Citations

ObjectiveHigh‐throughput DNA sequencing of the paranasal sinus microbiome has potential in the diagnosis and treatment of sinusitis. The objective of this study is to evaluate the use of high‐throughput DNA sequencing to diagnose sinusitis of odontogenic origin.Study DesignCase series with chart review.SettingSingle tertiary care academic medical center.Subjects and MethodsA chart review was performed of DNA sequencing results from the sinus aspirates obtained under endoscopic visualization in 142 patients with sinusitis. The identification of any potentially pathogenic bacteria associated with oral flora in a sample was classified as a positive result for sinusitis of odontogenic etiology. The sensitivity, specificity, and predictive values of using high‐throughput DNA sequencing to diagnose sinusitis of odontogenic etiology were determined, with the patient’s computed tomography sinus scan as the reference standard. On computed tomography scans, an odontogenic source was determined by the presence of a periapical lucency perforating the schneiderian membrane.ResultsSeven of the 142 patients enrolled in this study had an odontogenic source based on computed tomography scans. Relative to this reference standard, high‐throughput DNA sequencing produced a sensitivity of 85.7% (95% CI, 42.1%‐99.6%), a specificity of 81.5% (95% CI, 73.9%‐87.6%), a positive predictive value of 19.4% (95% CI, 13.1%‐27.7%), and a negative predictive value of 99.1% (95% CI, 94.7%‐99.9%).ConclusionThis study supports the use of high‐throughput DNA sequencing in supplementing other methods of investigation for identifying an odontogenic etiology of sinusitis.

AbstractThe acquisition of cellular invasiveness by breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS‐like cells increases survival, growth, and invasiveness. To explore this mechanism further and assess direct transcriptional targets of TBX3 in a high‐resolution, isoform‐specific context, we conducted genome‐wide chromatin‐immunoprecipitation (ChIP) arrays coupled with transcriptomic analysis. We show that TBX3 regulates several epithelial–mesenchymal transition (EMT)‐related genes, including SLUG and TWIST1. Importantly, we demonstrate that TBX3 is a direct regulator of SLUG expression, and SLUG expression is required for TBX3‐induced migration and invasion. Assessing TBX3 by immunohistochemistry in early‐stage (stage 0 and stage I) breast cancers revealed high expression in low‐grade lesions. Within a second independent early‐stage non‐high‐grade cohort, we observed an association between TBX3 level in the DCIS and size of the invasive focus. Additionally, there was a positive correlation between TBX3 and SLUG, and TBX3 and TWIST1 in the invasive carcinoma. Pathway analysis revealed altered expression of several proteases and their inhibitors, consistent with the ability to degrade basement membrane in vivo. These findings strongly suggest the involvement of TBX3 in the promotion of invasiveness and progression of early‐stage pre‐invasive breast cancer to invasive carcinoma through the low‐grade molecular pathway. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Abstract Primary spinal cord tumors represent a hetereogeneous group of central nervous system malignancies whose management is complex given the relatively uncommon nature of the disease and variety of tumor subtypes, functional neurologic deficits from the tumor, and potential morbidities associated with definitive treatment. Advances in neuroimaging; integration of diagnostic, prognostic, and predictive molecular testing into tumor classification; and developments in neurosurgical techniques have refined the current role of radiotherapy in the multimodal management of patients with primary spinal cord tumors, and corroborated the need for prospective, multidisciplinary discussion and treatment decision making. Radiotherapeutic technological advances have dramatically improved the entire continuum from treatment planning to treatment delivery, and the development of stereotactic radiosurgery and proton radiotherapy provides new radiotherapy options for patients treated in the definitive, adjuvant, or salvage setting. The objective of this comprehensive review is to provide a contemporary overview of the management of primary intradural spinal cord tumors, with a focus on radiotherapy.

Abstract Heart failure (HF) is an increasingly prevalent condition with a very high symptom burden. To address challenges faced by palliative care clinicians, we assembled a team of experts to provide high-yield tips for the management of these patients. Prognosis is unpredictable in HF and many patients and physicians overestimate survival. Ejection fraction, notably, is not predictive of prognosis. It is important to have thorough discussions about implantable cardioverter defibrillators in terminally ill HF patients. Diuresis is the mainstay of managing volume overload and dyspnea in these patients and it is important to be aggressive and creative to achieve symptom relief. However, HF patients have a high burden of comorbidities and have many symptoms beyond dyspnea as well. Management in hospice remains challenging for these patients, with a significant risk for readmission to the hospital. Almost a quarter of HF patients discharged to hospice from the hospital die in less than three days.

Abstract Purpose: Gliomas with isocitrate dehydrogenase 1 mutations (IDH1mut) are less aggressive than IDH1 wild-type (IDH1wt) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1mut phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), F3, is among the most hypermethylated and downregulated genes in IDH1mut gliomas, correlating with greatly reduced thrombosis in patients with IDH1mut glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1mut gliomas. Experimental Design: TF expression was manipulated in patient-derived IDH1mut and IDH1wt glioma cells, followed by evaluation of in vitro and in vivo behavior and analyses of cell signaling pathways. Results: A demethylating agent, decitabine, increased F3 transcription and TF-dependent coagulative activity in IDH1mut cells, but not in IDH1wt cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1mut cells, and increased the intracranial engraftment of IDH1mut GBM164 from 0% to 100% (P = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1wt/EGFRvIIIamp GBM6, and caused complete regression of IDH1wt/EGFRamp GBM12 (P = 0.001). In vitro and in vivo effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin. Conclusions: These data show that TF suppression is a component of IDH1mut glioma behavior, and that it may therefore be an attractive target against IDH1wt gliomas.

Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP+/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.