A20), suggesting that IRF4 acts downstream of NF-κB. Surprisingly, IRF4 overexpression failed to restore expression of MYC, a well-established target of IRF4, while largely reversed expression of cIAP1 and Mcl-1 at both mRNA and protein levels. Moreover, inhibitors of either IAP (birinapant/TL32711) or Mcl-1 (S63845) overcame btz-resistance conferred by IRF4 overexpression. DNAseq unveiled multiple IRF4 SNPs located in introns and exons (both 3'-UTR and coding region) of chromosome 6. WES revealed that IRF4 was highly expressed in primary bone marrow and extramedullary samples of MM patients (2~10 folds over normal donors). But no difference at mRNA and protein levels of IRF4 was observed between drug-naive and -resistant cell lines. The global PTM mapping identified two lysine residues (K59 and K399) that were highly ubiquitinated in PS-R cells (p = 0.0447 and p = 0.0004, vs U266 cells). Interestingly, ectopic expression of IRF4 mutants (e.g., K59N, K123R) lost the cytoprotective capability of their wild-type counterpart, in association with failure to reverse down-regulation of cIAP1 and Mcl-1. This observation argues that these point mutations are loss-of-function, which might explain better prognosis of patients carrying IRF4 mutations (including K59N and K123R) than wild-type IRF4 as reported previously. Last, the MM GEP database analysis validated the correlation between IRF4 and Mcl-1 or cIAP expression, as well as the adverse effect of their dysregulation on overall survival of MM patients. Conclusion: IRF4 is highly expressed in MM cells, likely via an NF-κB-dependent mechanism. IRF4 acts downstream of the NF-κB signaling pathways, which in turn directly targets cIAP1 and Mcl-1, rather than MYC, to confer drug resistance. IRF4 could be mutated in MM patients, while the point mutations, at least at certain lysine sites, seem to be loss-of-function and thus predict better outcome. Together, these findings suggest that the oncogenic function of IRF4 might be governed at genetic, transcriptional, and PTM levels in MM cells. Disclosures Kumar: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.