Citations

ABSTRACTBackground and objectiveThe main purpose of treatment in patients with malignant pleural effusion (MPE) is symptom palliation. Currently, patients undergo repeat thoracenteses prior to receiving a definitive procedure as clinicians are not aware of the risk factors associated with fluid recurrence. The primary objective of this study was to identify risk factors associated with recurrent symptomatic MPE.MethodsRetrospective multicentre cohort study of patients who underwent first thoracentesis was performed. The primary outcome was time to fluid recurrence requiring intervention in patients with evidence of metastatic disease. We used a cause‐specific hazard model to identify risk factors associated with fluid recurrence. We also developed a predictive model, utilizing Fine–Gray subdistribution hazard model, and externally validated the model.ResultsA total of 988 patients with diagnosed metastatic disease were included. Cumulative incidence of recurrence was high with 30% of patients recurring by day 15. On multivariate analysis, size of the effusion on chest X‐ray (up to the top of the cardiac silhouette (hazard ratio (HR): 1.84, 95% CI: 1.21–2.80, P = 0.004) and above the cardiac silhouette (HR: 2.22, 95% CI: 1.43–3.46, P = 0.0004)), larger amount of pleural fluid drained (HR: 1.06, 95% CI: 1.04–1.07, P < 0.0001) and higher pleural fluid LDH (HR: 1.008, 95% CI: 1.004–1.011, P < 0.0001) were associated with increased hazard of recurrence. Negative cytology (HR: 0.52, 95% CI: 0.43–0.64, P < 0.0001) was associated with decreased hazard of recurrence. The model had low prediction accuracy.ConclusionPleural effusion size, amount of pleural fluid drained, LDH and pleural fluid cytology were found to be risk factors for recurrence.

Expression of histone H3.3K27M mutant proteins in human diffuse intrinsic pontine glioma (DIPG) results in a global reduction of tri-methylation of H3K27 (H3K27me3), and paradoxically, H3K27me3 peaks remain at hundreds of genomic loci, a dichotomous change that lacks mechanistic insights. Here, we show that the PRC2 complex is sequestered at poised enhancers, but not at active promoters with high levels of H3.3K27M proteins, thereby contributing to the global reduction of H3K27me3. Moreover, the levels of H3.3K27M proteins are low at the retained H3K27me3 peaks and consequently having minimal effects on the PRC2 activity at these loci. H3K27me3-mediated silencing at specific tumor suppressor genes, including Wilms Tumor 1, promotes proliferation of DIPG cells. These results support a model in which the PRC2 complex is redistributed to poised enhancers in H3.3K27M mutant cells and contributes to tumorigenesis in part by locally enhancing H3K27me3, and hence silencing of tumor suppressor genes.

T1-weighted MRI has been extensively used to extract imaging biomarkers and build classification models for differentiating Alzheimer’s disease (AD) patients from healthy controls, but only recently have brain connectome networks derived from diffusion-weighted MRI been used to model AD progression and various stages of disease such as mild cognitive impairment (MCI). MCI, as a possible prodromal stage of AD, has gained intense interest recently, since it may be used to assess risk factors for AD. Little work has been done to combine information from both white matter and gray matter, and it is unknown how much classification power the diffusion-weighted MRI-derived structural connectome could provide beyond information available from T1-weighted MRI. In this paper, we focused on investigating whether diffusion-weighted MRI-derived structural connectome can improve differentiating healthy controls subjects from those with MCI. Specifically, we proposed a novel feature-ranking method to build classification models using the most highly ranked feature variables to classify MCI with healthy controls. We verified our method on two independent cohorts including the second stage of Alzheimer’s Disease Neuroimaging Initiative (ADNI2) database and the National Alzheimer’s Coordinating Center (NACC) database. Our results indicated that 1) diffusion-weighted MRI-derived structural connectome can complement T1-weighted MRI in the classification task; 2) the feature-rank method is effective because of the identified consistent T1-weighted MRI and network feature variables on ADNI2 and NACC. Furthermore, by comparing the top-ranked feature variables from ADNI2, NACC, and combined dataset, we concluded that cross-validation using independent cohorts is necessary and highly recommended.

AbstractBackgroundQuadripolar left ventricular (LV) leads provide a more optimal pacing configuration for cardiac resynchronization therapy (CRT) than conventional bipolar leads. The objective of this study is to determine the clinical outcomes of CRT using quadripolar leads.MethodsThis study included 516 CRT patients who received bipolar LV leads (n = 278) or quadripolar LV leads (n = 238) from January 2013 to June 2016. Data were retrospectively collected from a prospective CRT database and electronic health records. CRT response to CRT was defined as >5% improvement in the LV ejection fraction (LVEF) from baseline. Baseline characteristics and outcomes were compared between groups.ResultsNew York Heart Association Functional Classification and LVEF significantly improved in the quadripolar and bipolar groups after CRT. There was no difference in the all‐cause mortality rate. The implant success rate was significantly higher in the quadripolar group (100% vs 97.8%; P = 0.02). Quadripolar lead placement was an independent predictor of CRT response at 12 months (hazard ratio, 0.76; 95% confidence interval, 0.58–0.98; P = 0.04). The rate of LV lead–related complications requiring invasive lead revision or abandonment was significantly higher in the bipolar group (11.2% vs 4.6%; P = 0.007).ConclusionsQuadripolar leads achieve similar CRT outcomes as bipolar LV leads but with a higher implant success rate and fewer procedure‐related complications.

Abstract Background Bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. Methods From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for β-lactamase genes were performed on ceftriaxone-resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. Results We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P &lt; .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. Conclusions HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy.

AbstractThe eMERGE Network is establishing methods for electronic transmittal of patient genetic test results from laboratories to healthcare providers across organizational boundaries. We surveyed the capabilities and needs of different network participants, established a common transfer format, and implemented transfer mechanisms based on this format. The interfaces we created are examples of the connectivity that must be instantiated before electronic genetic and genomic clinical decision support can be effectively built at the point of care. This work serves as a case example for both standards bodies and other organizations working to build the infrastructure required to provide better electronic clinical decision support for clinicians.

Abstract Purpose: Homozygous deletions play important roles in carcinogenesis. The genome-wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done. Experimental Design: We performed integrative analyses of the copy-number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project. Results: We found that the type-I interferon, α-, and β-defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%–31%, median = 12%; interquartile range = 10%–16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy. Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance. Clin Cancer Res; 24(14); 3299–308. ©2018 AACR.

Abstract Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis. Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts. Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1. Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186–96. ©2018 AACR.