Sanford Health

BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

Importance: Therapeutic options are needed for patients with advanced gastric cancer whose disease has progressed after 2 or more lines of therapy. Objective: To evaluate the safety and efficacy of pembrolizumab in a cohort of patients with previously treated gastric or gastroesophageal junction cancer. Design, Setting, and Participants: In the phase 2, global, open-label, single-arm, multicohort KEYNOTE-059 study, 259 patients in 16 countries were enrolled in a cohort between March 2, 2015, and May 26, 2016. Median (range) follow-up was 5.8 (0.5-21.6) months. Intervention: Patients received pembrolizumab, 200 mg, intravenously every 3 weeks until disease progression, investigator or patient decision to withdraw, or unacceptable toxic effects. Main Outcomes and Measures: Primary end points were objective response rate and safety. Objective response rate was assessed by central radiologic review per Response Evaluation Criteria in Solid Tumors, version 1.1, in all patients and those with programmed cell death 1 ligand 1 (PD-L1)-positive tumors. Expression of PD-L1 was assessed by immunohistochemistry. Secondary end points included response duration. Results: Of 259 patients enrolled, most were male (198 [76.4%]) and white (200 [77.2%]); median (range) age was 62 (24-89) years. Objective response rate was 11.6% (95% CI, 8.0%-16.1%; 30 of 259 patients), with complete response in 2.3% (95% CI, 0.9%-5.0%; 6 of 259 patients). Median (range) response duration was 8.4 (1.6+ to 17.3+) months (+ indicates that patients had no progressive disease at their last assessment). Objective response rate and median (range) response duration were 15.5% (95% CI, 10.1%-22.4%; 23 of 148 patients) and 16.3 (1.6+ to 17.3+) months and 6.4% (95% CI, 2.6%-12.8%; 7 of 109 patients) and 6.9 (2.4 to 7.0+) months in patients with PD-L1-positive and PD-L1-negative tumors, respectively. Forty-six patients (17.8%) experienced 1 or more grade 3 to 5 treatment-related adverse events. Two patients (0.8%) discontinued because of treatment-related adverse events, and 2 deaths were considered related to treatment. Conclusions and Relevance: Pembrolizumab monotherapy demonstrated promising activity and manageable safety in patients with advanced gastric or gastroesophageal junction cancer who had previously received at least 2 lines of treatment. Durable responses were observed in patients with PD-L1-positive and PD-L1-negative tumors. Further study of pembrolizumab for this group of patients is warranted. Trial Registration: clinicaltrials.gov Identifier: NCT02335411.

PURPOSE: In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680). METHODS: Patients were randomly assigned (2:1) to receive pemetrexed and platinum plus pembrolizumab (n = 410) or placebo (n = 206) every 3 weeks for 4 cycles, then pemetrexed maintenance plus pembrolizumab or placebo for up to a total of 35 cycles. Eligible patients with disease progression in the placebo-combination group could cross over to pembrolizumab monotherapy. Response was assessed per RECIST (version 1.1) by central review. No alpha was assigned to this updated analysis. RESULTS: As of September 21, 2018 (median follow-up, 23.1 months), the updated median (95% CI) OS was 22.0 (19.5 to 25.2) months in the pembrolizumab-combination group versus 10.7 (8.7 to 13.6) months in the placebo-combination group (hazard ratio [HR], 0.56; 95% CI, 0.45 to 0.70]). Median (95% CI) PFS was 9.0 (8.1 to 9.9) months and 4.9 (4.7 to 5.5) months, respectively (HR, 0.48; 95% CI, 0.40 to 0.58). Median (95% CI) time from randomization to objective tumor progression on next-line treatment or death from any cause, whichever occurred first (progression-free-survival-2; PFS-2) was 17.0 (15.1 to 19.4) months and 9.0 (7.6 to 10.4) months, respectively (HR, 0.49; 95% CI, 0.40 to 0.59). OS and PFS benefits with pembrolizumab were observed regardless of PD-L1 expression or presence of liver/brain metastases. Incidence of grade 3-5 adverse events was similar in the pembrolizumab-combination (71.9%) and placebo-combination (66.8%) groups. CONCLUSION: First-line pembrolizumab plus pemetrexed-platinum continued to demonstrate substantially improved OS and PFS in metastatic nonsquamous NSCLC, regardless of PD-L1 expression or liver/brain metastases, with manageable safety and tolerability.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

The Human Phenotype Ontology (HPO)-a standardized vocabulary of phenotypic abnormalities associated with 7000+ diseases-is used by thousands of researchers, clinicians, informaticians and electronic health record systems around the world. Its detailed descriptions of clinical abnormalities and computable disease definitions have made HPO the de facto standard for deep phenotyping in the field of rare disease. The HPO's interoperability with other ontologies has enabled it to be used to improve diagnostic accuracy by incorporating model organism data. It also plays a key role in the popular Exomiser tool, which identifies potential disease-causing variants from whole-exome or whole-genome sequencing data. Since the HPO was first introduced in 2008, its users have become both more numerous and more diverse. To meet these emerging needs, the project has added new content, language translations, mappings and computational tooling, as well as integrations with external community data. The HPO continues to collaborate with clinical adopters to improve specific areas of the ontology and extend standardized disease descriptions. The newly redesigned HPO website (www.human-phenotype-ontology.org) simplifies browsing terms and exploring clinical features, diseases, and human genes.

