Lois Ramondetta MD

Professor Gynecologic Oncology MD Anderson Cancer Center

Chief Gynecologic Oncology and Director of Gynecologic Cancer Research at

Lyndon Baines Johnson Hospital

*Biobehavioral Factors, Stress, and Cancer

STRESS

Physical Symptoms

/StatePain, Fatigue,malnutrition

anemiaSpiritual BeliefsHope?

Personal Qualities(gender/copingStyle)

Financial Situation

DepressionAnxiety

Number of Treatments

Involvement Meaningful Activities-

Dignity

Therapeutic Alliance

Social Support Friends &

Family

*What is Stress?

Stress-

*Acute vs Chronic

*Psychological

*Emotional (depression, anxiety, hopelessness, death anxiety, loss of meaning or dignity), financial, social, loss of control

*Physical

*Pain, surgical, fatigue, nutritional/cachexia, anemia

*Sustained adrenergic activation: ovarian cancer growth and metastasis.

*Stress is a complex process consisting of environmental and psychosocial factors that initiate a cascade of information-processing pathways in both the peripheral and central nervous system

*Stress pathways elicit the “fight-or-flight” stress responses in the autonomic nervous system or “defeat/withdrawal” responses produced by the hypothalamic-pituitary-adrenal axis.

*Activation of these pathways prepares a person to endure a threat.

*Under chronic stress, most organs are negatively affected by prolonged exposure to glucocorticoids and catecholamines

Effects of stress and psychosocial processes on the tumor microenvironment.

Lutgendorf S K , and Sood A K Psychosom Med 2011;73:724-730Copyright © 2011 by the American Psychosomatic Society

* Stress Effects Cancer Cells

Chronic Stress can alter

*adhesion of tumor cells to the extracellular matrix

*cancer cell migration and invasion

*angiogenesis

*cell survivalP.H. Thaker et al Nat Med 12 (2006) 939-44

Antoni MH et al. Nat Rev Cancer. 2006 Mar;6(3):240-8.

* How? Chronic Stress increases IL-8

*In ovarian cancer cell lines, treatment with norepinephrine resulted in increased expression of VEGF, IL-8, and IL-6

*IL-8 encourages angiogenesis, movement of tumor cells toward blood vessels, and enhancement of growth in a variety of tumors

*IL8 is produced by tumor cells and macrophages

*Norepinephrine (NE) treatment of ovarian cancer cells resulted in

*250-300% increase in IL8 protein

*240-320% increase in its mRNA levels.

*3.5-4-fold increase in IL8 promoter activity.

*These effects were blocked by propranolol

* Reiche EM et al Lancet Oncol. 2004 Oct;5(10):617-25

* Glaser R et al Nat Rev Immunol. 2005;5:243-51.

* Behavioral Stress…how it does harm

*How Can We Modify Stress?

IM STRESSED JUST THINKING ABOUT IT!

*Psychological Modifiers

*Meditation

*Breathing exercises

*Yoga

*Therapy-group, individual, how long, how?

*Meaning based

*Dignity based

*Social support

*Empowerment

*Sleep

*Diet

*Building hope

*Physiologic Modifiers

*Anti anxiety medications

*Anti depressants

*Anti inflammatory agents-Cox 2 inhibitors, ASA

*Adrenergic Blockade

*Statins?

*Better pain control (morphine)

*Minimally invasive surgery-surgical technique

*Less blood loss, transfusion?

*Pre op nutrition vs post op nutrition

*Supplements

*Better overall eating habits

* Measuring Stress with Surveys“Experienced” Stress ?

*Perceived stress scale

*Responses to Stress Questionnaire-cancer version (RSQ-CV)

*QOL-FACT O/Sp

*ESAS (overall well being)

*Hope

*HADS

*Perceived Stress Scale0 = Never 1 = Almost Never 2 = Sometimes 3 = Fairly Often 4 = Very Often

1. In the last month, how often have you been upset

because of something that happened unexpectedly?.................................. 0 1 2 3 4

2. In the last month, how often have you felt that you were unable

to control the important things in your life? ..................................................0 1 2 3 4

3. In the last month, how often have you felt nervous and “stressed”? ............ 0 1 2 3 4

4. In the last month, how often have you felt confident about your ability

to handle your personal problems? ............................................................. 0 1 2 3 4

