Determination of permissive and restraining cancer-associated fibroblast (DeCAF) subtypes.

Cancer-associated fibroblast (CAF) subpopulations in pancreatic ductal adenocarcinoma (PDAC) have been identified using single-cell RNA sequencing (scRNAseq) with divergent characteristics, but their clinical relevance remains unclear. We translate scRNAseq-derived CAF cell-subpopulation-specific marker genes to bulk RNAseq data, and develop a single- sample classifier, DeCAF, for the classification of clinically rest raining and perm issive CAF subtypes. We validate DeCAF in 19 independent bulk transcriptomic datasets across four tumor types (PDAC, mesothelioma, bladder and renal cell carcinoma). DeCAF subtypes have distinct histology features, immune landscapes, and are prognostic and predict response to therapy across cancer types. We demonstrate that DeCAF is clinically replicable and robust for the classification of CAF subtypes in patients for multiple tumor types, providing a better framework for the future development and translation of therapies against permissive CAF subtypes and preservation of restraining CAF subtypes. Significance: We introduce a replicable and robust classifier, DeCAF, that delineates the significance of the role of permissive and restraining CAF subtypes in cancer patients. DeCAF is clinically tractable, prognostic and predictive of treatment response in multiple cancer types and lays the translational groundwork for the preclinical and clinical development of CAF subtype specific therapies.

Aggressive End-of-Life Care in the Veterans Health Administration versus Fee-for-Service Medicare among Patients with Advanced Lung Cancer.

Background: Unlike fee-for-service Medicare, the Veterans Health Administration (VHA) allows for the provision of concurrent care, incorporating cancer treatment while in hospice. Methods: We compared trends of aggressive care at end of life between Medicare and VHA decedents with advanced nonsmall cell lung cancer from 2006 to 2012, and the relation between regional level end-of-life care between Medicare and VHA beneficiaries. Results: Among 18,371 Veterans and 25,283 Medicare beneficiaries, aggressive care at end of life decreased 15% in VHA and 4% in SEER (Surveillance, Epidemiology, and End Results)-Medicare (p < 0.001). Hospice use significantly increased within both cohorts (VHA 28%-41%; SM 60%-73%, p < 0.001). Veterans receiving care in regions with higher hospice admissions among Medicare beneficiaries were significantly less likely to receive aggressive care at end of life (adjusted odds ratio: 0.13, 95% confidence interval: 0.08-0.23, p < 0.001). Conclusions: Patients receiving lung cancer care in the VHA had a greater decline in aggressive care at end of life, perhaps due to increasing concurrent care availability.

Concurrent Hospice Care and Cancer-Directed Treatment for Advanced Lung Cancer and Receipt of Aggressive Care at the End of Life in the Veteran's Health Administration.

Background: Aggressive care at the end of life (EOL) is a persistent issue for patients with stage IV nonsmall cell lung cancer (NSCLC). We evaluated the use of concurrent care (CC) with hospice care and cancer-directed treatment simultaneously within the Veteran's Health Administration (VHA) and aggressive care at the EOL. Objective: To determine whether VHA facility-level CC is associated with changes in aggressive care at the EOL. Design/Setting: Veterans with stage IV NSCLC who died between 2006 and 2012 and received lung cancer care within the VHA. Measurements: The primary outcome was aggressive care at EOL (i.e., hospital admissions, chemotherapy, and intensive care unit) within the last month of life. To compare aggressive care across VHA facilities, we used a random intercept multilevel logistic regression model to examine the association between facility-level CC within each study year (<10%, 10% to 19%, and ≥20%) and aggressive care at the EOL among the decedents as a binary outcome. Results: In total, 18,371 veterans with NSCLC at 154 VHA facilities were identified. Facilities delivering CC for ≥20% of veterans (high CC) increased from 20.0% in 2006 to 43.2% in 2012 (p < 0.001). Overall, hospice care significantly increased and aggressive care at EOL decreased over the study period. However, facility-level CC adoption was not associated with any difference in aggressive care at EOL (adjusted odds ratio high CC vs. low CC: 0.91 [95% CI, 0.79 to 1.05], p = 0.21). Conclusions: Although the VHA adoption of CC increased hospice use among patients with NSCLC, additional measures may be needed to decrease aggressive care at the EOL.

Effect of the Tool to Reduce Inappropriate Medications on Medication Communication and Deprescribing.

