Citations

We clarify that DNA damage triggers autophagy by CHK2-FOXK axis, and misregulation of this pathway leads to chemoresistance.

Background: Tumor necrosis factor alpha (TNF-alpha) inhibitors, such as infliximab, are commonly used to treat rheumatoid arthritis (RA) and other immune-mediated disorders. Objective: To determine whether infliximab-associated central nervous system (CNS) demyelination can be differentiated from multiple sclerosis (MS). Methods: We present a case of pathologically proven CNS demyelination in a patient treated with infliximab and describe clinical–radiographic–neuropathological findings. Putative mechanisms of TNF-alpha inhibitor-associated CNS demyelination are described. Results and conclusion: Infliximab treatment is associated with CNS inflammatory demyelinating activity, which is histopathologically indistinguishable from MS.

AbstractBackgroundHematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections.MethodsPatients were stratified by lymphopenia (<200/µL) and ribavirin use; were randomized, stratified by lymphopenia (<200/μL) and ribavirin use, to receive oral presatovir at 200 mg or a placebo on Days 1, 5, 9, 13, and 17, and were followed through Day 28. The coprimary efficacy endpoints were the time-weighted average change in the nasal RSV viral load between Days 1 and 9 and the proportion of patients developing lower respiratory tract complications (LRTCs) through Day 28.ResultsFrom 23 January 2015 to 16 June 2017, 189 patients were randomly assigned to treatment (96 to presatovir and 93 to the placebo). Presatovir treatment, compared with the placebo treatment, did not significantly affect (prespecified α = 0.01) a time-weighted average decline in the RSV viral load from Day 1 to 9 (treatment difference, −0.33 log10 copies/mL; 95% confidence interval [CI] −.64 to −.02 log10 copies/mL; P = .040) or the progression to LRTC (11.2% vs 19.5%, respectively; odds ratio, 0.50; 95% CI, .22–1.18; P = .11). In a post hoc analysis among patients with lymphopenia, presatovir decreased LRTC development by Day 28 (2/15 [13.3%] vs 9/14 [64.3%], respectively; P = .008), compared with the placebo. Adverse events were similar for patients receiving presatovir and the placebo.ConclusionsPresatovir had a favorable safety profile in adult HCT recipients with RSV but did not achieve the coprimary endpoints. Exploratory analyses suggest an antiviral effect among patients with lymphopenia.Clinical Trials RegistrationNCT02254408; EUDRA-CT#2014-002474-36.

Abstract Aims As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings. Methods and results Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set. Conclusion Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

OBJECTIVES: Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS: In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS: Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 ( P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION: We successfully developed a new testing approach using CD4 + T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

Abstract EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition is not effective in treating this tumor. EGFR inhibition may fail because EGFR is not a driver of the malignant phenotype in GBM, or because adaptive compensatory mechanisms are triggered by EGFR inhibition that prevent cell death from a loss of EGFR signaling. We have recently identified a TNFα-JNK-Axl-ERK signaling axis that mediates primary resistance to EGFR inhibition in GBM. Temozolomide (TMZ) is the most effective chemotherapy in GBM, although it has only a modest effect on overall survival. The efficacy of TMZ depends on the absence of the DNA repair protein O6-alkylguanine DNA alkyltransferase (MGMT) which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression. TMZ is less effective in MGMT unmethylated GBMs. Moreover, even initially responsive tumors develop a secondary resistance to TMZ. No treatment is effective in recurrent TMZ-resistant GBM. In this study, we compare the efficacy of temozolomide versus EGFR plus TNF inhibition in an orthotopic model of GBM. We find that efficacy of the two treatments is similar in MGMT-methylated GBMs. However, in MGMT-unmethylated GBMs, a combination of EGFR plus TNF inhibition is more effective. We demonstrate that the two treatment approaches target distinct and non-overlapping pathways. Furthermore, and importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Since the EGFR is expressed in the majority of GBMs, EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a broadly applicable and viable therapeutic approach in primary GBMs with MGMT unmethylation and in recurrent GBMs.

