Clara Oromendia

Prognostic Significance of a Negative Prostate Biopsy: An Analysis of Subjects Enrolled in a Prostate Cancer Screening Trial

Purpose: To our knowledge the optimal treatment of patients following a negative prostate biopsy is unknown. Consequently, resources are increasingly being directed toward risk stratification in this cohort. However, the risk of prostate cancer mortality in this group before the introduction of supplemental biomarkers and imaging techniques is unclear. Materials and Methods: The PLCO (Prostate, Lung, Colorectal and Ovarian Cancer) Screening Trial provides survival data prior to the implementation of new diagnostic interventions. We divided men with an initial positive screen and a subsequent prostate biopsy into cohorts based on positive or negative results. Prostate cancer specific mortality was then compared to that in the trial control arm to estimate the prognostic significance of biopsy results relative to the general population. Results: A total of 36,525 and 36,560 patients comprised the screening and control arms, respectively. Of 4,064 subjects with a positive first screen 1,233 underwent a linked biopsy, of which 473 were positive and 760 were negative. At a median followup of 12.9 years, 1.1% of men in the negative biopsy cohort had died of prostate cancer. The difference in mortality rates between the negative biopsy and control arms was 0.734 deaths per 1,000 person‐years. The proportional subhazard ratios of prostate cancer specific mortality for negative biopsy and positive biopsy relative to the control arm were 2.93 (95% CI 1.44–5.99) and 18.77 (95% CI 12.62–27.93), respectively. Conclusions: After a negative prostate biopsy, men face a relatively low risk of death from prostate cancer when followed with traditional markers and biopsy techniques. This suggests limited potential for new diagnostic interventions to improve survival in this group.

Prognostic Significance of Digital Rectal Examination and Prostate Specific Antigen in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Arm

Purpose: The absence of definitive data or explicit guidelines regarding the use of digital rectal examination for prostate cancer screening may lead to confusion for physicians and patients alike. We evaluated the prognostic value of abnormal digital rectal examination and prostate specific antigen following the widespread dissemination of prostate specific antigen testing in the U.S. Materials and Methods: Collectively, men comprising the screening arm of the PLCO cancer screening trial who underwent digital rectal examination screening (35,350) were followed for 314,033 person‐years. Adjusted analyses with competing risks regression were performed to assess the association of suspicious (nodularity, induration, asymmetry) digital rectal examination and abnormal prostate specific antigen (4 ng/ml or greater) with the detection of clinically significant prostate cancer, prostate cancer specific mortality and overall mortality. Results: Among all screening encounters with a suspicious digital rectal examination only 15.4% had a concurrently abnormal prostate specific antigen (McNemars test p <0.001). During followup there were 1,612 clinically significant prostate cancers detected, 64 prostate cancer specific deaths and 4,600 deaths. On multivariable analysis suspicious digital rectal examination and abnormal prostate specific antigen were associated with a greater risk of clinically significant prostate cancer (HR 2.21, 95% CI 1.99–2.44 vs HR 5.48, 95% CI 5.05–5.96, p <0.001 and p <0.001) and prostate cancer specific mortality (HR 2.54, 95% CI 1.41–4.58 vs HR 5.23, 95% CI 3.08–8.88, p=0.002 and p <0.001), respectively. Conclusions: In a secondary analysis of a contemporary U.S. cohort, suspicious digital rectal examination and abnormal prostate specific antigen on routine screening were independently associated with clinically significant prostate cancer and prostate cancer specific mortality. However, additional research is needed to optimize screening protocols.

