Genetic Medicine:

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Can meditation slow rate of cellular aging? Cognitive …


Understanding the malleable determinants of cellular aging is critical to understanding human longevity. Telomeres may provide a pathway for exploring this question. Telomeres are the protective caps at the ends of chromosomes. The length of telomeres offers insight into mitotic cell and possibly organismal longevity. Telomere length has now been linked to chronic stress exposure and depression. This raises the question of how might cellular aging be modulated by psychological functioning.

We consider two psychological processes or states that are in opposition to one another–threat cognition and mindfulness–and their effects on cellular aging. Psychological stress cognitions, particularly appraisals of threat and ruminative thoughts, can lead to prolonged states of reactivity. In contrast, mindfulness meditation techniques appear to shift cognitive appraisals from threat to challenge, decrease ruminative thought, and reduce stress arousal. Mindfulness may also directly increase positive arousal states.

We review data linking telomere length to cognitive stress and stress arousal and present new data linking cognitive appraisal to telomere length. Given the pattern of associations revealed so far, we propose that some forms of meditation may have salutary effects on telomere length by reducing cognitive stress and stress arousal and increasing positive states of mind and hormonal factors that may promote telomere maintenance. Aspects of this model are currently being tested in ongoing trials of mindfulness meditation.

Keywords: meditation, mindfulness, stress, appraisal, rumination, telomere length, telomerase

Chronological age is the ultimate predictor of disease and death. However, tremendous individual variability is found in onset of morbidity and mortality. Therefore, it is of great scientific and clinical interest to identify markers of biological age, as well as factors that influence them. Telomere length (TL) appears to be such an indicator. TL shortens with chronological age, predicts risk factors for cardiovascular disease (CVD) independent of age, and is shortened in people with age-related diseases, including atherosclerosis and diabetes.1 Stress appears to influence the rate of telomere shortening.2 Here we examine links between TL, stress arousal, and stress cognitions, and consider how mindfulness meditation might alter these pathways, as well as have direct effects independent of stress pathways.

There are specific types of stress cognitions that lead to greater stress arousal and thus may impact cell longevity. Threat appraisals enhance negative emotional responses to a stressor by construing it as a threat to oneself and amplifying the significance of the stressor. In addition to the content of an appraisal, the process of rumination about negative appraisals prolongs the stress arousal, and can induce distress about the emotional response itself. These two types of stress cognition then trigger negative emotional responses tied to specific forms of physiological arousal (high catabolic, low anabolic profiles) which can impair telomere length.

Mindfulness is a psychological process that acts on specific parts of this cognitive content and process, disrupting the stress pathways and possibly having direct salutary effects on physiological arousal systems. Based on a combination of empirical data and speculation, we propose that these processes, stress cognition and mindfulness, may be linked to cellular aging, shown in . Below we offer a selective review on the literatures of cell aging (telomeres and telomerase), stress cognition (threat appraisals and rumination) and their effects on arousal relevant to telomere maintenance, and lastly, the potential impact of mindfulness and meditation on these stress processes.

Model of Mindfulness Meditation Effects on Telomere Length through Positive and Stressful Cognitive States

Telomeres provide a unique model for understanding cell aging and senescence. Telomeres are the protective nucleoprotein structures capping the ends of eukaryotic chromosomes, consisting of a simple repeat sequence (TTAGGG). When cells divide, the end of the telomere cap may not be replicated because the DNA polymerase does not function properly at the end of a DNA strand.3 Therefore telomeres tend to shorten with mitosis so that cells in older organisms have on average shorter telomeres than cells in younger organisms.

Telomerase is a ribonucleoprotein reverse transcriptase cellular enzyme that counteracts TL shortening and adds telomeric DNA to shortened telomeres. Telomerase thus forestalls shortened telomeres from signaling the cell to cease dividing or to die. Telomerase promotes cell longevity even in the face of critically shortened telomeres.4 Conversely, cells with short telomeres without telomerase are at highest risk of fusions, senescence, and apoptosis.5,6 Thus, it is in part the interaction between short telomeres and low telomerase activity that appears to increase the risk of cell death.7

Telomere shortening and replicative senescence is thought to be indicative of bodily aging. Several genetic premature aging syndromes are characterized by cell sencescence (Werner Syndrome, Progeria Hutchinson Guilford, and ataxia teleangiecstasia); at least when subjects cells are examined in vitro, and are characterized by signs of accelerated aging and early mortality.8 There is a proliferation of research in this area, and many studies show that TL is linked to a variety of disease states. Shorter TL is related to aspects of cardiovascular disease, such as plaques,9 heart attacks10 greater calcific aortic valve stenosis 11, vascular dementia 12 and degenerative conditions such as osteoarthritis13 and osteoporosis.14 It has also been related to diabetes15,16 and general risk factors for chronic disease, including obesity and insulin resistance.16,17 Lastly, TL in leukocytes predicted earlier mortality in a community sample, and in samples with Alzheimers disease and history of stroke.18-20

Given the role of telomere maintenance to cell longevity and apparently human longevity, it is important to find the nexus of how psychological function might affect this longevity system. We first examined whether young healthy women under chronic stress had shorter telomeres than those with low levels of life stress. We found that objective stress (years of caregiving) and perceptions of life stress were both related to shorter telomere length.21 We have found similar relationships with dementia caregivers and controls (unpublished data). Others have since found shortened telomeres in major depression,22 and in those with lower socioeconomic status.23 Thus, stressful life circumstances, stress appraisals, and severe distress, appear to be related to greater telomere shortening.

It is nevertheless difficult to predict who is most vulnerable to telomere shortening when exposed to similar conditions of chronic stress. Here we briefly review some of the important psychological (cognitive and emotional) aspects of stress, and then physiological stress mediators that are likely related to cell aging as well. We note, however, that psychological function is only one of many factors influencing telomere length in adulthood, and a lifespan approach may be the best way to understand telomere length at any one moment in time 24.

Given the huge individual variance in perception and reaction to common stressful events, the process of coping with challenge is an important mediator of emotional reactions25 and presumably physiological reactivity.

A prevailing model for understanding what makes a situation stressful is Lazarus and Folkmans (1984) Stress and Coping Theory.26 Situations where a goal that matters to the person is at stake and the demands of the situation outweigh the persons resources for coping with it can cause feelings of stress. We may feel stressed when a situation harms or threatens important goals (threat appraisals). In contrast, in a stressful situation, a person might see the possibility of doing well at coping and thus perceive the stressor as a challenge (challenge appraisals). Here, we focus on threat appraisals, which according to our model is the harmful type of stress, linked to cell aging.