Abstract Stigma in patients suffering from chronic disease is associated with worse clinical outcomes and secondary medical issues such as depression, anxiety, and decreased quality of life. We believe various forms of stigma can have different clinical significance in patients with inflammatory bowel disease (IBD). With further insight and research, we suggest that these forms of stigma could be identified and targeted by researchers or clinicians to lessen the psychological disease burden in patients and to potentially improve their physical well-being. In the current review, we discuss public perceptions, knowledge, and stigmatization of IBD, the prevalence of various forms of IBD stigma, and the impact of such stigma on patient outcomes. We also discuss IBD disclosure, its association with stigma, and the tendencies and effects of such disclosures among youth and adult patient populations. We finish the review by highlighting possible modalities and research areas for future IBD interventions.

Abstract Background Cancer patients have a higher risk of thromboembolic events but it is not well known if these patients also have a higher risk of death, myocardial infarction (MI) or repeat revascularization after percutaneous coronary intervention (PCI) is unknown. Methods Cancer patients who underwent first-time single vessel PCI from January 1, 2003, through December 31, 2013 were identified by cross-matching of institutional cancer and PCI registries. These cancer patients were matched 4:1 to non-cancer patients, likewise undergoing first-time single vessel PCI in the time period. The combined primary endpoint was death, MI and revascularization at 5 year follow-up. Secondary endpoints were death and MI combined and the individual components of the primary endpoint. Both time dependent and non-time-dependent analyses were conducted. Results A total of 712 cancer patients were identified and matched to 2,848 non-cancer patients (one third women in either group). Bare-metal stents were used in one third of patients in both groups. The combined primary study endpoint was significantly more frequently encountered in the cancer than in the non-cancer group in both time-dependent (Figure 1) and non-time dependent analyses (5-year event rate 48.6% vs. 31.2%, p<0.001). This was driven by a higher 5-year event rate of death (39.0% vs. 20.1%) and MI (14.8% vs 4.86%) in the cancer group. The 5-year rate of revascularization did not differ significantly between the two groups (10.5% vs 10.3%). Figure 1. MI + revascularization-survival Conclusion Cancer patients have a two times higher rate of death and a three times higher rate of MI over the first 5 years after PCI. Future studies will need to define the etiology and factors accounting for this higher event rate in cancer patients, especially of these patients are predisposed to stent thrombosis and need longer term dual antiplatelet therapy.

Background: There is intense interest and speculation in the application of artificial intelligence (AI) to radiology. The goals of this investigation were (1) to assess thoracic radiologists’ perspectives on the role and expected impact of AI in radiology, and (2) to compare radiologists’ perspectives with those of computer science (CS) experts working in the AI development. Methods: An online survey was developed and distributed to chest radiologists and CS experts at leading academic centers and societies, comparing their expectations of AI’s influence on radiologists’ jobs, job satisfaction, salary, and role in society. Results: A total of 95 radiologists and 45 computer scientists responded. Computer scientists reported having read more scientific journal articles on AI/machine learning in the past year than radiologists (mean [95% confidence interval]=17.1 [9.01-25.2] vs. 7.3 [4.7-9.9], P=0.0047). The impact of AI in radiology is expected to be high, with 57.8% and 73.3% of computer scientists and 31.6% and 61.1% of chest radiologists predicting radiologists’ job will be dramatically different in 5 to 10 years, and 10 to 20 years, respectively. Although very few practitioners in both fields expect radiologists to become obsolete, with 0% expecting radiologist obsolescence in 5 years, in the long run, significantly more computer scientists (15.6%) predict radiologist obsolescence in 10 to 20 years, as compared with 3.2% of radiologists reporting the same (P=0.0128). Overall, both chest radiologists and computer scientists are optimistic about the future of AI in radiology, with large majorities expecting radiologists’ job satisfaction to increase or stay the same (89.5% of radiologists vs. 86.7% of CS experts, P=0.7767), radiologists’ salaries to increase or stay the same (83.2% of radiologists vs. 73.4% of CS experts, P=0.1827), and the role of radiologists in society to improve or stay the same (88.4% vs. 86.7%, P=0.7857). Conclusions: Thoracic radiologists and CS experts are generally positive on the impact of AI in radiology. However, a larger percentage, but still small minority, of computer scientists predict radiologist obsolescence in 10 to 20 years. As the future of AI in radiology unfolds, this study presents a historical timestamp of which group of experts’ perceptions were closer to eventual reality.