PURPOSE: To assess the reliability and reproducibility of automated large-core breast biopsy. MATERIALS AND METHODS: A consortium of 20 institutions reported, in a standardized fashion, their core breast biopsy data. All biopsies were performed with "long-throw" (2.3-cm) automated core biopsy devices fitted with 14-gauge needles. Needle guidance was accomplished by means of either a dedicated, stereotaxic device, in which the patient lies in the prone position, or high-frequency electronically focused ultrasound equipment. RESULTS: The data in 6,152 lesions were gathered. Clinical or surgical follow-up was available in 3,765 lesions; 1,363 of these lesions were subsequently surgically excised, and the core histologic study showed cancer in 910 lesions, mammary intraepithelial neoplasia in 173 lesions, and benign disease in 280 lesions. In these 280 lesions, there were 15 false-negative core biopsies. CONCLUSION: The data show that percutaneous large-core breast biopsy is a reproducible and reliable alternative to surgical biopsy.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin-affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. © 2018 by John Wiley & Sons, Inc.

Abstract BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin‐affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. © 2018 by John Wiley &amp; Sons, Inc.

OBJECTIVE: The current study investigated changes in neuropsychologists' validity testing beliefs and practices since publication of the last North American survey targeting these issues in 2007 and explored emerging issues in validity testing that had not been previously addressed in the professional survey literature. METHODS: Licensed North American neuropsychologists (n = 316), who primarily evaluate adults, were surveyed in regard to the following topics: (1) comparison of objective validity testing, qualitative data, and clinical judgment; (2) approaches to validity test administration; (3) formal communication in cases of suspected malingering; (4) reporting of validity test results; (5) suspected causes of invalidity; (6) integration of stand-alone, embedded, and symptom-report validity measures; (7) multiple performance validity test interpretation; (8) research practices; and (9) popularity of specific validity instruments. RESULTS: Overall, findings from the current survey indicated that all but a small minority of respondents routinely utilize validity testing in their examinations. Furthermore, nearly all neuropsychologists surveyed believed formal validity testing to be mandatory in forensic evaluations and at least desirable in clinical evaluations. While results indicated general agreement among neuropsychologists across many aspects of validity testing, responses regarding some facets of validity test implementation, interpretation, and reporting were more variable. Validity testing utilization generally did not differ according to level of forensic involvement but did vary in respect to respondent literature consumption. CONCLUSIONS: Study findings differ significantly from past professional surveys and indicate an increased utilization of validity testing, suggesting a pronounced paradigm shift in neuropsychology validity testing beliefs and practices.

Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.

Cervical cancer is the second most common female tumor worldwide, and its incidence is disproportionately high (>80%) in the developing world. In the United States, in which Papanicolaou (Pap) tests have reduced the annual incidence to approximately 11,000 cervical cancers, >60% of cases are reported to occur in medically underserved populations as part of a complex of diseases linked to poverty, race/ethnicity, and/or health disparities. Because carcinogenic human papillomavirus (HPV) infections cause virtually all cervical cancer, 2 new approaches for cervical cancer prevention have emerged: 1) HPV vaccination to prevent infections in younger women (aged < or =18 years) and 2) carcinogenic HPV detection in older women (aged > or =30 years). Together, HPV vaccination and testing, if used in an age-appropriate manner, have the potential to transform cervical cancer prevention, particularly among underserved populations. Nevertheless, significant barriers of access, acceptability, and adoption to any cervical cancer prevention strategy remain. Without understanding and addressing these obstacles, these promising new tools for cervical cancer prevention may be futile. In the current study, the delivery of cervical cancer prevention strategies to these US populations that experience a high cervical cancer burden (African-American women in South Carolina, Alabama, and Mississippi; Haitian immigrant women in Miami; Hispanic women in the US-Mexico Border; Sioux/Native American women in the Northern Plains; white women in the Appalachia; and Vietnamese-American women in Pennsylvania and New Jersey) is reviewed. The goal was to inform future research and outreach efforts to reduce the burden of cervical cancer in underserved populations.