OBJECTIVES: To examine the effect of the Tool to Reduce Inappropriate Medications (TRIM), a web tool linking an electronic health record (EHR) to a clinical decision support system, on medication communication and prescribing. DESIGN: Randomized clinical trial. SETTING: Primary care clinics at a Veterans Affairs Medical Center. PARTICIPANTS: Veterans aged 65 and older prescribed seven or more medications randomized to receipt of TRIM or usual care (N = 128). INTERVENTION: TRIM extracts information on medications and chronic conditions from the EHR and contains data entry screens for information obtained from brief chart review and telephonic patient assessment. These data serve as input for automated algorithms identifying medication reconciliation discrepancies, potentially inappropriate medications (PIMs), and potentially inappropriate regimens. Clinician feedback reports summarize discrepancies and provide recommendations for deprescribing. Patient feedback reports summarize discrepancies and self-reported medication problems. MEASUREMENTS: Primary: subscales of the Patient Assessment of Care for Chronic Conditions (PACIC) related to shared decision-making; clinician and patient communication. Secondary: changes in medications. RESULTS: 29.7% of TRIM participants and 15.6% of control participants provided the highest PACIC ratings; this difference was not significant. Adjusting for covariates and clustering of patients within clinicians, TRIM was associated with significantly more-active patient communication and facilitative clinician communication and with more medication-related communication among patients and clinicians. TRIM was significantly associated with correction of medication discrepancies but had no effect on number of medications or reduction in PIMs. CONCLUSION: TRIM improved communication about medications and accuracy of documentation. Although there was no association with prescribing, the small sample size provided limited power to examine medication-related outcomes.

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Modifiable risk factors for pneumonia requiring hospitalization of community-dwelling older adults: the Health, Aging, and Body Composition Study.

OBJECTIVES: To identify novel modifiable risk factors, focusing on oral hygiene, for pneumonia requiring hospitalization of community-dwelling older adults. DESIGN: Prospective observational cohort study. SETTING: Memphis, Tennessee, and Pittsburgh, Pennsylvania. PARTICIPANTS: Of 3,075 well-functioning community-dwelling adults aged 70 to 79 enrolled in the Health, Aging, and Body Composition Study from 1997 to 1998, 1,441 had complete data in the data set of all variables used, a dental examination within 6 months of baseline, and were eligible for this study. MEASUREMENTS: The primary outcome was pneumonia requiring hospitalization through 2008. RESULTS: Of 1,441 participants, 193 were hospitalized for pneumonia. In a multivariable model, male sex (hazard ratio (HR) = 2.07, 95% confidence interval (CI) = 1.51-2.83), white race (HR = 1.44, 95% CI = 1.03-2.01), history of pneumonia (HR = 3.09, 95% CI = 1.86-5.14), pack-years of smoking (HR = 1.006, 95% CI = 1.001-1.011), and percentage of predicted forced expiratory volume in 1 minute (moderate vs mild lung disease or normal lung function, HR = 1.78, 95% CI = 1.28-2.48; severe lung disease vs mild lung disease or normal lung function, HR = 2.90, 95% CI = 1.51-5.57) were nonmodifiable risk factors for pneumonia. Incident mobility limitation (HR = 1.77, 95% CI = 1.32-2.38) and higher mean oral plaque score (HR = 1.29, 95% CI = 1.02-1.64) were modifiable risk factors for pneumonia. Average attributable fractions revealed that 11.5% of cases of pneumonia were attributed to incident mobility limitation and 10.3% to a mean oral plaque score of 1 or greater. CONCLUSION: Incident mobility limitation and higher mean oral plaque score were two modifiable risk factors that 22% of pneumonia requiring hospitalization could be attributed to. These data suggest innovative opportunities for pneumonia prevention among community-dwelling older adults.

Burden in caregivers of older adults with advanced illness.

OBJECTIVES: To examine caregiver burden over time in caregivers of patients with advanced chronic disease. DESIGN: Observational cohort with interviews over 12 months. SETTING: Community. PARTICIPANTS: Caregivers of 179 community-living persons aged 60 and older with advanced cancer, heart failure (HF), or chronic obstructive pulmonary disease (COPD). MEASUREMENTS: Caregiver burden was assessed using a short-form of the Zarit Burden Inventory to measure psychosocial distress. RESULTS: At baseline, the median caregiver burden was 5 (interquartile range (IQR) 1-11), which indicates that the caregiver endorsed having at least two of 10 distressing concerns at least some of the time. Only 10% reported no burden. Although scores increased modestly over time, the association between time and burden was not significant in longitudinal multivariable analysis. High burden was associated with caregiver need for more help with daily tasks (odds ratio (OR)=23.13, 95% confidence interval (CI)=5.94-90.06) and desire for greater communication with the patient (OR=2.53, 95% CI=1.16-5.53). The longitudinal multivariable analysis did not yield evidence of associations between burden and patient sociodemographic or health characteristics. CONCLUSION: Caregiver burden was common in caregivers of patients with cancer, HF, and COPD. High burden was associated with the caregiver's report of need for greater help with daily tasks but not with objective measures of the patient's need for assistance, such as symptoms or functional status, suggesting that burden may be a measure of the caregiver's ability to adapt to the caregiving role.