Cognitive appraisal in turn affects choice of coping strategy. Coping refers to constantly changing (moment to moment) cognitive and behavioral efforts to manage the demands of a stressful situation.26 A key aspect of the appraisal process is the evaluation of personal control over the outcome. Situations in which there is the possibility of control usually call for behaviorally active, problem-focused coping strategies; situations in which nothing can be done usually call for cognitive strategies that help the person accept the situation or regulate their emotional responses to it.27,28 Accurate appraisals are important to enact effective coping (e. g., to prevent mismatches such as attempting to exert control over an uncontrollable situation).

In our original study on stress and cell aging among maternal caregivers, we examined perceptions of life stress, using the Perceived Stress Scale (PSS),29 among healthy women (n = 65), some caring for a child with a chronic condition and others caring for healthy children. As reported elsewhere, the full scale score assessing stress-related feelings and thoughts over the last month was significantly related to shorter TL (r = 0.31), after covarying age and body mass index.2 Here we examine which aspects of stress perception on the PSS are linked to TL. Three of the 10 items were significantly related to TL, and these items represent the three core components of perceived stress: the two cognitive components, which include the perception that demands outweigh coping resources and a loss of control, represented by the question difficulties were piling up so high I could not overcome them, (r = 0.40, p

Appraisals also drive emotional states. Threat appraisals drive negative emotions (such as fear and anxiety), whereas challenge appraisals can foster both negative (e.g., anxiety) and positive emotions (e.g., feeling energized and elated).26,30 According to Stress and Coping Theory, 26 the coping process begins when an event is appraised as threatening or challenging. These appraisals prompt both emotional states and coping efforts. If the event is resolved favorably, a positive emotional state (e.g., relief, satisfaction) ensues. If the event is resolved unfavorably or if it remains unresolved, a negative emotional state results (e.g., anger, guilt, anxiety) and the coping process continues through reappraisal and continued rounds of coping.

Many people in modern societies are dealing with at least one, if not multiple, chronic life stressor, such as financial, relationship, work or caregiving stressors. What are the coping mechanisms people use to maintain positive affect and a positive outlook? In dealing with chronic stressors, the negative emotion associated with unfavorable resolution can in some cases motivate positive changes. Negative states motivate meaning-focused coping processes such as those that draw on important goals and values, 31-33 including goal-directed problem-focused coping, positive reappraisal, benefit finding and benefit reminding about a specific situation, 34 and infusion of ordinary events with meaning.35 These coping processes result in positive emotion, which serve important coping functions: they provide a psychological time-out from the distress associated with chronic stress and help motivate and sustain ongoing efforts to cope with the negative effects of the chronic stressor.36

There appears to be such a strong drive to experience positive emotions, such that people facing chronic adversity may be driven to reorganize their outlook on life. In the course of coping with chronic stress, people often develop cognitive shifts or changes in ones mental filter that promotes positive appraisals. These are distinct from acute stress appraisals and coping strategies. We call these cognitive shifts psychological thriving.37 Thriving includes a range of positive appraisals such as greater appreciation of life, or self growth (new skills and feeling empowered). These changes are not tied to specific situations, but rather serve as meta-cognitions about ones life. These shifts may stay with a person (i.e., become ingrained schemas) and affect future appraisals as well. We suspect that psychological thriving shifts situational appraisals of everyday minor stressors toward challenge appraisals, and decreases rumination. In this way, psychological thriving may promote a state of enhanced allostasis, a state where one has lower basal stress arousal, more efficient reactivity peaks, quicker recovery, and greater anabolic functioning after stress, as described in detail elsewhere.37,38

We do not know which individual or situation factors, in the course of chronic stress, cause some people to engage in positive coping, while others remain more fixed in their thinking. It is possible that mindfulness training can help foster positive coping and eventually psychological thriving.

Here, we report a preliminary test of one aspect of this model, the link between acute stress appraisals and telomere length. We asked whether acute appraisals to a standardized stressor are linked to telomere length. In the maternal caregiver study described above, we also examined response to an acute laboratory psychosocial stressor, an adapted form of the Trier Social Stress Test (TSST).39 Before the stressor, we measured thoughts and emotions linked to threat and challenge appraisals based on theory and research.27,40,41 Participants rated how much they felt each of 6 emotions, including worried, anxious, or fearful (threat emotions) and eager, confident, and hopeful (challenge emotions). They also rated expectations for the task, including anticipated success, difficulty of the task, perceptions of control over the task, and effort they would need to exert.

An exploratory factor analysis was performed requesting two factors, with a varimax rotation. All items loaded on one of two factors, with loadings of .59 or higher, accounting for 51% of the total variance, supporting the existence of threat and challenge appraisal factors. The threat factor (Eigenvalue of 2.8) included the threat emotions and scoring high on expected difficulty. The challenge factor (Eigenvalue of 2.4) included scoring high on challenge emotions, high anticipated success, high perceived control, and expecting to exert high effort. Factor scores were created and examined independently and as a ratio of challenge to threat, in case relative levels of appraisal mattered. There were no correlations between TL with challenge (.07) or threat (r = .00) factors, suggesting that neither type of appraisal alone is associated with telomere shortening. However, the ratio of challenge to threat was significantly correlated with longer telomeres (r = .26, p

The neuroendocrine system and autonomic nervous system which regulate the stress response are important physiological mediators between emotional stress and illness. Chronic stress can depress levels of heart rate variability or vagal tone, an index of the counterregulatory response to sympathetic arousal. For example, low vagal tone has been related to work stress42, depression43 and low socioeconomic status.44

Chronic stress can lead to dysregulation of the hypothalamic pituitary axis, which can take many forms, such as a blunted diurnal rhythm of cortisol or elevated basal levels.45,46 Flattened rhythm in turn can predict various indicators of physical and mental health, such as coronary calcification47 and metastatic breast cancer progression.48 Chronic stress can suppress levels of certain anabolic hormones, such as DHEA or insulin like growth factor 49 and can increase levels of insulin and visceral fat 50. Anabolic hormones such as testosterone appear to suppress or counterregulate the catabolic and sympathetic stress response 51 thus playing an important role in endocrine balance. Lastly, acute and chronic stress appear to increase levels of oxidative stress.52 These relationships between stress and neuroendocrine balance have been reviewed extensively elsewhere.49,53-55