Doxorubicin (DOX) is a potent anti-tumor drug known to cause heart failure. The transcription factor GATA4 antagonizes DOX-induced cardiotoxicity. However, the protective mechanism remains obscure. Autophagy is the primary cellular pathway for lysosomal degradation of long-lived proteins and organelles, and its activation could be either protective or detrimental depending on specific pathophysiological conditions. Here we investigated the ability of GATA4 to inhibit autophagy as a potential mechanism underlying its protection against DOX toxicity in cultured neonatal rat cardiomyocytes. DOX markedly increased autophagic flux in cardiomyocytes as indicated by the difference in protein levels of LC3-II (microtubule-associated protein light chain 3 form 2) or numbers of autophagic vacuoles in the absence and presence of the lysosomal inhibitor bafilomycin A1. DOX-induced cardiomyocyte death determined by multiple assays was aggravated by a drug or genetic approach that activates autophagy, but it was attenuated by manipulations that inhibit autophagy, suggesting that autophagy contributes to DOX cardiotoxicity. DOX treatment depleted GATA4 protein levels, which predisposed cardiomyocytes to DOX toxicity. Indeed, GATA4 gene silencing triggered autophagy that rendered DOX more toxic, whereas GATA4 overexpression inhibited DOX-induced autophagy, reducing cardiomyocyte death. Mechanistically, GATA4 up-regulated gene expression of the survival factor Bcl2 and suppressed DOX-induced activation of autophagy-related genes, which may likely be responsible for the anti-apoptotic and anti-autophagic effects of GATA4. Together, these findings suggest that activation of autophagy mediates DOX cardiotoxicity, and preservation of GATA4 attenuates DOX cardiotoxicity by inhibiting autophagy through modulation of the expression of Bcl2 and autophagy-related genes.

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

There are few medical issues that have generated as much controversy as screening for breast cancer. In science, controversy often stimulates innovation; however, the intensely divisive debate over mammographic screening has had the opposite effect and has stifled progress. The same two questions-whether it is better to screen annually or bi-annually, and whether women are best served by beginning screening at 40 or some later age-have been debated for 20 years, based on data generated three to four decades ago. The controversy has continued largely because our current approach to screening assumes all women have the same risk for the same type of breast cancer. In fact, we now know that cancers vary tremendously in terms of timing of onset, rate of growth, and probability of metastasis. In an era of personalized medicine, we have the opportunity to investigate tailored screening based on a woman's specific risk for a specific tumor type, generating new data that can inform best practices rather than to continue the rancorous debate. It is time to move from debate to wisdom by asking new questions and generating new knowledge. The WISDOM Study (Women Informed to Screen Depending On Measures of risk) is a pragmatic, adaptive, randomized clinical trial comparing a comprehensive risk-based, or personalized approach to traditional annual breast cancer screening. The multicenter trial will enroll 100,000 women, powered for a primary endpoint of non-inferiority with respect to the number of late stage cancers detected. The trial will determine whether screening based on personalized risk is as safe, less morbid, preferred by women, will facilitate prevention for those most likely to benefit, and adapt as we learn who is at risk for what kind of cancer. Funded by the Patient Centered Outcomes Research Institute, WISDOM is the product of a multi-year stakeholder engagement process that has brought together consumers, advocates, primary care physicians, specialists, policy makers, technology companies and payers to help break the deadlock in this debate and advance towards a new, dynamic approach to breast cancer screening.

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors) prevent heart failure (HF) hospitalizations in patients with type 2 diabetes and improve outcomes in those with HF and reduced ejection fraction, regardless of type 2 diabetes. Mechanisms of HF benefits remain unclear, and the effects of SGLT2 inhibitor on hemodynamics (filling pressures) are not known. The EMBRACE-HF trial (Empagliflozin Evaluation by Measuring Impact on Hemodynamics in Patients With Heart Failure) was designed to address this knowledge gap. Methods: EMBRACE-HF is an investigator-initiated, randomized, multicenter, double-blind, placebo-controlled trial. From July 2017 to November 2019, patients with HF (regardless of ejection fraction, with or without type 2 diabetes) and previously implanted pulmonary artery (PA) pressure sensor (CardioMEMS) were randomized across 10 US centers to empagliflozin 10 mg daily or placebo and treated for 12 weeks. The primary end point was change in PA diastolic pressure (PADP) from baseline to end of treatment (average PADP weeks 8–12). Secondary end points included health status (Kansas City Cardiomyopathy Questionnaire score), natriuretic peptides, and 6-min walking distance. Results: Overall, 93 patients were screened, and 65 were randomized (33 to empagliflozin, 32 to placebo). The mean age was 66 years; 63% were male; 52% had type 2 diabetes; 54% were in New York Heart Association class III/IV; mean ejection fraction was 44%; median NT-proBNP (N-terminal pro B-type natriuretic peptide) was 637 pg/mL; and mean PADP was 22 mm Hg. Empagliflozin significantly reduced PADP, with effects that began at week 1 and amplified over time; average PADP (weeks 8–12) was 1.5 mm Hg lower (95% CI, 0.2–2.8; P =0.02); and at week 12, PADP was 1.7 mm Hg lower (95% CI, 0.3–3.2; P =0.02) with empagliflozin versus placebo. Results were consistent for PA systolic and PA mean pressures. There was no difference in mean loop diuretic management (daily furosemide equivalents) between treatment groups. No significant differences between treatment groups were observed in Kansas City Cardiomyopathy Questionnaire scores, natriuretic peptide levels, and 6-min walking distance. Conclusions: In patients with HF and CardioMEMS PA pressure sensor, empagliflozin produced rapid reductions in PA pressures that were amplified over time and appeared to be independent of loop diuretic management. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030222.