Understanding their options: determinants of hospice discussion for older persons with advanced illness.

BACKGROUND: Clinicians' discussions about hospice with patients and families are important as a means of communicating end-of-life options. OBJECTIVE: To identify determinants of clinicians' hospice discussions and the impact of such discussions on hospice use. DESIGN: We interviewed 215 patients age > or = 60 years with advanced cancer, chronic obstructive pulmonary disease (COPD), or heart failure (HF) at least every 4 months for up to 2 years. Participants provided information about their health status and treatment preferences. Clinicians completed a questionnaire every 6 months about their estimates of patient life expectancy and their communication with the patient and family about hospice. RESULTS: In their final survey, clinicians reported discussing hospice with 46% of patients with cancer, compared to 10% with COPD and 7% with HF. Apart from diagnosis of cancer, the factors most strongly associated with hospice discussion were clinicians' estimate of and certainty about patient life expectancy (P < 0.001). However, clinicians were unable to anticipate the deaths of a considerable portion of patients (40%). Although patient unwillingness to undergo minor medical interventions was associated with hospice discussion (P < 0.05), a sizeable portion of clinicians (40%) whose patients reported this characteristic did not have the discussion. Clinicians' discussion of hospice independently increased the likelihood of hospice use (OR = 5.3, 95% CI = 2.3-13). CONCLUSIONS: Clinicians' discussion of hospice for patients with advanced illness, and, ultimately, patients' use of hospice, relies largely on clinician estimates of patient life expectancy and the predictability of disease course. Many clinicians whose patients might benefit from learning about hospice are not having these discussions.

Using the experiences of bereaved caregivers to inform patient- and caregiver-centered advance care planning.

BACKGROUND: Traditional approaches to advance care planning (ACP) have many limitations; new approaches are being developed with the goal of improving end-of-life care. OBJECTIVE: To understand how the end-of-life care experiences of older patients and their caregivers can inform the development of new approaches to ACP. DESIGN: Qualitative cross-sectional study. PARTICIPANTS: Caregivers of community-dwelling persons age > or = 60 years who died with advanced cancer, chronic obstructive pulmonary disease, or heart failure during follow-up in a longitudinal study. APPROACH: In-depth interviews were conducted 6 months after the patient's death with 64 caregivers. Interviews began with open-ended questions to encourage the caregiver to tell the story of the patient's experiences at the end of life. Additional questions asked about how decisions were made, patient-caregiver, patient-clinician, and caregiver-clinician communication. MAIN RESULTS: Although the experiences recounted by caregivers were highly individual, several common themes emerged from the interviews. These included the following: 1) the lack of availability of treatment options for certain patients, prompting patients and caregivers to consider broader end-of-life issues, 2) changes in preferences at the very end of an illness, 3) variability in patient and caregiver desire for and readiness to hear information about the patient's illness, and 4) difficulties with patient-caregiver communication. DISCUSSION: The experiences of older patients at the end of life and their caregivers support a form of ACP that includes a broader set of issues than treatment decision-making alone, recognizes the dynamic nature of preferences, and focuses on addressing barriers to patient-caregiver communication.

Religion, risk, and medical decision making at the end of life.

OBJECTIVE: The purpose of this study is to present empirical evidence about whether religious patients are more or less willing to undergo the risks associated with potentially life-sustaining treatment. METHODS: At least every 4 months 226 older community-dwelling persons with advanced cancer, congestive heart failure, or chronic obstructive pulmonary disease were asked questions about several dimensions of religiousness and about their willingness to accept potentially life-sustaining treatment. RESULTS: Results were mixed but persons who said that during their illness they grew closer to God (odds ratio [OR] = 1.79; 95% confidence intervals [CI] = 1.15, 2.78) or those grew spiritually (OR = 1.61; 95% CI = 1.03, 2.52) were more willing to accept risk associated with potentially life-sustaining treatment than were persons who did not report such growth. DISCUSSION: Not all dimensions of religiousness have the same association with willingness to undergo potentially life-sustaining treatment. Seriously ill older, religious patients are not especially predisposed to avoid risk and resist treatment.

Refusal of medical and surgical interventions by older persons with advanced chronic disease.

