Eric Ballon-Landa

Respiratory virus–induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium

Inhibition of epidermal growth factor receptor during viral infection augments IRF1-dependent IFN-λ production and decreases viral titers.

EGFR activation suppresses respiratory virus-induced IRF1-dependent CXCL10 production.

Airway epithelial cells are the primary cell type involved in respiratory viral infection. Upon infection, airway epithelium plays a critical role in host defense against viral infection by contributing to innate and adaptive immune responses. Influenza A virus, rhinovirus, and respiratory syncytial virus (RSV) represent a broad range of human viral pathogens that cause viral pneumonia and induce exacerbations of asthma and chronic obstructive pulmonary disease. These respiratory viruses induce airway epithelial production of IL-8, which involves epidermal growth factor receptor (EGFR) activation. EGFR activation involves an integrated signaling pathway that includes NADPH oxidase activation of metalloproteinase, and EGFR proligand release that activates EGFR. Because respiratory viruses have been shown to activate EGFR via this signaling pathway in airway epithelium, we investigated the effect of virus-induced EGFR activation on airway epithelial antiviral responses. CXCL10, a chemokine produced by airway epithelial cells in response to respiratory viral infection, contributes to the recruitment of lymphocytes to target and kill virus-infected cells. While respiratory viruses activate EGFR, the interaction between CXCL10 and EGFR signaling pathways is unclear, and the potential for EGFR signaling to suppress CXCL10 has not been explored. Here, we report that respiratory virus-induced EGFR activation suppresses CXCL10 production. We found that influenza virus-, rhinovirus-, and RSV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-dependent CXCL10 production. In addition, inhibition of EGFR during viral infection augmented IRF1 and CXCL10. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.

Quality of diagnostic staging in patients with bladder cancer: A process-outcomes link

Muscle sampling is often used as a surrogate for staging quality in patients with bladder cancer. The association of staging quality at diagnosis and survival was examined among patients with bladder cancer.

Treatment and survival in patients with recurrent high-risk non-muscle-invasive bladder cancer.

BACKGROUND Multiple recurrences develop in patients with high-risk non-muscle-invasive bladder cancer. As neither the association of recurrences with survival nor the subsequent aggressive treatment in individuals with recurrent high-grade non-muscle-invasive bladder cancer has ever been quantified, we sought to determine whether the increasing number of recurrences is associated with higher subsequent treatment and mortality rates. METHODS Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified subjects with recurrent high-grade, non-muscle-invasive disease diagnosed in 1992 to 2002 and followed up until 2007. Using competing-risks regression analyses, we quantified the incidence of radical cystectomy, radiotherapy, and systemic chemotherapy after each recurrence. We then performed a propensity-score adjusted competing-risks regression analysis to determine whether the increasing recurrences portend worse survival. RESULTS Of 4,521 subjects, 2,694 (59.6%) had multiple recurrences within 2 years of diagnosis. Compared with patients who only had 1 recurrence, those with ≥ 4 recurrences were less likely to undergo radical cystectomy (hazard ratio [HR] = 0.73, 95% CI: 0.58-0.92), yet more likely to undergo radiotherapy (HR = 1.51, 95% CI: 1.23-1.85) and systemic chemotherapy (HR = 1.58, 95% CI: 1.15-2.18). For patients with ≥ 4 recurrences, only 25% were treated with curative intent. The 10-year cancer-specific mortality rates were 6.9%, 9.7%, 13.7%, and 15.7% for those with 1, 2, 3, and ≥ 4 recurrences, respectively. CONCLUSIONS Only 25% of patients with high-risk non-muscle-invasive bladder cancer who experienced recurrences at least 4 times underwent radical cystectomy or radiotherapy. Despite portending worse outcomes, increasing recurrences do not necessarily translate into higher treatment rates.