IMPORTANCE: Administration of pembrolizumab plus concurrent chemoradiation therapy (cCRT) may provide treatment benefit to patients with locally advanced, stage III non-small cell lung cancer (NSCLC). OBJECTIVE: To evaluate treatment outcomes and safety of pembrolizumab plus cCRT in stage III NSCLC. DESIGN, SETTING, AND PARTICIPANTS: The phase 2, nonrandomized, 2-cohort, open-label KEYNOTE-799 study enrolled patients between November 5, 2018, and July 31, 2020, from 52 academic facilities and community-based institutions across 10 countries. As of October 28, 2020, median (range) follow-up was 18.5 (13.6-23.8) months in cohort A and 13.7 (2.9-23.5) months in cohort B. Of 301 patients screened, 216 eligible patients with previously untreated, unresectable, and pathologically/radiologically confirmed stage IIIA/IIIB/IIIC NSCLC with measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) were enrolled. INTERVENTIONS: Patients in cohort A (squamous/nonsquamous) received 1 cycle (3 weeks) of carboplatin (area under the curve [AUC] 6 mg/mL/min), paclitaxel (200 mg/m2), and pembrolizumab (200 mg), followed by carboplatin (AUC 2 mg/mL/min) and paclitaxel (45 mg/m2) once weekly for 6 weeks and 2 cycles of pembrolizumab plus standard thoracic radiotherapy. Patients in cohort B (nonsquamous) received 3 cycles of cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and pembrolizumab (200 mg) every 3 weeks and thoracic radiotherapy in cycles 2 and 3. Patients received 14 additional cycles of pembrolizumab. MAIN OUTCOMES AND MEASURES: Coprimary end points were objective response rate per RECIST v1.1 by blinded independent central review and incidence of grade 3 to 5 pneumonitis. RESULTS: A total of 112 patients received treatment in cohort A (76 men [67.9%]; median [range] age, 66.0 [46-90] years; 66 patients [58.9%] with programmed cell death ligand 1 [PD-L1] tumor proportion score ≥1%) and 102 patients received treatment in cohort B (62 men [60.8%]; median [range] age, 64.0 [35-81] years; 40 patients [39.2%] with PD-L1 tumor proportion score ≥1%). Objective response rate was 70.5% (79 of 112; 95% CI, 61.2%-78.8%) in cohort A and 70.6% (72 of 102; 95% CI, 60.7%-79.2%) in cohort B. Median duration of response was not reached, but 79.7% and 75.6%, respectively, had response duration of 12 months or longer. Grade 3 or higher pneumonitis occurred in 9 of 112 patients (8.0%) in cohort A and 7 of 102 (6.9%) in cohort B. Grade 3 to 5 treatment-related adverse events occurred in 72 of 112 (64.3%) and 51 of 102 (50.0%) patients, respectively. CONCLUSIONS AND RELEVANCE: The findings of this phase 2, nonrandomized, 2-cohort study suggest promising antitumor activity of pembrolizumab plus cCRT and manageable safety in patients with previously untreated, locally advanced, stage III NSCLC.

The health effects of omega-3 fatty acids have been controversial. Here we report the results of a de novo pooled analysis conducted with data from 17 prospective cohort studies examining the associations between blood omega-3 fatty acid levels and risk for all-cause mortality. Over a median of 16 years of follow-up, 15,720 deaths occurred among 42,466 individuals. We found that, after multivariable adjustment for relevant risk factors, risk for death from all causes was significantly lower (by 15-18%, at least p < 0.003) in the highest vs the lowest quintile for circulating long chain (20-22 carbon) omega-3 fatty acids (eicosapentaenoic, docosapentaenoic, and docosahexaenoic acids). Similar relationships were seen for death from cardiovascular disease, cancer and other causes. No associations were seen with the 18-carbon omega-3, alpha-linolenic acid. These findings suggest that higher circulating levels of marine n-3 PUFA are associated with a lower risk of premature death.

