Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis ...of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.
OBJECTIVE:To examine the association between the extent of surgery and overall survival in a large contemporary cohort of patients with papillary thyroid cancer (PTC).
BACKGROUND:Guidelines recommend ...total thyroidectomy for PTC tumors >1 cm, based on older data demonstrating an overall survival advantage for total thyroidectomy over lobectomy.
METHODS:Adult patients with PTC tumors 1.0–4.0 cm undergoing thyroidectomy in the National Cancer Database, 1998–2006, were included. Cox proportional hazards models were applied to measure the association between the extent of surgery and overall survival while adjusting for patient demographic and clinical factors, including comorbidities, extrathyroidal extension, multifocality, nodal and distant metastases, and radioactive iodine treatment.
RESULTS:Among 61,775 PTC patients, 54,926 underwent total thyroidectomy and 6849 lobectomy. Compared with lobectomy, patients undergoing total thyroidectomy had more nodal (7% vs 27%), extrathyroidal (5% vs16%), and multifocal disease (29% vs 44%) (all Ps < 0.001). Median follow-up was 82 months (range, 60–179 months). After multivariable adjustment, overall survival was similar in patients undergoing total thyroidectomy versus lobectomy for tumors 1.0–4.0 cm hazard ratio (HR) = 0.96; 95% confidence interval (CI), 0.84–1.09); P = 0.54 and when stratified by tumor size1.0–2.0 cm HR = 1.05; 95% CI, 0.88–1.26; P = 0.61 and 2.1–4.0 cm HR = 0.89; 95% CI, 0.73–1.07; P = 0.21. Older age, male sex, black race, lower income, tumor size, and presence of nodal or distant metastases were independently associated with compromised survival (P < 0.0001).
CONCLUSIONS:Current guidelines suggest total thyroidectomy for PTC tumors >1 cm. However, we did not observe a survival advantage associated with total thyroidectomy compared with lobectomy. These findings call into question whether tumor size should be an absolute indication for total thyroidectomy.
Each decade, the American Heart Association (AHA) develops an Impact Goal to guide its overall strategic direction and investments in its research, quality improvement, advocacy, and public health ...programs. Guided by the AHA’s new Mission Statement, to be a relentless force for a world of longer, healthier lives, the 2030 Impact Goal is anchored in an understanding that to achieve cardiovascular health for all, the AHA must include a broader vision of health and well-being and emphasize health equity. In the next decade, by 2030, the AHA will strive to equitably increase healthy life expectancy beyond current projections, with global and local collaborators, from 66 years of age to at least 68 years of age across the United States and from 64 years of age to at least 67 years of age worldwide. The AHA commits to developing additional targets for equity and well-being to accompany this overarching Impact Goal. To attain the 2030 Impact Goal, we recommend a thoughtful evaluation of interventions available to the public, patients, providers, healthcare delivery systems, communities, policy makers, and legislators. This presidential advisory summarizes the task force’s main considerations in determining the 2030 Impact Goal and the metrics to monitor progress. It describes the aspiration that these goals will be achieved by working with a diverse community of volunteers, patients, scientists, healthcare professionals, and partner organizations needed to ensure success.
This study systematically reviews the diverse body of research on community flood risk management in the USA to identify knowledge gaps and develop innovative and practical lessons to aid flood ...management decision-makers in their efforts to reduce flood losses. The authors discovered and reviewed 60 studies that met the selection criteria (e.g., study is written in English, is empirical, focuses on flood risk management at the community level in the USA, etc.). Upon reviewing the major findings from each study, the authors identified seven practical lessons that, if implemented, could not only help flood management decision-makers better understand communities’ flood risks, but could also reduce the impacts of flood disasters and improve communities’ resilience to future flood disasters. These seven lessons include: (1) recognizing that acquiring open space and conserving wetlands are some of the most effective approaches to reducing flood losses; (2) recognizing that, depending on a community’s flood risks, different development patterns are more effective at reducing flood losses; (3) considering the costs and benefits of participating in FEMA’s Community Rating System program; (4) engaging community members in the flood planning and recovery processes; (5) considering socially vulnerable populations in flood risk management programs; (6) relying on a variety of floodplain management tools to delineate flood risk; and (7) ensuring that flood mitigation plans are fully implemented and continually revised.
The coronavirus disease 2019 pandemic has or threatens to overwhelm health care systems. Many institutions are developing ventilator triage policies.
To characterize the development of ventilator ...triage policies and compare policy content.
Survey and mixed-methods content analysis.
North American hospitals associated with members of the Association of Bioethics Program Directors.