Community-Partnered Collaboration to Build an Integrated Palliative Care Clinic: The View From Urology

Background: We partnered with patients, families, and palliative care clinicians to develop an integrated urology–palliative care clinic for patients with metastatic cancer. We assessed clinician satisfaction with a multidisciplinary palliative care clinic model. Methods: We conducted semi-structured interviews with 18 clinicians who practice in our integrated clinic. We analyzed transcripts using a multistage, cutting-and-sorting technique in an inductive approach based on grounded theory analysis. Finally, we administered a validated physician job satisfaction survey. Results: Clinicians found that referring a patient to palliative care in the urology clinic was feasible and appropriate. Patients were receptive to supportive care, and clinicians perceived that quality of care improved following the intervention. Conclusion: An integrated, patient-centered model for individuals with advanced urologic malignancies is feasible and well received by practitioners.

Nutrition, physical activity, and lifestyle factors in prostate cancer prevention

Purpose of review To review current evidence for prostate cancer prevention with nutrition, physical activity, and lifestyle interventions and identify future research directions. Recent findings Multiple preclinical and observational studies have observed that diet, exercise, and lifestyle interventions may play a role in mitigating disease progression, mortality, and overall disease burden for high-grade and fatal prostate cancer. Increased vegetable and fruit intakes, decreased red meat and saturated fat intakes, and increased exercise are potentially associated with decreased risk of incident disease and increased progression-free, prostate cancer-specific, and overall survival. Randomized controlled trials (RCTs) have demonstrated that selenium and vitamin C supplements are ineffective in preventing incident prostate cancer and that vitamin E supplements potentially increase incident prostate cancer risk. A large RCT of a high vegetable diet intervention among prostate cancer patients on active surveillance, the Mens Eating and Living study, will soon complete analysis. An RCT for an exercise intervention among men with metastatic castrate-resistant prostate cancer is currently accruing. Summary Although preclinical and observational studies have identified potential benefits for high vegetable, low fat, low meat diets, and increased exercise, Level I evidence is limited. To inform clinical care, future research should focus on RCTs evaluating clinical effectiveness.

Engaging Physician Learners Through a Web-Based Platform Individualized End-of-Life Education

Background: Web-based modules provide a convenient and low-cost education platform, yet should be carefully designed to ensure that learners are actively engaged. In order to improve attitudes and knowledge in end-of-life (EOL) care, we developed a web-based educational module that employed hyperlinks to allow users access to auxiliary resources: clinical guidelines and seminal research papers. Methods: Participants took pre-test evaluations of attitudes and knowledge regarding EOL care prior to accessing the educational module, and a post-test evaluation following the module intervention. We recorded the type of hyperlinks (guideline or paper) accessed by learners, and stratified participants into groups based on link type accessed (none, either, or both). We used demographic and educational data to develop a multivariate mixed-effects regression analysis to develop adjusted predictions of attitudes and knowledge. Results: 114 individuals participated. The majority had some professional exposure to EOL care (prior instruction 62%; EOL referral 53%; EOL discussion 56%), though most had no family (68%) or personal experience (51%). On bivariate analysis, non-partnered (p = .04), medical student training level (p = .03), prior palliative care referral (p = .02), having a family member (p = .02) and personal experience of EOL care (p < .01) were all associated with linking to auxiliary resources via hyperlinks. When adjusting for confounders, β coefficient estimates and least squares estimation demonstrated that participants clicking on both hyperlink types were more likely to score higher on all knowledge and attitude items, and demonstrate increased score improvements. Conclusion: Auxiliary resources accessible by hyperlink are an effective adjunct to web-based learning in end-of-life care.

Treatment patterns in patients with recurrent high-risk bladder cancer.

303 Background: Patients with high-risk bladder cancer are apt to develop multiple recurrences. Since the association of recurrences with aggressive treatment in individuals with recurrent high-grade disease has not been quantified, we sought to determine whether increasing number of recurrences correlates with higher treatment rates. Methods: Using linked SEER-Medicare data, we identified subjects with recurrent high-grade, non-muscle-invasive disease diagnosed in 1992–2002 and followed until 2007. Using propensity score and competing-risks regression analyses, we quantified the incidence of radical cystectomy, radiotherapy, and systemic chemotherapy after each recurrence. We further restricted our analyses of treatment in auspicious environments, defined as those patients most suited for aggressive intervention: age <70, Charlson 0, and undifferentiated T1 tumors treated at academic cancer centers. Results: Of 4,521 subjects, (59.6%) 2,694 recurred more than once within two years of diagnosis. Compared ...