5. In the last month, how often have you felt that things

were going your way?.................................................................................. 0 1 2 3 4

6. In the last month, how often have you found that you could not cope

with all the things that you had to do? ......................................................... 0 1 2 3 4

7. In the last month, how often have you been able

to control irritations in your life?................................................................... 0 1 2 3 4

8. In the last month, how often have you felt that you were on top of things?.. 0 1 2 3 4

9. In the last month, how often have you been angered

because of things that were outside of your control?................................... 0 1 2 3 4

10. In the last month, how often have you felt difficulties

were piling up so high that you could not overcome them? ......................... 0 1 2 3 4

* Physiologic Measurements of Stress:

Stress Targeted Therapy

*HR, BP

*Cortisol

* TH1 T helper 1

* TH2 T-helper 2

* TIL tumor infiltrating lymphocytes

*VEGF vascular endothelial growth factor

* IL-6 interleukin-6

* IL-8 interleukin-8

* IL-10 interleukin-10

* TNFα tumor necrosis factor alpha

*NE norepinephrine

* TAM tumor associated macrophage

*NK Natural Killer cells

*Matrix Metalloprotinease (MMP-3, MMP-9)

* TGF-β tumor growth factor beta

*NFκB nuclear factor kappa beta

* STAT signal transducers

*Stress Work at MDACC

I. Longitudinally evaluating components of psychological stress in ovarian cancer patients

II. Retrospectively assessing adrenergic blockade in ovarian cancer patients

III.Prospectively assessing beta blockade in ovarian cancer patients

IV. Prospectively assessing beta blockade and relaxation in cervical cancer patients

V. Reducing surgical stress and prospective physical stress studies

*Where to Start?

*Hope, Depression, Worry*Women with ovarian cancer beginning a new

chemotherapy regimen (254 pts)

*55% acknowledged fear of dying

*Correlated with younger age, Caucasian, poor physical well being

*32% acknowledged loss of hope in the fight

*Loss of hope correlated with depressive symptoms, lack of social support, and number of treatments.

*Did not correlate with stage of disease, demographic variables or religious affiliation.

Shinn Pall Supp Care 2009

*Longitudinal study of hope, meaning/peace

(M/P), and QOL: Baseline Ovarian Coping Data

Results: Mean age (N=104) 55.3 yrs; 63% W; 19% H; 14% AA 65% married/partnered.

25% depressed/borderline depressed; 40% clinically anxious/borderline anxious

Death Anxiety scores negatively correlated with Hope (p < 0.001) and whether already had chemotherapy (p = 0.025)

*Results

In a multivariate analysis, DA did not correlate with site, race, religiosity, or faith (HOGE or FACT-Sp). DA correlated with HOPE (HHS, p = 0.001) and cycle (p = 0.017).

After controlling for independent variables, M/P subscale (p = 0.005) and hope (p = 0.001) were associated with HADS-Depression

Higher levels of M/P and HOPE (HHS) were associated with decreased HADS-Anxiety (p < 0.001; p = 0.001 respectively)

*Results

PWB EWB FWB SWB OVCA-WB

ESAS Anxiety(HADS)

Depr(HADS)

Hope 0.49;< 0.001

0.39;< 0.001

0.62;< 0.001

0.31;0.001

0.66;< 0.001

-1.010.015

-0.30;0.001

-0.32;0.001

M/P

NS

0.37;< 0.001

0.40;0.004

0.29;0.001 NS

-1.110.006

-0.30;< 0.001

-0.24;0.005

HogeNS NS

-0.14; 0.036 NS NS NS NS NS

Black

NS NS NS

-2.110.040 NS

15.5;0.005

2.20;0.029

Hispanic NS NS NS

-1.900.048 NS NS NS NS

Conclusions:

*Anxiety and Depression affects 25%-40% of our OC population. *Hope associated with well being, decreased symptom burden, less anxiety, and less depression*Religiosity did not correlate with anxiety/depression/DA

*Directionality is unclear but increased hope, and to a lesser extent M/P was associated with better QOL and decreased symptom burden

*Interventions to decrease anxiety and depression should focus on M/P and hope

* Longitudinal study of hope, meaning/peace (M/P), and quality of life in pts with ovarian ca

OC pts at a cancer center (CC), academic hospital (AH) and county hospital (CH for primarily uninsured) participated. 