There are 22.3 million people in the United States with diabetes, of whom 15–25% are at risk for foot ulceration. Diabetic foot ulcers (DFUs) are a growing health problem. DFUs are a leading cause of infection, amputation, and hospitalization in patients with diabetes mellitus. Guidelines for the treatment of DFUs were published by the Wound Healing Society (WHS) in 2006. However, in the past few years new evidence has emerged that improves our understanding of previous recommendations. The objectives of the WHS DFU guidelines are to systematically evaluate the medical literature to assist clinicians in making health care decisions, identify areas that need additional research, and to clarify controversial diagnosis and treatment strategies. An advisory panel comprised of academicians, clinicians, researchers, and industry representatives was chosen to update the 2006 guidelines. In 2006, in an effort to develop guidelines that could provide clinicians with a reasonable approach to caring for patients, even in the absence of high quality human data, the WHS developed guidelines using a different approach to evidence citations and past approaches to evidence-based guidelines. Most past approaches relied only on publications regarding clinical human studies. Laboratory or animal studies were not cited. We have used well-controlled animal studies that present proof of principle, especially when a clinical series corroborated the laboratory results. Because of this variation, a different system was used to grade the weight of evidence supporting a given guideline. The strength of evidence supporting a guideline is listed as Level I, Level II, or Level III. Since the 2006 guidelines, we sought to capture the highest quality of literature available regarding DFU diagnosis and treatment using a key word search of PubMed, Embase, and Cochrane Library databases. Similarly, the citations of relevant articles were examined by hand. Key terms were generated from the existing guidelines. In this search as opposed to the previous data collection prior to 2006, we used human and disease specific data and limited to meta-analyses, systematic reviews, RCTs, retrospective series reviews, clinical case series, and expert panel recommendations published between January 2006 and present. References prior to 2006 supporting the original guideline recommendations are not included. Therefore, in some cases no additional updated references were included and the support for the guideline recommendation is based on evidence presented in the 2006 guideline. Therefore, no updated references are presented. It was further limited to only English publications. Any relevant additional references found after the formal search were also included. The findings of these articles have been divided into one or more of the appropriate categories as performed in the original guideline Each of the separate guidelines has undergone a Delphi consensus among the panel members. Not all panel members thought they had sufficient expertise to critique all of the separate sections of the guidelines. The first draft was of the guidelines was presented in 2014 for public comment and subsequent drafts revised based on those comments. Evidence Reference: Preamble: Ulcers of the lower extremity may be caused by a variety of conditions, including neuropathy, ischemia, venous hypertension, and pressure. Patients with diabetes develop wounds secondary to neuropathy with or without biomechanical abnormalities, peripheral vascular disease with ischemia, or both. There are over 20 million people in the United States with diabetes, of whom 15–25% are at risk for ulceration. It is imperative that the etiology be established to provide for proper therapy. Guideline #1.1: Clinically significant arterial disease should be ruled out by establishing that pedal pulses are clearly palpable or that the ankle:brachial index (ABI) is > 0.9. An ABI > 1.3 suggests noncompressible arteries. In elderly patients or patients with an ABI > 1.2, a normal Doppler-derived waveform, a toe:brachial index of > 0.7, or a transcutaneous oxygen pressure of > 40 mmHg and/or hyperspectral imaging analysis may help to suggest an adequate arterial flow. Color duplex ultrasound scanning provides anatomic and physiologic data confirming an ischemic etiology for the leg wound. (Level I) Principle: Diabetic ulcers can result from arterial insufficiency or neuropathy. Although clinical history and physical examination can be very suggestive of an ischemic etiology of the lower extremity diabetic ulcers, a definitive diagnosis must be established. When significant arterial disease is present, successful treatment requires that arterial insufficiency be addressed. Updated Evidence: Guideline #1.2: The presence of significant neuropathy can be determined by testing with a 10 g (5.07) Semmes–Weinstein monofilament. (Level II) Principle: Diabetic sensory neuropathy creates an environment in which repetitive trauma, injury and infection are unrecognized by the patient. Several simple clinical techniques can be used to identify sensory neuropathy with loss of protective sensation. The presence of sensory neuropathy can be determined by testing with a 10 g Semmes Weinstein monofilament, 128 Hz tuning fork, vibration perception threshold testing or a good neurological clinical examination for sensory loss. Updated Evidence: Preamble: Diabetic ulcerations on the sole of the foot are often associated with moderate to high pressures because of foot deformity, limited joint mobility, and neuropathy. Off-loading devices reduce pressure on the sole of the foot and often reduce the activity level of the patient. Off-loading