Use of Digital Rectal Examination as an Adjunct to Prostate Specific Antigen in the Detection of Clinically Significant Prostate Cancer

Purpose: Guidelines from the NCCN® (National Comprehensive Cancer Network®) advocate digital rectal examination screening only in men with elevated prostate specific antigen. We investigated the effect of prostate specific antigen on the association of digital rectal examination and clinically significant prostate cancer in a large American cohort. Materials and Methods: We evaluated the records of the 35,350 men who underwent digital rectal examination in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial for the development of clinically significant prostate cancer (Gleason 7 or greater). Followup was 343,273 person‐years. The primary outcome was the rate of clinically significant prostate cancer among men with vs without suspicious digital rectal examination. We performed competing risks regression to evaluate the interaction between time varying suspicious digital rectal examination and prostate specific antigen. Results: A total of 1,713 clinically significant prostate cancers were detected with a 10‐year cumulative incidence of 5.9% (95% CI 5.6–6.2). Higher risk was seen for suspicious vs nonsuspicious digital rectal examination. Increases in absolute risk were small and clinically irrelevant for normal (less than 2 ng/ml) prostate specific antigen (1.5% vs 0.7% risk of clinically significant prostate cancer at 10 years), clinically relevant for elevated (3 ng/ml or greater) prostate specific antigen (23.0% vs 13.7%) and modestly clinically relevant for equivocal (2 to 3 ng/ml) prostate specific antigen (6.5% vs 3.5%). Conclusions: Digital rectal examination demonstrated prognostic usefulness when prostate specific antigen was greater than 3 ng/ml, limited usefulness for less than 2 ng/ml and marginal usefulness for 2 to 3 ng/ml. These findings support the restriction of digital rectal examination to men with higher prostate specific antigen as a reflex test to improve specificity. It should not be used as a primary screening modality to improve sensitivity.

Recurrent thrombosis in patients with antiphospholipid antibodies and arterial thrombosis on antithrombotic therapy

Management for patients with antiphospholipid syndrome (APS) and arterial thrombosis is controversial. There are no prospective data demonstrating the superiority of high- or moderate-intensity anticoagulation with vitamin K antagonists over antiplatelet agents. Using 2 antiphospholipid antibody databases (single center [New York Presbyterian Hospital] and multicenter [Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking]), we retrospectively collected demographic and clinical data of patients with APS and arterial thrombosis. The primary outcome was recurrent thrombosis rate after initial arterial thrombosis in patients with APS treated with antiplatelet and/or anticoagulant therapy. We identified 139 patients with a median follow-up time of 4.24 years after initial thrombosis. Thirty-seven patients (27.3%) received anticoagulants, 43 (30.9%) antiplatelets, and 58 (41.7%) combined therapy. Sixteen patients (37.2%) in the antiplatelet group, 9 (23.7%) in the anticoagulant group, and 4 (6.9%) in the combined therapy group experienced recurrent thrombosis. We estimate that 20% of patients will experience a recurrence by 3.4, 7.3, and 16.3 years, respectively, depending on assignment to antiplatelet, anticoagulant, or combined therapy. These results suggest that combined therapy decreases the rate of and increases the time to thrombosis recurrence in patients with APS presenting with arterial thrombosis.

National trends in management of localized prostate cancer: A population based analysis 2004-2013

Recent years have brought many changes in the management of localized prostate cancer as national screening guidelines have been updated and diagnostic practice patterns evolved. We sought to better understand how the changing landscape influenced treatment utilization in the United States.

Long-term consequences of vocal fold hemorrhage.

To assess the long‐term impact of vocal fold hemorrhage (VFH) on vocal function and health, and compare these parameters to those in similar patients who have not had VFH.

Acute respiratory distress syndrome without identifiable risk factors: A secondary analysis of the ARDS network trials

Purpose: We examined whether patients with acute respiratory distress syndrome (ARDS) lacking risk factors are enrolled in therapeutic trials and assessed their clinical characteristics and outcomes. Methods: We performed a secondary analysis of patient‐level data pooled from the ARMA, ALVEOLI, FACTT, ALTA and EDEN ARDSNet randomized controlled trials obtained from the Biologic Specimen and Data Repository Information Coordinating Center of the National Heart, Lung and Blood Institute. We compared baseline characteristics and clinical outcomes (before and after adjustment using Poisson regression model) of ARDS patients with versus without risk factors. Results: Of 3733 patients with ARDS, 81 (2.2%) did not have an identifiable risk factor. Patients without risk factors were younger, had lower baseline severity of illness, were more likely to have the ARDS resolve rapidly (i.e., within 24 h) (p < 0.001) and they had more ventilator‐free days (median 21; p = 0.003), more intensive care unit‐free days (18; p = 0.010), and more non‐pulmonary organ failure‐free days (24; p < 0.001) than comparators (17, 14 and 18, respectively). Differences persisted after adjustment for potential confounders. Conclusions: Patients with ARDS without identifiable risk factors are enrolled in therapeutic trials and may have better outcomes, including a higher proportion of rapidly resolving ARDS, than those with risk factors. HighlightsPatients with ARDS without identifiable risk factors are enrolled in therapeutic trials.Patients without risk factors may have better outcomes, including a higher proportion of rapidly resolving ARDS, than those with risk factors.Clinicians should be aware that some of the patients without risk factors may respond rapidly to standard care.