Surveys completed at initiation of chemotherapy (CTX); completion of CTX; and 1 yr later. Surveys included FACT-O, -SP, Herth Hope Index, Hospital Anxiety and Depression Scale (HADS), ESAS, and Locus of Control (LOC).

Results:  N=115.  Median age=55 yrs, married 64%, Christian 96%.

CH had more AA/Hispanics pts (p=.001) and unmarried pts (p=.001). 

QOL and symptoms improved for all sites over time (p =.03);

CH pts had the worst scores (p= <.001). 

CC pts expressed more hope, less anxiety and depression (A/D) compared to CH and AC pts for all time points (p=.03).

CH pts had higher and increasing A/D over time while CC pts had least (p=.02). 

* Ramondetta et al SGO 2012

LOC scores differed by site (p=.01). 

CH pts -strongest belief that life controlled by chance and “others”; CC pts had least. 

No association between site/time for belief of internal control

CH pts consistently had the lowest M/P scores (p=004).

Adjusting for site, disease status and time,

Higher M/P associated with higher hope, better QOL, symptoms and faith (p= <.0001). 

Lower M/P associated with increased A/D (p=.003) and symptoms (p<.0001). 

Poorer M/P over time correlated with belief that life was controlled by chance (p=.01) and "powerful others"(p=.02).

Level of M/P did not correlate with belief of internal control over one’s life.

Conclusions:  

M/P did not change over time. CC pts had highest M/P. Higher

M/P associated with higher hope and faith, better QOL, less symptoms and A/D. 

Lower M/P associated with sense that life is controlled by chance and powerful others. 

Data show medically underserved pts have poorer QOL, more symptoms and A/D and may believe the future is determined by luck/chance and by “others”. 

Triaging for spiritual crisis may be important in these pts. 

Interventions to decrease A/D and symptoms may improve pts’ sense of M/P over the cancer journey.

* Cortisol and inflammatory processes in ovarian cancer pts following primary treatment: relationships with depression, fatigue, and

disability

Ovarian cancer pts undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6 months, and at 1 year.

At 6 months, significant reductions in nocturnal cortisol secretion, plasma IL-6, and more normalized diurnal cortisol rhythm, changes maintained at 1 year.

The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability.

Thus- primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1 year appear to maintain more normalized levels of cortisol and IL-6. Brain Behav Immun. 2013 Mar;30 Suppl:S126-34 Schrepf A et al

*A Hint ?

Tissue from 10 ovarian carcinomas in pts with high depressive symptoms and low social support and c/w pts with low levels of depressive symptoms were analyzed

Findings:Increased activity of several B-adrenergically linked transcription control pathways, including the cyclic-AMP response element-binding protein/activating transcription factor and proinflammatory signal transducers

Gene expression profiles in primary ovarian tumor specimens are systematically altered in association with the patient’s biobehavioral risk factors

B adrenergic transcription control pathways are the key mediators of differences in gene expression profiles.

Tissue levels of the sympathetic catecholamine norepinephrine were elevated in ovarian tumor specimens obtained from patients with high biobehavioral risk profiles

S.K. Lutgendorf et al J Clin Oncol 26 (2008), 4820-7.

S.K. Lutgendorf, et al Brain Behav Immun 22 (2008), 890-900.

*How Does It Work?

Adrenergic blockade may affect survival in several ways:

•Decreasing angiogenesis, VEGF , matrix metalloproteinase, IL-6

• Decreasing prometastatic immune response (eg, interleukin-8)

• Decreasing symptoms such as cachexia

* β-Adrenergic Receptors and Role in Cancer Development

Four β adrenergic receptors (bARs) exist,and characterized according to physiological functions

bARs are G protein-coupled receptors that are the targets of catecholamines such as norepinephrine and epinephrine and whose primary function is to transmit information from the extracellular environment to the interior of the cell, leading to activation of adenylyl cyclase and accumulation of the secondary messenger cAMP

β1 antagonists have negative inotropic and chronotropic effects. (affecting the heart rate and thereby increasing cardiac output), release renin, and increase lipolysis. Primarily in the heart

β2-adrenergic receptors cause dilation of blood vessels and bronchioles, stimulate insulin release, and increase lipolysis, glycogenolysis, and gluconeogenesis.