Program directors.
Characteristics of institutions and policies, including triage criteria and triage committee membership.
Sixty-seven program directors responded (response rate, 91.8%); 36 (53.7%) hospitals did not yet have a policy, and 7 (10.4%) hospitals' policies could not be shared. The 29 institutions providing policies were relatively evenly distributed among the 4 U.S. geographic regions (range, 5 to 9 policies per region). Among the 26 unique policies analyzed, 3 (11.3%) were produced by state health departments. The most frequently cited triage criteria were benefit (25 policies 96.2%), need (14 53.8%), age (13 50.0%), conservation of resources (10 38.5%), and lottery (9 34.6%). Twenty-one (80.8%) policies use scoring systems, and 20 of these (95.2%) use a version of the Sequential Organ Failure Assessment score. Among the policies that specify the triage team's composition (23 88.5%), all require or recommend a physician member, 20 (87.0%) a nurse, 16 (69.6%) an ethicist, 8 (34.8%) a chaplain, and 8 (34.8%) a respiratory therapist. Thirteen (50.0% of all policies) require or recommend that those making triage decisions not be involved in direct patient care, but only 2 (7.7%) require that their decisions be blinded to ethically irrelevant considerations.
The results may not be generalizable to institutions without academic bioethics programs.
Over one half of respondents did not have ventilator triage policies. Policies have substantial heterogeneity, and many omit guidance on fair implementation.
None.
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further ...studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane-bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti-CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy.
IMPORTANCE: Radical cystectomy is the guidelines-recommended treatment of muscle-invasive bladder cancer, but a resurgence of trimodal therapy has occurred. Limited comparative data are available on ...outcomes and costs attributable to these 2 treatments. OBJECTIVE: To compare the survival outcomes and costs between trimodal therapy and radical cystectomy in older adults with muscle-invasive bladder cancer. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used data from the Surveillance, Epidemiology, and End Results–Medicare linked database. A total of 3200 older adults (aged ≥66 years) with clinical stage T2 to T4a bladder cancer diagnosed from January 1, 2002, to December 31, 2011, and with claims data available through December 31, 2013, were included in the analysis. Patients who received radical cystectomy underwent either only surgery or surgery in combination with radiotherapy or chemotherapy. Patients who received trimodal therapy underwent transurethral resection of the bladder followed by radiotherapy and chemotherapy. Propensity score matching by sociodemographic and clinical characteristics was used. Data analysis was performed from August 1, 2017, to March 11, 2018. MAIN OUTCOMES AND MEASURES: Overall survival and cancer-specific survival were evaluated using the Cox proportional hazards regression model and the Fine and Gray competing risk model. All Medicare health care costs for inpatient, outpatient, and physician services within 30, 90, and 180 days of treatment were compared. The total amount spent nationwide was estimated, using 180-day medical costs between treatments, by the total number of new cases of muscle-invasive bladder cancer in the United States in 2011. RESULTS: Of the 3200 patients who met the inclusion criteria, 2048 (64.0%) were men and 1152 (36.0%) were women, with a mean (SD) age of 75.8 (6.0) years. After propensity score matching, 687 patients (21.5%) underwent trimodal therapy and 687 patients (21.5%) underwent radical cystectomy. Patients who underwent trimodal therapy had significantly decreased overall survival (hazard ratio HR, 1.49; 95% CI, 1.31-1.69) and cancer-specific survival (HR, 1.55; 95% CI, 1.32-1.83). No differences in costs at 30 days were observed between trimodal therapy ($15 233 in 2002 vs $18 743 in 2011) and radical cystectomy ($17 990 in 2002 vs $21 738 in 2011). However, median total costs were significantly higher with trimodal therapy than with radical cystectomy at 90 days ($80 174 vs $69 181; median difference, $8964; Hodges-Lehmann 95% CI, $3848-$14 079) and at 180 days ($179 891 vs $107 017; median difference, $63 771; Hodges-Lehmann 95% CI, $55 512-$72 029). Extrapolating these figures to the total US population revealed $335 million in excess spending for trimodal therapy compared with the less costly radical cystectomy ($492 million) for patients who received a muscle-invasive bladder cancer diagnosis in 2011. CONCLUSIONS AND RELEVANCE: Trimodal therapy was associated with significantly decreased overall survival and cancer-specific survival as well as $335 million in excess spending in 2011. These findings have important health policy implications regarding the appropriate use of high value–based care among older adults with invasive bladder cancer who are candidates for either radical cystectomy or trimodal therapy.
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