Summary Lung cancer is the most frequent cause of cancer-related deaths worldwide. Every year, 1·8 million people are diagnosed with lung cancer, and 1·6 million people die as a result of the ...disease. 5-year survival rates vary from 4–17% depending on stage and regional differences. In this Seminar, we discuss existing treatment for patients with lung cancer and the promise of precision medicine, with special emphasis on new targeted therapies. Some subgroups, eg—patients with poor performance status and elderly patients—are not specifically addressed, because these groups require special treatment considerations and no frameworks have been established in terms of new targeted therapies. We discuss prevention and early detection of lung cancer with an emphasis on lung cancer screening. Although we acknowledge the importance of smoking prevention and cessation, this is a large topic beyond the scope of this Seminar.
Among anxious populations, attention has been demonstrated to be preferentially biased to threatening material compared to neutral or other valenced material. Individuals who have high levels of ...trait worry, such as those with Generalized Anxiety Disorder (GAD), may be biased to threat but research has produced equivocal findings. This review aimed to systematically review the extant experimental literature to establish the current evidence of attentional bias to threat among trait worriers compared to healthy controls and other clinical populations. Twenty-nine published articles were included in the final review. There was strong evidence of a bias to threat among GAD patients compared to other groups and this was found across most experimental paradigms. Few studies had investigated this bias in non-clinical trait worriers. Among GAD patients this bias to threat was most strongly evidenced when visual threat material was in a verbal-linguistic format (i.e., words) rather than when in pictorial form (i.e., images or faces). The bias was also found across several domains of negative material, supporting the general nature of worry. Further research should look to examine the specific components of the threat bias in GAD, as well as investigating the bias to threat in trait worriers.
•Twenty-nine published articles were included in the final review.•Strong evidence of a bias to threat among people with GAD compared to other groups.•Few studies had investigated this bias in high trait worriers.•Bias to threat in people with GAD is strongest when threat material were words.
Summary Targeted therapies are substantially changing the management of lung cancers. These treatments include drugs that target driver mutations, those that target presumed important molecules in ...cancer cell proliferation and survival, and those that inhibit immune checkpoint molecules. This area of research progresses day by day, with novel target discoveries, novel drug development, and use of novel combination treatments. Researchers and clinicians have also extensively investigated the predictive biomarkers and the molecular mechanisms underlying inherent or acquired resistance to these targeted therapies. We review recent progress in the development of targeted treatments for patients with advanced non-small-cell lung cancer, especially focusing on data from published clinical trials.
The approval of anti-programmed death receptor (PD)-1 therapies for non-small cell lung cancer has directed the spotlight on programmed death ligand-1 (PD-L1) immunohistochemistry as the latest ...predictive biomarker potentially required in this disease. Several other drugs in this class will likely be approved in the future and each has been developed with a unique anti-PD-L1 immunohistochemistry test. The prospect of 5 drugs competing in the same treatment area, each possibly requiring PD-L1 immunohistochemistry testing, presents a challenge for pathologists unlike any previously faced. The key issue is whether laboratories will attempt to deliver the trial-validated assays for one or more of these treatments, or introduce instead one or more laboratory developed tests, or attempt to provide a single PD-L1 immunohistochemistry assay for all possible anti-PD-1 and anti-PD-L1 treatments that may be used. This paper discusses some of the issues, challenges, hazards, and possible solutions that have recently emerged in this most complex interface between cancer therapeutics and laboratory biomarker testing.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen‐4 (CTLA‐4), programmed cell death ligand‐1 (PD‐L1) and programmed cell ...death‐1 (PD‐1). Immunotherapy targeting the PD‐1/PD‐L1 checkpoints has shown promising efficacy in non‐small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte‐activation gene‐3 (LAG‐3) is another vital checkpoint that may have a synergistic interaction with PD‐1/PD‐L1. Here we review the LAG‐3 function in cancer, clinical trials with agents targeting LAG‐3 and the correlation of LAG‐3 with other checkpoints.
Immunotherapy in cancer is a hot topic and many oncologists want to learn about the relevant biomarkers with the current focus on CTLA 4 and PD 1/PD L1. However, also of interests are the varieties of alternative immune checkpoints including Lag 3/MHC II. In this paper, we review LAG 3 structure, function, the synergistic effects with CTLA 4 and PD 1/PD L1, as well as discussing LAG 3 clinical trials which are ongoing.