β3-adrenergic receptors are involved in lipolysis and mediate vascular relaxation but are activated by higher concentrations of catecholamines.

*bARs

*bARs have been found in breast, esophageal, pancreatic, ovarian, lung, head and neck, prostate, and colon cancer tissue*Badino GR Pharmacol Res. 1996 Apr-May;33(4-5):255-60.

* Liu X Cell Biochem. 2008 Sep 1;105(1):53-60.

*Ramberg H Prostate. 2008;Jul 1:68(10):1133-42.

*Madden KS Breast Cancer Res Treat. 2011;Jan 14.

*Al-Wadei HA PLoS One. 2012;7(1):e29915.

*in vivo model demonstrated the incidence of lymph node metastases increased with the administration of norepinephrine but decreased with the introduction of the B-blocker propranolol* Palm D et al. Int J Cancer. 2006;118:2744–9

*Propranolol

First-generation β-blocker

Non-selectively blocks both β1- and β2-adrenergic receptors.

Used with an orthotopic mouse model of ovarian cancer

Chronic behavioral stress resulted in increased levels of tissue catecholamines, an increased tumor burden, increased VEGF and increasingly invasive growth of ovarian carcinoma in that model.

These effects appeared to be mediated by activation of the tumor cell cyclic AMP-protein kinase A signaling pathway by β2-adrenergic receptor.

The effects of chronic behavioral stress abrogated by β-blockers

Thaker PH Nat Med. 2006 Aug;12(8):939-44

*Retrospective Data

Retrospective data on a cohort of ovarian cancer patients in whom use of B blockers reduced the risk of death by 56% below that in nonusers.

Diaz E, et al Gyn Onc 2011;120:S81.

Retrospectively studied breast cancer patients and showed that -blocker–based therapy reduced the number of distant metastases, the incidence of cancer recurrence, and mortality

* Powe DG. Oncotarget. 2010 October 19:1-11.

Improved relapse-free survival durations in patients with triple-negative breast cancers using beta-blockers

Melhem-Berrandt A. J Clin Oncol. 2011;29(19):2645-52

B blockers was associated with a reduced risk of progression of thick malignant melanoma and that Bblocker intake was associated with increased survival durations in melanoma patients

Lemeshow S Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2273-9.

* Improved Outcomes with Beta Blocker Use in Epithelial Ovarian Cancer Patients

J. Watkins et al SGO 2013

A multicenter review of 1,425 women with histopathologically confirmed EOC was performed.

Comparisons were made between patients with documented beta blocker use during their chemotherapy and those without beta blocker use.

*Results

Median age was 61 years (range; 31-93)

91.5% had tumors of serous histology

90.2% had advanced stage (III or IV) disease.

501 (35.2%) pts with hypertension and 269 (18.9%) of whom were on beta blockers.

195 (13.7%) were on β1 selective agents and remaining on non-selective beta-antagonists.

Median disease-specific survival (DSS) for

Patients with HTN was 41.4 months c/w 47.4 months for those without HTN (p=0.004).

Patients on beta blockers, the median DSS was 48.6 versus 42.4 months (p=0.02).

The median DSS based on beta blocker receptor selectivity was 90 months for those on non-selective beta blockers versus 38.2 months for those on β1 selective agents (p<0.001).

Conclusions:

Use of beta blockers in patients treated for EOC was associated with improved survival compared to non-beta blocker users. Our findings of improved survival for those on non-selective beta antagonists have implications for new therapeutic approaches.

* Beta blockers and Ovarian Cancer

*Imposed behavioral stress results in higher levels of tissue catecholamines, greater tumor burden, and a more invasive pattern of ovarian cancer growth in an orthotopic mouse model *mediated by b2 adrenergic receptor activation

*Ovarian carcinomas in patients with high depressive symptoms and low social support compared to low risk patients and found increased activity of several beta-adrenergically-linked transcription control pathways

*Elevated tissue levels of sympathetic catecholamine norepinephrine found in tumor samples from high biobehavioral risk profile patients

Thaker PH,et al. Nat Med 2006;12: 939-44.

Lutgendorf SK, et al. Brain Behav Immunity 2008;22: 890-900.