Strong positive and negative emotions associated with appraisals can induce changes in physiological arousal systems. A primary construct for understanding appraisal and arousal is perceived control. Perceptions of control help determine whether a situation is appraised as a threat or challenge, and these appraisals in turn are primary determinants of physiological stress responses. Classic stress research has shown that feeling a lack of control over a stressor, including a sense of unpredictability and uncertainty, stimulates cortisol reactivity.56 A meta-analysis across studies of psychological laboratory stressors showed that conditions of social evaluative threat (perceptions that ego relevant aspects of ones identity will be negatively judged) and low control, are potent stimulants of the adrenal gland, with additive effects for both.57

Little research has examined positive emotions and physiology, and no research to our knowledge has compared high vs. low arousal positive states. Positive emotional states may promote a more salutary pattern of arousal. High arousal positive states, such as sports competition, vicariously experiencing winning, or experiencing challenge appraisals while successfully coping with an acute stressor, may activate certain anabolic hormones such as testosterone and DHEA-S.58-60 Lower arousal emotions, such as feeling composed, calm and peaceful are associated with greater vagal tone (parasympathetic activity) 61 and possibly to higher DHEA.62 Low DHEA at baseline has also been related to greater subsequent threat appraisals and negative affect in response to a stressor, suggesting it promotes affective vulnerability to acute stress.63 Thus, there are likely bidirectional relationships between neuroendocrine balance of anabolic and catabolic hormones, and appraisals. We suggest that the anabolic (mainly androgens and vagal tone) response to positive states, both high arousal states (challenge) and low arousal states (relaxation) may be one key to the effects of mindfulness on physical health (See , Positive states).

When a coping outcome is appraised as unfavorable and the goal remains highly valued, people feel more negative affect and may engage in rumination, repetitive thought that is not goal directed. Depressive rumination, a negative self-focus on assumed basic faults, can prolong negative mood and over time predict depression.64 Negative affect and rumination may further lead to prolonged cardiovascular recovery.65-67 State rumination has been related to higher salivary cortisol after acute stress.68

As yet few studies attempt to link cell aging to stress arousal. In our initial study of healthy young women, those with shorter telomeres excreted higher levels of both cortisol and epinephrine in their urine overnight, 69 suggesting chronically elevated stress response system activity. When examining telomerase, we found that low telomerase was related to greater basal hemodynamic arousal (heart rate, blood pressure), lower heart rate variability, and greater sympathetic reactivity to lab stress.69 Low telomerase was related to lower resting vagal tone and a greater dip in vagal tone in response to an acute lab stressor independent of resting vagal tone.

Endocrine and biochemical milieu can affect rate of telomere shortening with each cell division. Oxidative stress, characterized by excess free radicals, shortens telomeres, whereas telomerase can rebuild and thus lengthen the telomere. Further, in vitro evidence in various cell lines suggests that certain anabolic hormones, including growth hormone, 70 IGF-1,71-73 and estrogen, 74,75 can promote telomerase activity. In contrast, insulin and insulin resistance are related to telomere shortness.17 These same pathways may be affected by chronic stress and meditation, discussed further below.

Here we review meditation techniques theorized to positively modulate stress-related cognitive processes and arousal with implications for cellular aging. We first outline the theoretical claims and practice of mindfulness meditation, in particular, based on a large body of theory and research in this area, and examine other forms of meditation when applicable. We then review research linking mindfulness states, mindfulness meditation, and other types of meditation to aspects of stress cognition, coping, and emotional reactivity. Lastly, we review research linking meditation to stress arousal.

At the outset, we note the Buddhist origins of mindfulness meditation techniques and acknowledge that scientific understandings of mindfulness have developed largely independent of Buddhist paradigms, theory, and goals (for a discussion on this issue, see 76,77). Mindfulness meditation has been adapted to Western secular contexts to treat patients with a variety of physical and psychological conditions and research to date has predominantly focused on its efficacy to improve these conditions and examine underlying mechanisms. In contrast, in Buddhist settings, mindfulness is one aspect of a set of integrated spiritual practices, beliefs, and teachings aimed at achieving insight into the nature and cause of suffering and realizing spiritual freedom.77 These differing goals and contexts have implications for the understanding of mindfulness and so we emphasize the importance of not mistaking secular, therapeutic conceptualizations of mindfulness, as we focus on here, for Buddhist conceptualizations. Notwithstanding these issues, we would argue that the adaptation of mindfulness to Western contexts retains at least some of its essential ingredients and appears to be beneficial. Thus, it is within this larger context that we aim to review the scientific literature on mindfulness. We specifically focus on the relation of mindfulness to stress related cognitions, affect, and coping processes using Stress and Coping theory as a framework to propose mechanisms through which mindfulness, and other forms of meditation, may positively impact stress arousal and cellular aging.

Mindfulness is considered an inherent aspect of consciousness that can be enhanced through a variety of mental training techniques collectively referred to as mindfulness meditation. Mindfulness, translated from the Pali word sati (Sanskrit: smrti), literally means to remember. In the traditional Buddhist context, it means to adhere to an object of consciousness with a clear mental focus in a given moment 78. This simple definition contrasts with the multidimensional conceptualization of mindfulness by contemporary Western scientists. Although scientists have yet to agree on a precise definition,76,79-81 the most commonly cited one belongs to pioneer Jon Kabat-Zinn, who defined it as paying attention in a particular way: on purpose, in the present moment and non-judgmentally 82 (p.4). Kabat-Zinn adds an attitudinal dimension to the state of mindfulnesss, that of nonjudgmentalness. Other researchers following his lead have described the attitude as one of curiosity and acceptance80 or kindness, compassion, and patience. 83 Thus, in addition to characterizing mindfulness as a form of attention regulation as in the Buddhist definition, scientists emphasize the importance of the cognitive and emotional manner in which attention is deployed.