This review evaluates the importance of root exudates in determining rhizosphere bacterial community structure. We present evidence that indicates that: (1) the direct influence of root exudates on ...rhizosphere bacterial communities is limited to small spatiotemporal windows related to root apices; (2) upon rapid assimilation by microorganisms, root exudates are modified, independent of plant influences, before rerelease into the rhizosphere by the microorganisms themselves - thus, at short distances from root apices, rhizosphere carbon pools are unlikely to be dominated by root exudates; and (3) many of the major compounds found in root exudates are ubiquitous in the rhizosphere as they are found in other pools of rhizodeposits and in microbial exudates. Following this argument, we suggest that the importance of root exudates in structuring rhizosphere bacterial communities needs to be considered in the context of the wider contribution of other rhizosphere carbon pools. Finally, we discuss the implications of rhizosphere bacterial distribution trends for the development of effective strategies to manage beneficial plant-microorganism interactions.
Trends in the peak magnitude, frequency, duration, and volume of frequent floods (floods occurring at an average of two events per year relative to a base period) across the United States show large ...changes; however, few trends are found to be statistically significant. The multidimensional behavior of flood change across the United States can be described by four distinct groups, with streamgages experiencing (1) minimal change, (2) increasing frequency, (3) decreasing frequency, or (4) increases in all flood properties. Yet group membership shows only weak geographic cohesion. Lack of geographic cohesion is further demonstrated by weak correlations between the temporal patterns of flood change and large‐scale climate indices. These findings reveal a complex, fragmented pattern of flood change that, therefore, clouds the ability to make meaningful generalizations about flood change across the United States.
Key Points
One of the first studies to characterize the multidimensional behavior of flood change across the United States
Changes in frequent floods lacked geographic cohesion, with half of the streamgages experiencing no statistically significant change
Meaningful generalizations about flood change across the United States remain elusive
The Blueprint Programmed Death Ligand 1 (PD-L1) Immunohistochemistry (IHC) Assay Comparison Project is an industrial-academic collaborative partnership to provide information on the analytical and ...clinical comparability of four PD-L1 IHC assays used in clinical trials.
A total of 39 NSCLC tumors were stained with four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263), as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs.
Analytical comparison demonstrated that the percentage of PD-L1–stained tumor cells was comparable when the 22C3, 28-8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining. Of the 38 cases, 19 (50.0%) were classified above and five (13%) were classified below the selected cutoffs of all assays. For 14 of the 38 cases (37%), a different PD-L1 classification would be made depending on which assay/scoring system was used.
The Blueprint PD-L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained. All of the assays demonstrated immune cell staining, but with greater variability than with tumor cell staining. By comparing assays and cutoffs, the study indicated that despite similar analytical performance of PD-L1 expression for three assays, interchanging assays and cutoffs would lead to “misclassification” of PD-L1 status for some patients. More data are required to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs.
The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of ...harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples.
BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials.
The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient ICC = 0.86–0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18–0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78–0.85).
BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays.
Objective: Repetitive negative thinking (RNT) for example, worry in generalized anxiety disorder (GAD) and rumination in depression, is often targeted during psychological treatments. To test the ...hypothesis that negative interpretation bias contributes to worry and rumination, we assessed the effects of inducing more positive interpretations in reducing RNT. Method: Volunteers diagnosed with GAD (66) or depression (65) were randomly allocated to one of two versions of cognitive bias modification for interpretation (CBM-I), either with or without RNT priming prior to training, or a control condition, each involving 10 Internet-delivered sessions. Outcome measures of interpretation bias, a behavioral RNT task and self-reported worry, rumination, anxiety and depression were obtained at baseline, after home-based training and at 1-month follow-up (self-report questionnaires only). Results: CBM-I training, across diagnostic groups, promoted a more positive interpretation bias and led to reductions in worry, rumination, and depressive symptoms, which were maintained at follow-up. Anxiety symptoms were reduced only in the GAD group at follow-up. There were no differences between CBM-I versions; brief priming of RNT did not influence CBM-I effectiveness. Level of interpretation bias post training partially mediated the effects of CBM-I on follow-up questionnaire scores. Conclusions: In contrast to some recent failures to demonstrate improvements following Internet-delivered CBM, we found that self-reported RNT and negative mood were reduced by CBM-I. This is consistent with a causal role for negative interpretation bias in both worry and rumination, suggesting a useful role for CBM-I within treatments for anxiety and depression.
What is the public health significance of this article?
Many people worry about the future, or mull over negative events from the past (rumination). These types of unhelpful repetitive negative thinking can maintain clinical anxiety and depression. This study indicates that simple regular practice in making positive interpretations of emotionally ambiguous information reduces repetitive negative thinking in individuals with clinical anxiety or depression, and also improves mood.
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