*Summary B Blockade

1) Chronic stress results in physiological changes

2) Retrospective studies indicate that use of beta-blocking anti-hypertensives is associated with improved survival and that the presence of adrenergic receptor beta (ADRB) correlates with prognostic indicators in certain cancer subtypes

3) In vitro and animal studies describing anticancer signaling activity, including reduction of serum and tumor VEGF levels with the use of beta adrenergic blocking agents

*Feasibility Study: Therapeutic Targeting of

Stress Factors in Ovarian Cancer Pts (13/25)

Primary Objectives:

Feasibility of pharmacologic beta-adrenergic blockade in women with Stages II-IV epithelial ovarian cancer patients (n=25) either during initial tumor reductive surgery and through the first six cycles of standard intravenous chemotherapy or during neoadjuvant chemotherapy followed by surgery and further chemo up to a total of 6 cycles

Secondary Objectives:

* To characterize the biobehavioral states of these patients by using the Functional Assessment of Chronic Illness and Therapy- Ovary (FACT-O), Hospital Anxiety and Depression Survey (HADS) and the Center for Epidemiologic Studies Depression Scale (CESD) and serum levels of angiogenic cytokines at points pre- and post-treatment with beta-blockers.

To follow patients for progression-free survival (PFS)

Translational objectives

To determine VEGF, IL-6, IL-8, MMP-2 and MMP-9 levels in pts with ovarian cancer who are receiving beta-blockers and comparing these levels pre-treatment and during treatment with chemotherapy.

* SCHEMA

*Blood drawn prior to administration of Propranolol after consented for study

*Fill out questionnaires (HADs, FACT O, ESAS, etc)

*Propranolol 20mg po bid x 48-72 hours pre-treatment (surgery or neoadjuvant chemotherapy) after being identified as having a possible ovarian, fallopian tube, or primary peritoneal carcinoma

*Restart oral Propranolol when patient is tolerating oral intake post-operatively (take continuously with neoadjuvant chemotherapy)

*For post-op patients, start intravenous platinum or taxane chemotherapy (without bevacizumab) x 6 cycles at the discretion of treating physician.

*For neoadjuvant patients give 3 cycles of intravenous platinum or taxane chemotherapy (without bevacizumab) followed by surgery, then 3 more cycles of chemotherapy.

SCHEMA

Blood drawn prior to administration of Propranolol after consented for study Fill out questionnaires

Instruct on use of R/GI MP3 use and diary

Propranolol 20mg po bid initiated

Patient instructed to listen to MP3 2x a week and record in diary

Increase propranolol to 40 mg po bid if the patient is tolerating at one month time point. Continue oral Propranolol until

removal from study

Blood drawn and completion of questionnaires after the completion of every two cycles (2 mos and 4 mos)

2013-0113 - Effect of a Beta Andrenergic Blockade & Relaxation/Guided Imagery Audio Intervention on symptom distress

in Advanced, Recurrent Incurable Cx Ca - Feasibility study

*Inclusion

•Proven recurrent cervical cancer of any histology not eligible for curative radiotherapy or surgery

•Failed chemotherapy for first recurrence (excluding chemotherapy with concurrent irradiation)

•Measurable or non-measurable disease

•1-3 prior therapies

*Exclusion*Patients whose disease may be cured by surgery or radiaotherapy.

*Contraindications to use of a Beta-Blocker or already receiving a Beta-Blocker.

*Performance status>3. (must have had treatment for first line recurrence)

*With exception of non-melanoma skin cancer & other specific malignancies, pts with other invasive malignancies who had (or have) any evidence of the other cancer present within the last five years or whose previous cancer treatment contraindicates this protocol therapy are excluded.

*Patients with a Zubrod Performance status 3 or 4.

*Comorbid conditions: Addison’s disease, autoimmune hepatitis, hepatitis B, hepatitis C, AIDS or HIV, lupus erythematosus, rheumatoid arthritis.

*Severe sinus bradycardia; heart block, second or third degree or sick sinus syndrome (if no artificial pacemaker present).

*Severe hyperactive airway disease (COPD, asthma).

*Any patients on Avastin or any other anti-angiogenic drugs.

*Patients with brittle diabetes mellitus.

*Pts participating in or who plan to participation in other trials during course of study.

*Key TargetsDiagnosis, Change of

Chemotherapy, Surgery?

* Surgical stress promotes tumor growth in ovarian carcinoma

Higher levels of distress among pts with ov ca at time of surgery associated with-

*Poor NK cell activity in TILs

*Lower T cell production of TH1 vs TH2 cytokines in peripheral blood and TIL

*Social support related to greater NK activity

*Clin Cancer Res. 2009 Apr 15;15(8):2695-702. Lee JW…Sood AK et al

*Stress and Well being?

Pre surgical clinic visit (FACT sp, BDI, Perceived Stress Scale)

165 pts with ovarian cancer ( Measured IL6, IL8, VEGF (ELISA))

Higher spirituality correlated with lower depression (p<.001) and perceived stress (p<.001)

Higher spirituality correlated with lower IL6

Spirituality not related to IL8 or VEGFThaker et al Abstract SGO 2013

*Stress Reduction Methods for

Surgery?

YOGA

PROZAC

MEDITATION

* Enhanced Recovery After Surgery (ERAS) program attenuates stress and accelerates recovery after resection for colorectal ca: a

prospective RCT

Pts undergoing elective colorectal resection randomized to ERAS (n = 299) or the control group (n = 298).

Results

Pts in the ERAS group showed improved nutritional status when compared to control group.

Cortisol level of the control group was elevated on both POD 1 (p = 0.007) and POD 5 (p = 0.002) compared to the preoperative level.

Cortisol level of the ERAS group was not increased until POD 5 (p = 0.001).

Reduced levels of TNF-α, IL-1β, IL-6, and IFN-γ in the ERAS group indicated less postoperative stress responses.

* World J Surg. 2012 Feb;36(2):407-14. doi: 10.1007/s00268-011-1348-4.

* Psychological/Behavioral Approaches

* GOG225: Can Diet and Physical Activity Modulate Ovarian, Fallopian Tube and Primary Peritoneal Cancer Progression-Free

Survival?

Eligible participants will be randomly assigned:

Usual Care Group or Lifestyle Intervention Group.

* Participants assigned to the lifestyle intervention group will be asked to modify their diet and physical activity levels while those assigned to the usual care group will be asked to continue usual diet/exercise routine.

* They will be asked to fill out questionnaires, give a blood specimen, wear a pedometer, and participate in telephone coaching calls over a period of two years

* Groups will be compared to see if diet and exercise impact the incidence of ovarian, fallopian tube and primary peritoneal cancer recurrence.

*What Else Can You Do?

You can't stop the waves, but you can learn to surf.”

― Jon Kabat-Zinn

*Viktor E. Frankl, Man's Search for

Meaning

“Everything can be taken from a man but one thing: the last of the human freedoms—to choose one’s attitude in any given set of circumstances, to choose one’s own way.”

*Meaning Centered Group Therapy

Developed to help advanced cancer patients sustain or enhance a sense of meaning, peace and purpose even near the end of life.

8-week intervention influenced by work of Viktor Frankl

Utilizes didactics, discussion and experiential exercises

Decreased distress, increased mindfulness and post traumatic growth

Stafford et al Suppor Care Cancer 2013

Psycho-Oncology 19: 21–28 (2010)

“Man does not simply exist but always decides what his existence will be, what he will become the next moment. By the same token, every human being has the freedom to change at any instant.”

― Viktor E. Frankl, Man's Search for Meaning

Discovering Meaning…

* Creating a work or doing a deed* Experiencing something or

encountering someone*Truth, goodness, beauty…nature, culture…loving another

* By the Attitude we take toward unavoidable suffering turning personal tragedy into a triumph, a human achievement*Frankl

*Meaning Making Interventions

*Video legacy*Dignity Therapy*Faith Based*Letters to special people*Support groups +/-*Gratitude Diary*Enhancing control*Tape recorder?

*How care givers help women with cancer de-stress

*Recognize hope exists at every stage of illness*Ask*Help identify goals, create plan and instill hope

*Address depression and anxiety*Have a shared presence, listen*Encourage closeness of friends and family*Address lack of social supports*Introduce patients to others who have done well

*Build sense of control by informing*Assist transitioning “hope objects”

*Krista Tippet On Being NPR

*Arthur Zajonc on Holding Life Consciously

*http://www.onbeing.org/program/arthur-zajonc-on-holding-life-consciously/109