the area of high pressure has been the mainstay to heal DFUs and prevent recurrence of foot ulcerations (Level I). Guideline #2.1: Protective footwear should be prescribed in any patient at risk for amputation (significant arterial insufficiency, significant neuropathy, previous amputation, previous ulcer formation, preulcerative callus, foot deformity, evidence of callus formation). (Level II) Protective footwear results in reduction in recurrent ulcerations in high-risk patients with a previous foot ulcer or amputation. (Level I). Principle: The etiology of many foot ulcers involves a biomechanical component. Most treatments do not eliminate the underlying biomechanical etiology of the foot ulcer. Abnormal pressure and shear stress is still present, so long-term off-loading is necessary. By reducing pressure and shear forces on the sole of the foot, repetitive injury to the foot is reduced, and existing wounds can heal or high-risk areas are protected from recurrent ulcers. Updated Evidence: Guideline #2.2: Acceptable methods of offloading include crutches, walkers, wheelchairs, custom shoes, depth shoes, shoe modifications, custom inserts, custom relief orthotic walkers, diabetic boots, forefoot and heel relief shoes, and total contact casts. (Level I) Principle: Relieving pressure on the diabetic wound is necessary to maximize healing potential. Updated Evidence: Preamble: Infection results when the bacteria: host defense equilibrium is upset in favor of the bacteria. Infection plays various roles in the etiology, healing, operative repair, and complications of diabetic ulcers. Guideline #3.1: Remove all necrotic or devitalized tissue by surgical, enzymatic, mechanical, biological, or autolytic debridement. (Level II; detailed discussion of debridement is in Wound Preparation Guidelines). Principle: Devitalized tissue provides a safe haven for bacterial proliferation, a barrier for antibiotics to reach bacterial pathogens. In addition, it limits the body's cellular defenses to fight infection. Removal of devitalized tissue reduces bacterial bioburden. Updated Evidence: Guideline #3.2: If there is suspected infection in a debrided ulcer, or if epithelialization from the margin is not progressing within two weeks of debridement and initiation of offloading therapy, determine the type and level of infection in a debrided diabetic ulcer by tissue biopsy or by a validated quantitative swab technique. (Level II) Principle: High levels of bacteria (≥106 CFU/g of tissue) impede wound healing and surgical wound closure. Reduction of the bacterial bioburden in the wound reduces the risk of clinical infection and improves wound healing. Cultures should be performed to isolate both aerobic and anaerobic bacteria. Updated Evidence: Guideline #3.3: For ulcers with levels of bacteria (>105 CFU/g of tissue) following adequate debridement, topical antimicrobial agent can decrease the bacterial levels. Once in bacterial balance, topical antimicrobial agent should be discontinued to minimize cytotoxic effects and emergence of bacterial resistance organisms. (Level I). Principle: Systemically administered antibiotics do not effectively decrease bacterial levels in granulating wounds, Topically applied antimicrobials can be effective to decrease bacterial levels in granulating wounds. Updated Evidence: Guidelines #3.4: Topical antimicrobial and antiseptic therapies are not effective to improve wound healing (Level I). Principle: New to the guidelines is evidence that topical antimicrobial and antiseptic therapies, while decreasing bioburden, do not improve wound healing. Updated Evidence: Guideline #3.5: For acute diabetic foot infections not confined to the granulating wound, systemic antibiotics are effective. (Level II) Principle: Systemic antibiotics have been demonstrated in most trials to be helpful in treating acute diabetic foot infections. Deep tissue cultures are most helpful in determining antibiotic usage. Updated Evidence: Guideline #3.6: Cellulitis (inflammation and infection of the skin and subcutaneous tissue most commonly due to streptococci or staphylococci) surrounding the ulcer should be treated with systemic Gram-positive bactericidal antibiotics. (Level II) Principle: Edema fluid (plasma) neutralizes the fatty acids of sebum and inactivates the normal bactericidal properties of skin. This renders the skin and subcutaneous tissue susceptible to infection by streptococci or staphylococci. Gram positive bacteria are the most common pathogens in cellulitis in DFUs. Updated Evidence: Guideline #3.7: If osteomyelitis is suspected, appropriate diagnostic measures include bone biopsy, probing the wound area to the bone with a sterile instrument, serial x-rays, MRI, CT and radionucleid scans. (Level II). PET leukocyte screening, and Tc99m WBC labeled-SPECT/CT. (Level II) Principle: Bone underlying a diabetic ulcer is often infected. Biopsy of the bone gives a definitive diagnosis, but less invasive techniques can be useful in establishing a diagnosis with a high degree of specificity and sensitivity. Updated Evidence: Guideline 3.8: If osteomyelitis is suspected, determine the type of bacterial pathogens by bone biopsy (Level II). Principle: Culture-directed antibiotic treatment seems to provide better clinical outcomes than empiric therapy. If diabetic foot osteomyelitis (DFO) is suspected, bone specimens should be obtained to identify the bacterial pathogens and to direct antibiotic therapy. Since the last publication of the WHS guidelines, data has emerged suggesting that culture-directed antibiotic treatment results in enhanced outcomes in osteomyelitis. Therefore, we have added this guideline to suggested treatment