Instructions for the formal practice of mindfulness meditation entail purposefully directing attention to ones experience in the present moment with an attitude of open curiosity and acceptance.80 An upright sitting posture with minimal movement is encouraged (with eyes either open or closed) to allow the body to relax and the mind to remain alert. Attention is directed to a pre-determined object, usually localized sensations involving respiration, such as those at the tip of the nose (external objects can also be used, such as a picture). Novice practitioners usually report that after a short period of time, they become distracted by thoughts, feelings, sounds, or physical sensations and their focus on the intended object is lost. At this point, the instruction is to notice these experiences (distractions) fully without judgment, to let them go, and return attention back to its intended object. Instructions for attending to distractions vary – from silently applying a specific label to the object (e.g., anger, anticipation, sound) to applying the general term thinking to any thought, to not making any mental notation whatsoever. Labeling an experience is believed to strengthen recognition of it and this may be particularly helpful for some individuals or when experiencing intense distractions. The process of becoming distracted and returning the attention is repeated over and over again during formal mindfulness practice. The goal is to increase awareness of present-moment experience to increasingly subtle levels and to strengthen stability of attention. The goal is not to ignore or get rid of thought in order to have a blank mind, but to notice with full attention whatever arises. In this sense, there are no distractions; whatever is noticed in the field of awareness can be observed. Interestingly, it can be painful to observe thoughts one wishes to avoid, so in this sense, the practice cultivates a willingness to experience discomfort and reduces attempts to escape it. At the other extreme, the goal is not to indulge in pleasant thought or achieve a pleasant experience (although this may occur), but to remain aware of each experience as it occurs.

A fundamental shift in the relation to thought and other objects of awareness is considered a pivotal, key mechanism of mindfulness training. This metacognitive process has been referred to as decentering and reperceiving, processes which have been similarly defined.79,84 Here we use the term reperceiving, which is defined as a shift in perspective in that what was previously subject becomes object (p. 378); or, in other words, consciousness becomes awareness of thought rather than thought itself. This shift in perspective is hypothesized to lead to the realization that I am not that thought allowing for greater flexibility in how to respond to thought or any experience when it occurs. This insight is argued to have manifold salutary effects on psychological functioning further elaborated below.81 We feel this is a key process for defusing stress cognitions, as described in detail below (under appraisal and rumination sections).

Mindful states of consciousness are not confined to formal meditation practice, but are thought to carry over into daily activities. Additionally, as mindfulness is considered an innate capacity of human consciousness, individuals without formal training are thought to vary in the extent to which they are mindful. As such, self-report measures of dispositional mindfulness have been developed using non-meditators 85,86. Effects of mindfulness training have most commonly been studied a) in the context of an eight-week group intervention program, Mindfulness-Based Stress Reduction (MBSR) 87 or variations of this program tailored to meet the needs of specific populations, b) using brief inductions of mindfulness in laboratory settings, or c) comparing experienced meditators to controls, findings of which are highlighted below.

As noted, a central aspect of mindfulness training involves the self-regulation of attention. In support, recent studies find improved performance on attention-related behavioral tasks after mindfulness training. Jha and colleagues found improved ability to orient attention in response to an environmental cue, enhancing response accuracy and reaction time on a computerized task among MBSR participants compared to meditation-nave participants.88 The researchers also found individuals who completed a one-month mindfulness-based residential retreat increased accuracy of a target location when no prior cue was presented compared to controls, indicating an enhanced vigilant state of alertness. These findings suggest that mindfulness enhances attention-related responsiveness to environmental cues and ability to maintain alertness.

In line with these findings, two studies have shown that meditation training is associated with inhibition of habitual responding on the classic Stroop task, in which participants are asked to name the colored text of a word rather than the word itself (e.g., the correct response to the word red appearing in blue-colored font is blue). 89,90 Although a contrived laboratory task, the findings support the suggestion that automatic, top-down information processing is reduced following certain forms of meditation practice. One implication of the deautomatization of thought is that it should lead to enhanced ability to notice nuanced details of experience from a fresh perspective and inhibit reliance on memories, expectations, and schemas during information processing.91

Meditation training has further been shown to reduce elaborative processing of previous stimuli thereby increasing attentional resources to present-moment experience.92 The distribution of attentional resources as measured by performance on an attentional-blink task improved after a 3-month intensive mindfulness-based meditation retreat compared to controls.92 Scalp-recorded brain potentials showed reduced brain-resource allocation to the first target embedded in a rapid stream of stimuli enabling increased identification of the second target.

Enhanced attention-related processes are hypothesized to improve early detection of potential stressors and increase the probability that effective coping will be implemented in a timely manner (Teasdale et al, 1995). Increased awareness of present-moment experience may also disrupt ruminative thought processes that play a role in prolonged stress reactivity and vulnerability to mental illness (Teasdale et al, 1995).

In addition, training in present-moment awareness appears to increase interoceptive processes, which involve awareness of visceral signals and subtle emotional feelings thought to be important in emotion regulation.93 Using functional magnetic resonance imaging, increased neural activity of brain regions involved in processing present-moment experience was found following eight weeks of mindfulness training compared to controls.94 Specifically, viscerosomatic brain areas showed greater activation (including the insula, secondary somatosensory cortex and infereior parietal lobule) when meditators compared to novices were asked to maintain an experiential momentary experience vs. a narrative self-focus after presentation of personality traits.94 In a study of long-term mindfulness meditation practitioners, magnetic resonance imaging revealed greater cortical thickness in brain regions associated with interoception, including the right anterior insula, compared to controls.95 These studies provide neural evidence that mindfulness meditation cultivates interoceptive awareness, which is thought to play a key role in maintaining present moment awareness and regulating emotions.

In regards to cognitive appraisals, to the extent mindfulness reduces identification with self-related cognition and goals through enhanced attention to present-moment experience and reperceiving, situations may be appraised as less threatening. Heppner and Kernis 96 argue that individuals who report greater dispositional mindfulness are less likely to interpret ambiguous behavior by others as reflecting hostile intent, and report less anger and desire to retaliate. In a mindfulness meditation induction experiment (as described in Heppner et al, 2007, citing unpublished analyses), participants exposed to a brief mindfulness practice (mindful eating of a raisin) displayed less aggressive behavior following social rejection compared to control participants. They suggest these participants may have experienced reduced reactivity to social threat because they attributed less hostile intent to the actor. In a study of relationship stress among romantic couples, those with higher dispositional mindfulness reported relatively more positive perceptions of their partner and relationship after discussing a conflict in a laboratory setting.97 A randomized waitlist-controlled trial of an abbreviated MBSR program conducted among adults at their work-site, found reductions in global appraisals of life stress (using the Perceived Stress Scale) compared to control group participants.98

These studies support the notion that mindfulness facilitates interpretation of situations as less threatening, perhaps due to less activation of self-relevant concerns, so that events are responded to more thoughtfully, rather than reacted to through automatic filters of cognitive and emotional processes. Mindfulness is argued to promote cognitive balance, the ability to see clearly beyond assumptions, preventing common and habitual cognitive distortions.99