Circulating RIPK3 levels are associated with mortality and organ failure during critical illness

BACKGROUND Necroptosis is a form of programmed necrotic cell death that is rapidly emerging as an important pathophysiological pathway in numerous disease states. Necroptosis is dependent on receptor-interacting protein kinase 3 (RIPK3), a protein shown to play an important role in experimental models of critical illness. However, there is limited clinical evidence regarding the role of extracellular RIPK3 in human critical illness. METHODS Plasma RIPK3 levels were measured in 953 patients prospectively enrolled in 5 ongoing intensive care unit (ICU) cohorts in both the USA and Korea. RIPK3 concentrations among groups were compared using prospectively collected phenotypic and outcomes data. RESULTS In all 5 cohorts, extracellular RIPK3 levels in the plasma were higher in patients who died in the hospital compared with those who survived to discharge. In a combined analysis, increasing RIPK3 levels were associated with elevated odds of in-hospital mortality (odds ratio [OR] 1.7 for each log10-unit increase in RIPK3 level, P < 0.0001). When adjusted for baseline severity of illness, the OR for in-hospital mortality remained statistically significant (OR 1.33, P = 0.007). Higher RIPK3 levels were also associated with more severe organ failure. CONCLUSIONS Our findings suggest that elevated levels of RIPK3 in the plasma of patients admitted to the ICU are associated with in-hospital mortality and organ failure. FUNDING Supported by NIH grants P01 HL108801, R01 HL079904, R01 HL055330, R01 HL060234, K99 HL125899, and KL2TR000458-10. Supported by Samsung Medical Center grant SMX1161431.

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS)

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS.

Rapidly improving acute respiratory distress syndrome in therapeutic randomized controlled trials

BACKGROUND: Observational studies suggest that some patients meeting criteria for ARDS no longer fulfill the oxygenation criterion early in the course of their illness. This subphenotype of rapidly improving ARDS has not been well characterized. We attempted to assess the prevalence, characteristics, and outcomes of rapidly improving ARDS and to identify which variables are useful to predict it. METHODS: A secondary analysis was performed of patient level data from six ARDS Network randomized controlled trials. We defined rapidly improving ARDS, contrasted with ARDS > 1 day, as extubation or a Pao2 to Fio2 ratio (Pao2:Fio2) > 300 on the first study day following enrollment. RESULTS: The prevalence of rapidly improving ARDS was 10.5% (458 of 4,361 patients) and increased over time. Of the 1,909 patients enrolled in the three most recently published trials, 197 (10.3%) were extubated on the first study day, and 265 (13.9%) in total had rapidly improving ARDS. Patients with rapidly improving ARDS had lower baseline severity of illness and lower 60‐day mortality (10.2% vs 26.3%; P < .0001) than ARDS > 1 day. Pao2:Fio2 at screening, change in Pao2:Fio2 from screening to enrollment, use of vasopressor agents, Fio2 at enrollment, and serum bilirubin levels were useful predictive variables. CONCLUSIONS: Rapidly improving ARDS, mostly defined by early extubation, is an increasingly prevalent and distinct subphenotype, associated with better outcomes than ARDS > 1 day. Enrollment of patients with rapidly improving ARDS may negatively affect the prognostic enrichment and contribute to the failure of therapeutic trials.