approaches to advance treatment of bioburden that results in osteomyelitis. Updated Evidence: Guideline #3.9: Osteomyelitis is best treated by removal of the infected bone, followed by 2–4 weeks of antibiotics. However, when this is not practical, osteomyelitis underlying a diabetic ulcer can be effectively treated with prolonged antibiotic therapy. (Level II) Principle: Osteomyelitis underlying a diabetic ulcer, like osteomyelitis elsewhere, is most effectively treated by debridement of the infected bone. When debridement has been adequate, a 2–4-week course of antibiotics is adequate. If the infected bone is not totally resected, a longer course (at least 6 weeks) is usually required. Updated Evidence: Guideline #3.10: Minimize the tissue level of bacteria, preferably to 105 CFU/g of tissue with no beta hemolytic Streptococci in the ulcer before attempting surgical closure by skin graft, skin equivalent, pedicled, or free flap. (Level II) Principle: A wound containing contaminated foci with greater than 105 organisms per gram of tissue cannot be readily closed, as the incidence of wound infection that follows is 50–100%. Updated Evidence: None. (Detailed discussions of infection control, dressings, and tissue engineering/growth factors are in infection control guidelines, dressings guidelines, and adjuvant agents [topical, device, and systemic] guidelines). Preamble: Wound bed preparation is defined as the management of the wound to accelerate endogenous healing or facilitate the effectiveness of other therapeutic measures. The aim of wound bed preparation is to convert the molecular and cellular environment of a chronic wound to that of an acute healing wound. Guideline #4.1: Examination of the patient as a whole is important to evaluate and correct causes of tissue damage. This includes factors such as: (A) systemic diseases and medications, (B) nutrition, and (C) tissue perfusion and oxygenation. (Level I) Principle: (4.1.A) A general medical history, including a medication record, will help in identifying and correcting systemic causes of impaired healing. The presence of a major illness or systemic disease and drug therapies such as immunosuppressive drugs and systemic steroids will interfere with wound healing by alterations in immune functioning, metabolism, inflammation, nutrition, and tissue perfusion. Autoimmune diseases such as rheumatoid arthritis, uncontrolled vasculitis, or pyoderma gangrenosum can all delay healing and may require systemic steroids or immunosuppressive agents before local wound healing can occur. Patients undergoing major surgery have a diminished wound-healing capacity as do chronic smokers. Smoking is associated with impaired wound healing and increased risk of infection. Updated Evidence: Principle: (4.1.B) Nutrition must be adequate to provide sufficient protein to support the growth of granulation tissue. The patient's weight, prealbumin level (reflecting recent protein consumption), and serum albumin (reflecting long-term protein consumption) are useful in identifying patients who are outside the norms. Although most diabetic ulcer patients are ambulatory and not at the extremes of nutrition, nutritional support is required if an individual is undernourished. Updated Evidence: Principle: (4.1.C) Wounds will heal in an environment that is adequately oxygenated. Oxygen delivery to the wound will be impaired if tissue perfusion is inadequate. Dehydration and factors that increase sympathetic tone such as cold, stress, or pain will decrease tissue perfusion. Cigarette smoking decreases tissue oxygen by peripheral vasoconstriction. For optimal tissue perfusion, these factors must be eliminated or minimized. Updated Evidence: Guideline #4.2: Initial debridement is required to remove the obvious necrotic tissue, excessive bacterial burden, and cellular burden of dead and senescent cells. Maintenance debridement is needed to maintain the appearance and readiness of the wound bed for healing. The health care provider can choose from a number of debridement methods including surgical, enzymatic, mechanical, biological, or autolytic. More than one debridement method may be appropriate. (Sharp surgical debridement is preferred; Level I). Principle: Necrotic tissue, excessive bacterial burden, senescent cells, and cellular debris can all inhibit wound healing. The method of debridement chosen may depend on the status of the wound, the capability of the health provider, the overall condition of the patient, and professional licensing restrictions. Updated Evidence: Guideline #4.3: Wounds should be cleansed initially and at each dressing using a wound should be with a of and/or (Level Principle: and the wound to wound healing. or is usually should only be used if the is data suggest that a may be useful as may fluid by increased pressure. Updated Evidence: Guideline There should be an and of wound history, and condition of the surrounding and to evaluate wound bed The of wound healing should be to determine treatment is (Level II) Principle: of wound bed preparation are if the ulcer is not healing at the for wound bed preparation need to be The longer the of the ulcer, the more it is to If an ulcer is etiology, patient or of and long-term need to be Updated Evidence: Guideline Patients who to a reduction in ulcer by or more after weeks of should be and other treatments should be (Level II) Principle: in wound area of DFUs over weeks of treatment is a good of effectiveness of and of healing. Updated Evidence: Guideline control improves wound healing. (Level II) Principle: Wound healing is more to be optimal in the of good diabetes Abnormal levels also the of infection and cellular Updated