Mindfulness may also improve coping with events that are appraised as threatening in which there is little possibility of control. Mindfulness may serve to increase a sense of control, not simply by reacting more coolly, (with attenuated cycles of negative thoughts and emotions), but by lessening ones perceived need to be in control, especially when situations are determined to be uncontrollable. In one controlled mindfulness-based meditation intervention of 28 healthy participants, those in the treatment group reported both increases in sense of control over life and increased willingness to let go of control efforts (greater use of acceptance/yielding to cope with stressors).100

Mindfulness training also improves the ability of patients to cope with a variety of chronic disease-related stressors that often afford limited opportunities for control. A meta-analysis of 20 studies examining effects of MBSR in patients with chronic illnesses (including cancer, fibromyalgia, and chronic pain) as well as those seeking to reduce stress, found a moderate effect size (Cohens d = ~.50) across observational, waitlist-controlled, and active-controlled studies.101 Improvements in psychological functioning (e.g., anxiety and depressive symptoms, copying style) were observed in addition to improvements in physical health symptoms, including pain and physical impairment and function. Large, well-controlled studies that assess the active ingredients of mindfulness are still needed, yet the accumulated studies offer encouragement that MBSR is helpful in enhancing patients ability to cope with a wide range of chronic illnesses.

Several other forms of meditation have been shown to reduce threat appraisals and enhance adaptive coping. A randomized controlled trial of mantra meditation (repeating a spiritually-related word or phrase throughout the day, including a focus on noticing and interrupting stressful thoughts) showed an increase in positive reappraisal, the tendency to reframe situations in a more positive light.102 Robins, McCain et al. 2006 conducted an uncontrolled study of Tai Chi, a form of moving meditation focusing on breath, in a sample of 59 participants with HIV. Although they found no changes in other types of coping, there was a significant increase in positive reappraisal.103

Lastly, a randomized study of Cognitive Behavioral Stress Management (CBSM) which incorporates a variety of somatic and cognitive techniques including meditation, progressive muscle relaxation, cognitive restructuring, assertiveness training, and anger management, examined responses to a standardized laboratory stressor (TSST, described above). They found that those in CBSM made fewer stress appraisals, both threat and challenge, and experienced greater expected control. These appraisals mediated lower cortisol responses to the stressor.104 A similar study followed 28 students, randomized to CBSM or a waitlist control group, and measured stress appraisals before a naturalistic stressor (an exam). Compared to the control group, those who received CBSM were less likely to appraise the exam as threatening (although equally likely to appraise it as challenging, thus changing the appraisal ratio), and had marginally greater perceived competence.105 These studies show that forms of meditation practice and stress reduction other than mindfulness also reduce stress-related cognitions, partly by shifting appraisals of events from threatening to positive and/or challenging.

One key way in which mindfulness may protect one from the negative effects of stress is by decreasing rumination. Increasing awareness of present-moment experience may disrupt ruminative thought processes that play a role in prolonged stress reactivity. 106 The typical instructions for mindfulness meditation, to notice thoughts and let them go, target the discursive mind the tendency to revisit the same thoughts repeatedly. As thoughts and feelings are experienced as transient mental events occurring within a wider context of awareness, attenuation of automatic identification and reactivity to them may occur. Over time, this more objective perspective on mental content, referred to as meta-cognitive awareness, may interrupt ruminative thinking, increase the ability to evaluate the accuracy of thoughts, and allow greater freedom of choice in responding to thoughts and emotions.84

The practice of changing how one relates to thoughts and emotions contrasts with cognitive behavioral therapies that emphasize changing the content of thoughts. Mindfulness practice involves first allowing awareness of thought and then becoming less engaged or attached to the thoughts themselves before attempting to evaluate their accuracy.99 This type of non-reactivity to inner experiences such as negative thoughts is one factor of a multi-factorial self-report measure of mindfulness.86

There are several studies that examine mindfulness and rumination. Mindfulness, as an individual difference variable, is related to less rumination.107,108 Conversely, mindfulness is negatively related to the more trait-like automatic habit of negative thinking,108 suggesting that it may prevent tonic dysphoria and low self esteem, in addition to playing a role in coping with stressors. A recent randomized trial suggests that mindfulness training reduces ruminative thought and distraction to a larger extent than somatic relaxation. This reduction in rumination is thought to be key to reducing distress.109

Mindfulness may also influence the secondary response to negative emotions that perpetuates the cycle of negative thoughts (distress about distress). Mindfulness-Based Cognitive Therapy (MBCT), based on the MBSR program, specifically targets rumination and negative thought patterns associated with depression. A primary goal of the MBCT intervention developed for people with a history of depression is to shift the way participants relate to depressive thoughts and emotions, a process referred to as decentering, in that thoughts are experienced more objectively as passing events in the mind rather than accurate reflections of reality. The program has been found to be effective for reducing depression relapse in currently non-depressed patients in randomized usual-care controlled trials.84,110 Using semi-structured interview techniques to elicit memories of mildly depressive situations, the researchers found that mindfulness training increased the ability of participants to view their depressive thoughts and emotions with greater discrimination, evaluate the appropriateness of their thoughts and feelings, and gain greater perspective that their thoughts were self-generated rather than accurate reflections of reality.

Mindfulness is theorized to enhance emotion regulation skills by increasing awareness of emotions, increasing the willingness to tolerate and accept distressing or uncomfortable emotions, and reducing emotional reactivity to provocative events and emotions themselves.111

The proposal that mindfulness improves affect regulation through enhanced awareness of emotional processes is supported by three studies on reactivity to emotional stimuli. In one study, participants were asked to label emotions expressed on human faces while undergoing functional magnetic resonance imaging (fMRI). Individuals scoring higher on a measure of trait mindfulness showed enhanced prefrontal cortical regulation of affect and reduced bilateral amygdala activity (typically associated with negative affective states) during affect labeling compared to a control labeling task.112 Furthermore, those with high vs. low trait mindfulness showed strong negative associations between areas of prefrontal cortex and right amygdala activity. These findings point to neural substrates that may underlie aspects of the reperceiving process in which consciousness is shifted from identification with emotion to conscious awareness of emotion. The effect of this cognitive shift may be to disrupt or inhibit automatic affective responses, reducing their intensity and duration.112,113

Brief mindfulness-based meditation training has been shown to reduce reactivity to emotional stimuli and increase willingness to be exposed to or tolerate negative stimuli. Participants who participated in a 15-minute focused breathing exercise akin to exercises taught in MBSR, reported less negative affect in response to images known to elicit negative emotions compared to two control groups instructed to either let their minds wander for 15 minutes or worry about certain aspects of their lives.111 The mindfulness participants also continued to report moderate levels of positive affect throughout exposure to emotionally neutral images and were more willing to view additional negative images compared to the control groups.

In a randomized waitlist-controlled MBSR trial among employees, Davidson and colleagues (2003) found an increased pattern of left-sided anterior brain activation, known to be associated with state and trait positive affect, in response to positive and negative mood inductions in MBSR participants compared to waitlist group from pre to post intervention. Left-sided anterior activation has been associated with quicker emotional recovery following a negative event.114 These studies indirectly support the idea that mindfulness promotes adaptive regulation of emotion.

In addition, mindfulness is linked to greater emotional well-being across studies with differing methodologies, including correlations of self-report levels of mindfulness with self-report emotional well-being, mindfulness induction experiments conducted in laboratories, and clinical trial interventions, as reviewed by Brown et al (2007). Trait levels of mindfulness have been associated with fewer emotional disturbances (e.g., depressive and anxiety symptoms), greater affective balance high positive affect and low negative affect, and less difficulties with emotional regulation.85,86 In a 2-week experience-sampling study, reports of greater state mindfulness were associated with affective balance (higher positive affect and lower negative affect), independent of trait mindfulness.85

Mindfulness is also although thought to increase intensity and frequency of positive and pro-social emotions, including empathy, kindness and compassion for self and others (Wallace and Shapiro, 2006). A randomized study of mindfulness-based stress reduction demonstrated increased scores on a measure of empathy, the capacity to notice and feel what another is feeling.115

In summary, the early research reviewed above suggests that mindfulness appears to reduce stress cognitions both the negative content of threat appraisals, the ruminative process of revisiting negative thoughts, as well as the secondary response of feeling distress about feeling distress.

In addition to mitigating stress-related cognitions and emotions, some types of meditation appear to reduce markers of stress arousal, both through the HPA axis, increasing vagal tone, and reducing markers of sympathetic arousal. Transcendental meditation (TM), a concentrative technique that uses silent repetition of a word or phrase as the object of awareness, has been the most extensively studied meditative technique. It appears to reduce systolic and diastolic blood pressure to levels comparable to pharmacologic treatment116 and improves heart rate variability compared to an active control group.117 It also appears to lower basal cortisol and lead to greater cortisol peaks in response to an acute stressor,118-120 a profile that might be described as enhanced allostasis.38,121 TM and a similar type of concentrative meditation (the relaxation response technique) are also characterized by decreased oxygen consumption,122,123 carbon dioxide elimination,124,125 and salutary EEG patterns (theta and alpha activation).126

Little research has evaluated specifically the effects of mindfulness meditation on HPA axis arousal or autonomic activity127 although similar effects as those found with transcendental meditation and the relaxation response could be predicted to occur. In one uncontrolled MBSR intervention study, cancer patients consistently showed decreased daily average cortisol values after one year of follow-up .128 In a second study, lower cortisol responses to mental stress were observed after five days of practicing an integrated mind-body meditation approach incorporating mindfulness compared to a randomized relaxation control group.129 However, one caveat is that mindfulness includes acknowledgement of distressing thoughts and feelings, which may initially increase arousal and emotional activity, but viewed as a developmental process, may progressively lead to decreased reactivity through enhanced awareness, tolerance of discomfort, and acceptance. Thus, for beginners, and periodically for experienced practitioners, mindfulness meditation is expected to produce increases in physiologic arousal.130

Several randomized controlled trials have demonstrated the effectiveness of CBSM on reducing peripheral stress arousal. CBSM training reduced urinary free cortisol and epinephrine in clinical samples.131,132 In one study of healthy participants, CBSM led to lower cortisol reactivity in response to a standardized laboratory stressor within 2 weeks104 and, to a lesser extent, four months after the intervention.133 To the extent that mindfulness or other forms of meditation promote the ability to buffer oneself from social evaluative threat — recognizing that negative social judgments or reflected appraisals of the self (what one thinks others think about oneself) do not necessarily represent reality or a threat to ones self-worth, practitioners should indeed become less stress reactive.

Although concentrative and mindfulness meditation techniques may reduce HPA axis and autonomic arousal, the brain appears to respond to specific types of meditation in ways that may represent an adaptive attentional state to appraise stimuli. An fMRI study of meditation practitioners (who practiced Kundalini meditation in which focused attention on respiration is linked to silent repetition of a phrase found increased activation of localized neural structures involved in attention (frontal and parietal cortex) and control of the autonomic nervous system (pregenual anterior cingulate, amygdala, midbrain, and hypothalamus) compared to a control nonmeditative condition.134 These data suggest that as some meditation practices produce deep physical relaxation evidenced by reductions in autonomic and HPA arousal, these practitioners were engaged in an active attentional state of autonomic control, countering the notion that meditation is a state of mental as well as physical relaxation.

Further evidence suggests that meditation effects are not simply the result of volitionally reduced peripheral arousal. Results of a study comparing neural correlates of mindfulness meditation and respiratory biofeedback found that while some regions are engaged by both tasks, mindfulness meditation activates additional neural regions (e.g., right anterior insula).135 Thus, while some forms of meditation engage attentional resources to induce a hypometablic state benefical for managing stress-related arousal, they also appear to modulate cognitive and emotional processes involved in the appraisal of stress, such as interoception.

Several meditation studies have measured markers of positive health, such as anabolic hormones, and these may have relevance for cellular aging. As discussed above and reviewed elsewhere, several stress reduction interventions have induced increased heart rate variability and increased anabolic hormones such as DHEA.136 Several uncontrolled studies of TM show healthier profiles of arousal, including greater levels of DHEA-S.120,137

Across controlled studies, mindfulness meditation appears to improve physical health symptoms and functioning across a variety of disorders, and increases measures of mental health, including reduced negative affect and increased quality of life.138,139 It is thought that these positive effects are mediated in part by reductions in psychological and physiological stress. TM has been linked to reduced cardiovascular disease risk factors and in controlled trials, has reduced blood pressure116 and carotid artery atherosclerosis 140 as reviewed by Walton and colleagues.1412893

Oxidative stress may be an important mediator between stress and disease. It is linked to cardiovascular disease, as well as telomere shortening. Although few studies have examined oxidative stress balance, two initial studies found that meditation practitioners (TM and Zen) had lower levels of a marker of oxidative stress (lipid peroxidation).142,143

Stress cognitions are important for survival, but if they are based on distorted perceptions, they may promote excessive stress arousal, creating a harmful milieu for cellular longevity. During the longevity conference that these proceedings are based upon, H.H. the Dalai Lama explained that emotions based on reason and analysis, tend to drive meaningful behavior. In contrast, emotions based on false projections or fear-based beliefs are harmful to longevity. Here, as shown in , we speculate that certain types of meditation can increase awareness of present moment experience leading to positive cognitions, primarily by increasing meta-cognitive awareness of thought, a sense of control (and decreased need to control), and increased acceptance of emotional experience. These cognitive states and skills reduce cognitive stress and thus ability for more accurate appraisals, reducing exaggerated threat appraisals and rumination, and distress about distress. These positive states are thus stress-buffering. Increasing positive states and decreasing stress cognitions may in turn slow the rate of cellular aging.

There is some indirect support of aspects of this hypothesis involving stress cognitions. In our previous study, perceived life stress — primarily an inability to cope with demands and feeling a lack of control, and higher nocturnal stress hormones (cortisol and catecholamines) were related to shorter telomere length.2 Trait negative mood was related to lower telomerase activity, a precursor of telomere shortening.144 Here we presented preliminary data from the same sample linking telomere length to higher proportions of challenge appraisals relative to threat appraisals in response to a standardized stressor. The results suggest that the relative balance of threat to challenge cognitions may be important in buffering against the long term wear and tear effects of stressors. To the extent that meditation mitigates stress-related cognitions and propagation of negative emotions and negative stress arousal, a longstanding practice of mindfulness or other forms of meditation may indeed decelerate cellular aging.

We also speculate about the physiological mechanisms. Above we have reviewed data linking stress arousal and oxidative stress to telomere shortness. Meditative practices appear to improve the endocrine balance toward positive arousal (high DHEA, lower cortisol) and decrease oxidative stress. Thus, meditation practices may promote mitotic cell longevity both through decreasing stress hormones and oxidative stress and increasing hormones that may protect the telomere. There is much evidence of neuroendocrine and physical health benefits from TM, which has a longer history of study than MBSR. The newer studies of mindfulness meditation are promising, and offer insight into specific cognitive processes of how it may serve as an antidote to cognitive stress states.

This field of stress induced cell aging is young, our model is highly speculative, and there are considerable gaps in our knowledge of the potential effects of meditation on cell aging. Several laboratories are working on diverse aspects of this model, which will soon allow it to be evaluated in light of the empirical data.

24. Epel ES. Telomeres: A new psychobiomarker for a lifespan approach? Current Directions in Psychology. 2008 in press.

26. Lazarus R, Folkman S. Stress, appraisal, and coping. Springer-Verlag; New York: 1984.

31. Folkman S, Moskowitz J. The scope of social psychology: Theory and applications. Psychology Press; Hove, UK: 2007. Positive affect and meaning-focused coping during significant psychological stress; pp. 193208.

33. Park CL, Folkman S. Meaning in the context of stress and coping. Review of General Psychology. 1997;2:115144.

34. Tennen H, Affleck G. Benefit-finding and benefit-reminding. In: Snyder CR, Lopez SJ, editors. Handbook of positive psycholog. 584-597. Oxford University Press; London: 2002.

35. Folkman S, Moskowitz J, Ozer E, Park C. Positive meaningful events and coping in the context of HIV/AIDS. In: Gottlieb B, editor. Coping with Chronic Stress. Plenum; New York: 1997. pp. 293314.

36. Lazarus RS, Kanner AD, Folkman S. Emotions: A cognitive-phenomenological analysis. In: Plutchik R, Kellerman H, editors. Theories of emotion. Academic Press; New York: 1980.

37. Bower J, Low C, Moskowitz J, Sepah S, Epel E. Pathways from benefit finding to physical health: Enhanced psychological and physiological responses to stress. Social and Personality Psychology Compass. 2008 in press.

38. Epel E, McEwen B, Ickovics J. Embodying psychological thriving: Physical thriving in response to stress. Journal of Social Issues. 1998;54:301322.

49. Epel E, Burke H, Wolkowitz O. Psychoneuroendocrinology of Aging: Focus on anabolic and catabolic hormones. In: Aldwin C, Spiro A, Park C, editors. Handbook of Health Psychology of Aging. Guildford Press; 2007. pp. 119141.

53. Sterling P, Eyer J. Allostasis: A new paradigm to explain arousal pathology. In: Fisher S, Reason J, editors. Handbook of Life Stress: Cognition and Health. John Wiley & Sons, Ltd.; 1988. pp. 629649.

60. Mendes WB, Ayduk O, Epel ES, Akinola M, Gyurak A. When stress is good for you: Neuroendocrine concomitants of physiological thriving. Harvard University; Boston: 2008.

62. Whitmore R, Maninger N, Wolfson W, Mendes WB, Epel ES. Relaxation increases DHEA; Paper presented at: Society of Behavioral Medicine; San Diego. 2008.

77. Rosch E. More than mindfulness: When you have a tiger by the tail, let it eat you. Taylor & Francis; United Kingdom: 2007.

78. Rosch E. More Than Mindfulness: When You Have a Tiger by the Tail, Let It Eat You. Psychological Inquiry. 2007 in press.

80. Bishop SR, Lau M, Shapiro S, et al. Mindfulness: A proposed operational definition. Clinical Psychology: Science and Practice. 2004 Fal11(3):230241.

81. Brown K, Ryan R, Creswell JD. Mindfulness: Theoretical foundations and evidence for its salutary effects. Psychological Inquiry. 2007;18(4):211237.

82. Kabat-Zinn J. Wherever you go, there you are: Mindfulness meditation in everyday life. Hyperion; New York: 1994.

87. Kabat-Zinn J. Full Catastrophe Living. Dell Publishing; New York: 1990.

91. Siegel D. The Mindful Brain. W.W. Norton and Company; New York: 2007.

96. Heppner WL, Kernis MH. Quiet ego functioning: The complementary roles of mindfulness, authenticity, and secure high self-esteem. Taylor & Francis; United Kingdom: 2007.

135. Lazar SW. Neural correlates of respiratory control during mindfulness meditation: Behavioral influences on respiration; Paper presented at: American Psychosomatic Society; Baltimore. 2008.

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Non-Small Cell Lung Cancer Treatment (PDQ)Health …

General Information About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2016:[1]

Lung cancer is the leading cause of cancer-related mortality in the United States.[1] The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional, and distant-stage disease, respectively.[2]

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

Anatomy of the respiratory system.

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.[3]

NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include:

The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked

Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk for lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.[19]

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[20] Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[21]

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[18,22-25][Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Refer to the PDQ summaries on Lung Cancer Prevention and Smoking in Cancer Care for more information.

In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical computed tomography (CT) scanning.[26] Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

(Refer to the Screening by low-dose helical computed tomography subsection in the PDQ summary on Lung Cancer Screening for more information.)

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient.

The procedures used to determine the presence of cancer include the following:

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[27] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[28] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.

Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors.[21,29-32] Factors that have correlated with adverse prognosis include the following:

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[47]

Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the NCI website.

Other PDQ summaries containing information related to lung cancer include the following:

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

There are numerous additional subtypes of decreasing frequency.[1]

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including the following:

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[2] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Other mutations of potential relevance to treatment decisions include:

These mutations are mutually exclusive, except for those involving PI3KCA and BRAF mutations, EGFR mutations, or ALK translocations.[3,4]

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% confidence interval [CI], 1317), 6% from current smokers (20 of 344; 95% CI, 49), and 52% from never-smokers (302 of 580; 95% CI, 4856; P

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Sensitizing fusions of ALK with other genes have also been reported. Other mutations that occur in less than 5% of NSCLC tumors include:

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

In non-small cell lung cancer (NSCLC), the determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are under consideration for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.[1] The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine staging include the following:

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

Prognostic and treatment decisions are based on some of the following factors:

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

Surgical staging of the mediastinum is considered standard if accurate evaluation of the nodal status is needed to determine therapy.

Accurate staging of the mediastinal lymph nodes provides important prognostic information.

Evidence (nodal status):

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[4]

Evidence (CT scan):

The wider availability and use of FDG-PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of FDG-PET scanning in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, FDG-PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (FDG-PET scan):

Decision analyses demonstrate that FDG-PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.[9-11] Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.[9-11] A randomized study found that the addition of FDG-PET scanning to conventional staging was associated with significantly fewer thoracotomies.[12] A second randomized trial evaluating the impact of FDG-PET scanning on clinical management found that FDG-PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[13]

The combination of CT imaging and FDG-PET scanning has greater sensitivity and specificity than CT imaging alone.[14]

Evidence (CT/FDG-PET scan):

For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on FDG-PET scan. Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and FDG-PET scan do not corroborate each other.

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[17] Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that FDG-PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. FDG-PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET scanning is not reliable for detection of metastases in these sites.[17]

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[18,19] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Summary of Changes

This staging system is now recommended for the classification of both NSCLC and small cell lung carcinomas and for carcinoid tumors of the lung.[19]

The T (primary tumor) classifications have been redefined as follows:[19]

No changes have been made to the N (regional lymph nodes) classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M (distant metastasis) classifications have been redefined as follows:

The AJCC has designated staging by TNM classification to define NSCLC.[19]

In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

Surgery is the most potentially curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation (PCI) may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of PCI on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, though overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[5,6] however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[7] In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 and other genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

The standard treatment options for each stage of NSCLC are presented in Table 11.

In addition to the standard treatment options presented in Table 11, treatment options under clinical evaluation include the following:

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.[8-15] Studies have used different timing of assessments, FDG-PET parameters, and cutpoints to define FDG-PET response. Reduction in maximum standardized uptake value (SUV) of higher than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[16] Median survival after resection was greater for patients with tumor SUV values of lower than 4 (56 months vs. 19 months).[15] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[17]

FDG-PET may be more sensitive and specific than computed tomography (CT) scan in assessing response to induction therapy. Optimal timing of imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of FDG-PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[16]

There is no clear role for routine posttreatment PET-CT scans.[18][Level of evidence: 3iiA]

Evidence (surveillance imaging after radiation therapy with or without chemotherapy):

Check the list of NCI-supported cancer clinical trials that are now accepting patients with non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other non-small cell lung cancer (NSCLC) patients with similar stage disease.

Standard treatment options for occult NSCLC include the following:

Check the list of NCI-supported cancer clinical trials that are now accepting patients with occult non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage 0 non-small cell lung cancer (NSCLC) frequently progresses to invasive cancer.[1-3] Patients may be offered surveillance bronchoscopies and, if lesions are detected, potentially curative therapies.

Standard treatment options for stage 0 NSCLC include the following:

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue since patients with stage 0 NSCLC are at a high risk for second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Patients with central lesions may be candidates for curative endobronchial therapy. Endobronchial therapies that preserve lung function include photodynamic therapy, electrocautery, cryotherapy, and Nd-YAG laser therapy.[3-6]

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Non-Small Cell Lung Cancer Treatment (PDQ)Health …

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Spinal cord injury Causes – Mayo Clinic

Spinal cord injuries result from damage to the vertebrae, ligaments or disks of the spinal column or to the spinal cord itself.

A traumatic spinal cord injury may stem from a sudden, traumatic blow to your spine that fractures, dislocates, crushes, or compresses one or more of your vertebrae. It also may result from a gunshot or knife wound that penetrates and cuts your spinal cord.

Additional damage usually occurs over days or weeks because of bleeding, swelling, inflammation and fluid accumulation in and around your spinal cord.

A nontraumatic spinal cord injury may be caused by arthritis, cancer, inflammation, infections or disk degeneration of the spine.

The central nervous system comprises the brain and spinal cord. The spinal cord, made of soft tissue and surrounded by bones (vertebrae), extends downward from the base of your brain and is made up of nerve cells and groups of nerves called tracts, which go to different parts of your body.

The lower end of your spinal cord stops a little above your waist in the region called the conus medullaris. Below this region is a group of nerve roots called the cauda equina.

Tracts in your spinal cord carry messages between the brain and the rest of the body. Motor tracts carry signals from the brain to control muscle movement. Sensory tracts carry signals from body parts to the brain relating to heat, cold, pressure, pain and the position of your limbs.

Whether the cause is traumatic or nontraumatic, the damage affects the nerve fibers passing through the injured area and may impair part or all of your corresponding muscles and nerves below the injury site.

A chest (thoracic) or lower back (lumbar) injury can affect your torso, legs, bowel and bladder control, and sexual function. In addition, a neck (cervical) injury affects movements of your arms and, possibly, your ability to breathe.

The most common causes of spinal cord injuries in the United States are:


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Spinal cord injury Causes – Mayo Clinic

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