BACKGROUND: Patients with advanced chronic disease are frequently offered medical and surgical interventions with potentially large trade-offs between benefits and burdens. Little is known about the frequency or outcomes of treatment refusal among these patients. OBJECTIVE: To assess the frequency of, reasons for, factors associated with, and outcomes of treatment refusal among older persons with advanced chronic disease. DESIGN: Observational cohort study. PARTICIPANTS: Two hundred twenty-six community-dwelling persons with advanced cancer, chronic obstructive pulmonary disease, or congestive heart failure, interviewed at least every 4 months for up to 2 years. MEASUREMENTS: Participants were asked if they had refused any treatments recommended by their physicians, and why. RESULTS: Thirty-six of 226 patients (16%) reported refusing 1 or more medical or surgical treatments recommended by their physician. The most frequently refused interventions were cardiac catheterization and surgery. The most common reason for refusal was fear of side effects (41%). Treatment refusal was more frequent among patients who wanted prognostic information (10% vs 2%, p = .02) or estimated their own longevity at 2 years or less (18% vs 5%, p = .02). There was an increased risk of mortality among refusers compared with non-refusers (HR 1.98, 95% CI 1.02-3.86). CONCLUSIONS: Refusal of medical and surgical interventions other than medications is common among persons with advanced chronic disease, and is associated with a greater desire for, and understanding of, prognostic information.

Changes in preferences for life-sustaining treatment among older persons with advanced illness.

BACKGROUND: There are conflicting assumptions regarding how patients' preferences for life-sustaining treatment change over the course of serious illness. OBJECTIVE: To examine changes in treatment preferences over time. DESIGN: Longitudinal cohort study with 2-year follow-up. PARTICIPANTS: Two hundred twenty-six community-dwelling persons age > or =60 years with advanced cancer, congestive heart failure, or chronic obstructive pulmonary disease. MEASUREMENTS: Participants were asked, if faced with an illness exacerbation that would be fatal if untreated, whether they would: a) undergo high-burden treatment at a given likelihood of death and b) undergo low-burden treatment at a given likelihood of severe disability, versus a return to current health. RESULTS: There was little change in the overall proportions of participants who would undergo therapy at a given likelihood of death or disability from first to final interview. Diversity within the population regarding the highest likelihood of death or disability at which the individual would undergo therapy remained substantial over time. Despite a small magnitude of change, the odds of participants' willingness to undergo high-burden therapy at a given likelihood of death and to undergo low-burden therapy at a given likelihood of severe cognitive disability decreased significantly over time. Greater functional disability, poorer quality of life, and lower self-rated life expectancy were associated with decreased willingness to undergo therapy. CONCLUSIONS: Diversity among older persons with advanced illness regarding treatment preferences persists over time. Although the magnitude of change is small, there is a decreased willingness to undergo highly burdensome therapy or to risk severe disability in order to avoid death over time and with declining health status.

Prospective study of health status preferences and changes in preferences over time in older adults.

BACKGROUND: Instructional forms of advance care planning depend on the ability of patients to predict their future treatment preferences. However, preferences may change with changes in patients' health states. METHODS: We conducted in-home interviews of 226 older community-dwelling persons with advanced cancer, congestive heart failure, or chronic obstructive pulmonary disease at least every 4 months for up to 2 years. Patients were asked to rate whether treatment for their illness would be acceptable if it resulted in 1 of 4 health states. RESULTS: The likelihood of rating as acceptable a treatment resulting in mild (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.06-1.16) or severe (OR, 1.06; 95% CI, 1.03-1.09) functional disability increased with each month of participation. Patients who experienced a decline in their ability to perform instrumental activities of daily living were more likely to rate as acceptable treatment resulting in mild (OR, 1.23; 95% CI, 1.08-1.40) or severe (OR, 1.23; 95% CI, 1.11-1.37) disability. Although the overall likelihood of rating treatment resulting in a state of pain as acceptable did not change over time (OR, 0.98; 95% CI, 0.96-1.01), patients who had moderate to severe pain were more likely to rate this treatment as acceptable (OR, 2.55; 95% CI, 1.56-4.19) than were those who did not have moderate to severe pain. CONCLUSIONS: For some patients, the acceptability of treatment resulting in certain diminished states of health increases with time, and increased acceptability is more likely among patients experiencing a decline in that same domain. These changes pose a challenge to advance care planning, which asks patients to predict their future treatment preferences.

Are patient preferences for life-sustaining treatment really a barrier to hospice enrollment for older adults with serious illness?

OBJECTIVES: To determine whether patient preferences are a barrier to hospice enrollment. DESIGN: Prospective cohort study. SETTING: Fifteen ambulatory primary care and specialty clinics and three general medicine inpatient units. PARTICIPANTS: Two hundred three seriously ill patients with cancer (n=65, 32%), congestive heart failure (n=77, 38%), and chronic obstructive pulmonary disease (n=61, 30%) completed multiple interviews over a period of up to 24 months. MEASUREMENTS: Preferences for high- and low-burden life-sustaining treatment and site of death and concern about being kept alive by machines. RESULTS: Patients were more likely to enroll in hospice after interviews at which they said that they did not want low-burden treatment (3 patients enrolled/16 interviews at which patients did not want low-burden treatment vs 47 patients enrolled/841 interviews at which patients wanted low-burden treatment; relative risk (RR)=3.36, 95% confidence interval (CI)=1.17-9.66), as were interviews at which patients said they would not want high-burden treatment (5/28 vs 45/826; RR=3.28, 95% CI=1.14-7.62), although most patients whose preferences were consistent with hospice did not enroll before the next interview. In multivariable Cox regression models, patients with noncancer diagnoses who desired low-burden treatment (hazard ratio (HR)=0.46, 95% CI=0.33-0.68) were less likely to enroll in hospice, and those who were concerned that they would be kept alive by machines were more likely to enroll (HR=5.46, 95% CI=1.86-15.88), although in patients with cancer, neither preferences nor concerns about receiving excessive treatment were associated with hospice enrollment. Preference for site of death was not associated with hospice enrollment. CONCLUSION: Overall, few patients had treatment preferences that would make them eligible for hospice, although even in patients whose preferences were consistent with hospice, few enrolled. Efforts to improve end-of-life care should offer alternatives to hospice that do not require patients to give up life-sustaining treatment, as well as interventions to improve communication about patients' preferences.

Doctor-patient communication about prognosis: the influence of race and financial status.

CONTEXT: Although many studies have documented problems in communication between physicians and patients, few have focused on discussions regarding prognosis among community dwelling patients with terminal illness. OBJECTIVE: To examine the association of patient race and financial status with patient and clinician reports of discussions about prognosis. DESIGN: Cross-sectional survey. SETTING: Participants' homes. PARTICIPANTS: Two hundred fourteen patients age 60 years or older seriously ill secondary to congestive heart failure, chronic obstructive pulmonary disease, or cancer; and their primary clinicians. MAIN OUTCOME MEASURES: Patient/clinician agreement regarding discussions of prognosis. RESULTS: In adjusted analysis, patients and clinicians were more likely to agree that discussions about prognosis had taken place when patients had a lower financial status (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.03-4.96), or were nonwhite (OR 2.56, CI 0.85-7.68), compared to patients who had a higher financial status or were white. Agreement about prognosis discussions was also more likely (adjusted OR 4.12, 95% CI 1.15-14.76) when patients were younger (i.e., age < 80). CONCLUSIONS: Among a cohort of seriously ill community-dwelling patients, patients and clinicians were more likely to agree that discussions about prognosis had occurred when patients were poorer and nonwhite. These findings contrast with the majority of studies examining the relationship between race or income and patient-physician communication about other end-of-life issues.

Unmet desire for caregiver-patient communication and increased caregiver burden.

OBJECTIVES: To examine the adequacy of caregiver-patient communication in serious illness and its relationship to caregiver burden. DESIGN: Cross-sectional cohort study. SETTING: Participants' homes. PARTICIPANTS: One hundred ninety-three persons aged 60 and older seriously ill with cancer, congestive heart failure, or chronic obstructive pulmonary disease and their caregivers. MEASUREMENTS: Communication concerns, measured in terms of agreement with statements regarding desire for and difficulty with communication about the patient's illness. Caregiver burden, measured using a 10-item subset of the Zarit Burden Inventory, with scores ranging from 0 to 40 and higher scores indicating greater burden. RESULTS: Of caregivers, 39.9% desired more communication, and 37.3% reported that communication was difficult. Of patients, 20.2% desired more communication, and 22.3% reported that communication was difficult. Disagreement regarding communication concerns was frequent in caregiver-patient pairs; of caregivers who desired more communication, 83.1% of patients did not, and of patients who desired more communication, 66.7% of caregivers did not. Caregivers who desired more communication had significantly higher caregiver burden scores than did caregivers who did not (9.2 vs 4.7, P<.001), even after adjusting for patient's diagnosis, income, and functional status and caregivers' age, sex, and relationship to the patient. CONCLUSION: A large proportion of caregivers and seriously ill older persons had an unmet desire for increased communication, although they frequently disagreed with each other about this desire. Caregivers' desire for increased communication may be a modifiable determinant of caregiver burden.