Evidence: Preamble: There are a number of topical therapies available for DFUs. Most dressings are used in with debridement, and infection It is thought that a wound environment and There are that should be when a dressing including the for and wound dressings should not the wound. If the wound and surrounding tissue have contact with wound the local tissue can and impede healing. dressings that are not can cause to the surrounding skin or wound The of health care provider healing and the of dressings should be when determining clinical studies have not that any dressing approach is more effective than to facilitate wound healing. Guideline a dressing that will maintain a wound-healing (Level Principle: A wound environment and while healing of wounds by autolytic debridement. Updated Evidence: Guideline clinical to a wound (Level Principle: dressings are not dressings are as effective as other of wound healing in terms of healing This guideline has not the 2006 recommendations. However, additional on adjuvant agents and dressings is available in Guideline Updated Evidence: None. Guideline a dressing that will the wound and the skin. (Level I) Principle: and contact with wound can the wound and impede healing. Updated Evidence: None. Guideline a dressing that in shear and and not cause additional tissue damage. (Level II) Principle: Wound skin and patient activity can all the of Updated Evidence: None. Guideline a dressing that is effective. (Level I) Principle: Because of dressings are often as the least most However, when determining it is important to into health care provider of and healing as as the of the Updated Evidence: None. Guideline adjuvant agents device, and/or after a patient and ulcer and when there is a of healing in to more (Level I) (Detailed discussions of these are in Principle: therapies and devices may and increase healing in patients or wounds. therapies are and are in in the Updated Evidence: Evidence references are detailed in the Systemic Guidelines). Preamble: The of dressings and offloading are not successful in healing all diabetic ulcers. the surgical have been to diabetic ulcers with of clinical trials operative techniques are but data are available supporting surgery in Guideline improves healing of diabetic forefoot wounds. (Level II) the reduces pressure on forefoot ulcers in patients with limited of the has been associated with a reduction in ulcer recurrence (Level I). Principle: A to increased forefoot the reduces pressure on forefoot ulcers in patients with limited and may be of in healing DFUs. Updated Evidence: Guideline Patients with should be for a and in are associated with a significant in ulcer healing. (Level Principle: In patients with arterial in is associated with an increase in nutrition, and wound healing. Updated Evidence: Preamble: agents have been suggested to be used as to dressings and off-loading in the treatment of diabetic ulcers. adjuvant agents can be divided into topical agents to be applied to the ulcer, devices at ulcer healing, and systemic drugs to the patient. Several of these agents have evidence to guidelines regarding Guideline of growth reduces the to heal and the of ulcers that (Level I) Principle: growth factors are in wound healing. Diabetic foot wounds are in growth of growth factors to wounds can accelerate wound healing. Updated Evidence: Guideline and growth factors have demonstrated with healing. (Level I) Principle: and growth factors are in wound healing. Updated Evidence: Guideline (Level and growth (Level II) have not demonstrated an increase in the of wounds that heal and the healing of DFUs. Principle: There is one systematic and with and that suggest no wound healing Updated Evidence: Guideline pressure wound has been to increase the of wounds that heal and the of wound healing with wound care in diabetic lower extremity wounds. (Level I) Principle: treatment may improve wound healing by reducing bacterial and the of the wound, and should be when other treatments are not effective. Updated Evidence: Guideline and skin improve DFU healing. (Level I) Principle: skin assist in healing DFUs by therapeutic of growth and other that the wound Updated Evidence: Guideline is to accelerate wound closure. (Level I) Principle: of to diabetic foot wounds local tissue perfusion and may protein and bacterial growth to improve wound healing. Updated Evidence: Guideline diabetic ulcer healing (Level I). Principle: has been used in a variety of clinical for repair, and wound healing. for patients with diabetic foot ulcers. Updated Evidence: Guideline oxygen should be used to improve wound healing and reduce major amputation (Level I). Principle: oxygen may increase the of oxygen to a wound in diabetic patients and improve healing. Updated Evidence: Preamble: Diabetic ulcers of the lower extremity are a chronic problem. are Therefore, must be even for ulcers. Guideline Patients with diabetic ulcers should protective footwear to prevent (Level I) Principle: Most treatments do not eliminate the underlying increased pressure on the foot, so offloading is necessary Updated Evidence: Guideline foot care and of the will not reduce the recurrence of diabetic ulceration. (Level I) Principle: There is data regarding the effectiveness of good foot care including proper will reduce in diabetic such as good foot care proper and care should be included as of a care that includes professional foot and therapeutic and Updated Evidence: Guideline of foot with an reduces (Level I). Principle: areas of increased are a of and tissue injury that the of ulceration. By of patients could identify of tissue and reduce activity to the of an ulceration. Updated Evidence: