Organoid models of human and mouse ductal pancreatic cancer.

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.

Identification of novel vascular projections with cellular trafficking abilities on the microvasculature of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a nearly lethal neoplasm. It is a remarkably stroma-rich, vascular-poor and hypo-perfused tumour, which prevents efficient drug delivery. Paradoxically, the neoplastic cells have robust glucose uptake, suggesting that the microvasculature has adopted an alternative method for nutrient uptake and cellular trafficking. Using adapted thick tumour section immunostaining and three-dimensional (3D) construction imaging in human tissue samples, we identified an undiscovered feature of the mature microvasculature in advanced PDAC tumours; long, hair-like projections on the basal surface of microvessels that we refer to as 'basal microvilli'. Functionally, these basal microvilli have an actin-rich cytoskeleton and endocytic and exocytic properties, and contain glucose transporter-1 (GLUT-1)-positive vesicles. Clinically, as demonstrated by PET-CT, the tumour microvasculature with the longest and most abundant basal microvilli correlated with high glucose uptake of the PDAC tumour itself. In addition, these basal microvilli were found in regions of the tumour with low GLUT-1 expression, suggesting that their presence could be dependent upon the glucose concentration in the tumour milieu. Similar microvasculature features were also observed in a K-Ras-driven model of murine PDAC. Altogether, these basal microvilli mark a novel pathological feature of PDAC microvasculature. Because basal microvilli are pathological features with endo- and exocytic properties, they may provide a non-conventional method for cellular trafficking in PDAC tumours.

Thalamic Functional Connectivity in Mild Traumatic Brain Injury: Longitudinal Associations With Patient-Reported Outcomes and Neuropsychological Tests.

OBJECTIVES: (1) To examine differences in patient-reported outcomes, neuropsychological tests, and thalamic functional connectivity (FC) between patients with mild traumatic brain injury (mTBI) and individuals without mTBI and (2) to determine longitudinal associations between changes in these measures. DESIGN: Prospective observational case-control study. SETTING: Academic medical center. PARTICIPANTS: A sample (N=24) of 13 patients with mTBI (mean age, 39.3±14.0y; 4 women [31%]) and 11 age- and sex-matched controls without mTBI (mean age, 37.6±13.3y; 4 women [36%]). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Resting state FC (3T magnetic resonance imaging scanner) was examined between the thalamus and the default mode network, dorsal attention network, and frontoparietal control network. Patient-reported outcomes included pain (Brief Pain Inventory), depressive symptoms (Patient Health Questionnaire-9), posttraumatic stress disorder ([PTSD] Checklist - Civilian Version), and postconcussive symptoms (Rivermead Post-Concussion Symptoms Questionnaire). Neuropsychological tests included the Delis-Kaplan Executive Function System Tower test, Trails B, and Hotel Task. Assessments occurred at 6 weeks and 4 months after hospitalization in patients with mTBI and at a single visit for controls. RESULTS: Student t tests found increased pain, depressive symptoms, PTSD symptoms, and postconcussive symptoms; decreased performance on Trails B; increased FC between the thalamus and the default mode network; and decreased FC between the thalamus and the dorsal attention network and between the thalamus and the frontoparietal control network in patients with mTBI as compared with controls. The Spearman correlation coefficient indicated that increased FC between the thalamus and the dorsal attention network from baseline to 4 months was associated with decreased pain and postconcussive symptoms (corrected P<.05). CONCLUSIONS: Findings suggest that alterations in thalamic FC occur after mTBI, and improvements in pain and postconcussive symptoms are correlated with normalization of thalamic FC over time.

Psychosocial Factors Predict Pain and Physical Health After Lower Extremity Trauma.

BACKGROUND: There has been increasing evidence to support the importance of psychosocial factors to poor outcomes after trauma. However, little is known about the contribution of pain catastrophizing and fear of movement to persistent pain and disability. QUESTIONS/PURPOSES: Therefore, we aimed to determine whether (1) high pain catastrophizing scores are independently associated with pain intensity or pain interference; (2) high fear of movement scores are independently associated with decreased physical health; and (3) depressive symptoms are independently associated with pain intensity, pain interference, or physical health at 1 year after accounting for patient characteristics of age and education. METHODS: Of 207 eligible patients, we prospectively enrolled 134 patients admitted to a Level I trauma center for surgical treatment of a fracture to the lower extremity. Sixty percent of patients (80 of 134) had an isolated lower extremity injury and the remainder sustained additional minor injury to the head/spine, abdomen/thorax, or upper extremity. Pain catastrophizing was measured with the Pain Catastrophizing Scale, fear of movement with the Tampa Scale for Kinesiophobia, and depressive symptoms with the Patient Health Questionnaire. Pain and physical health outcomes were assessed with the Brief Pain Inventory and the SF-12, respectively. Assessments were completed at 4 weeks and 1 year after hospitalization. Multiple variable hierarchical linear regression analyses were used to address study hypotheses. One hundred ten patients (82%) completed the 1-year followup. RESULTS: Pain catastrophizing at 4 weeks was associated with pain intensity (ß = 0.67; p < 0.001) and pain interference (ß = 0.38; p = 0.03) at 1 year. No association was found between fear of movement and physical health (ß = 0.15; p = 0.34). Depressive symptoms at 4 weeks were associated with pain intensity (ß = 0.49; p < 0.001), pain interference (ß = 0.51; p < 0.001), and physical health (ß = -0.32; p = 0.01) at 1 year. CONCLUSIONS: Catastrophizing behavior patterns and depressive symptoms are associated with more severe pain and worse function after traumatic lower extremity injury. Cognitive and behavioral strategies that have proven effective for chronic pain populations may be beneficial for trauma patients. Future research is needed to determine whether the early identification and treatment of subgroups of at-risk patients based on catastrophizing behavior or depressive symptoms can improve long-term outcomes. LEVEL OF EVIDENCE: Level I, prognostic study.

Hospital delirium and psychological distress at 1 year and health-related quality of life after moderate-to-severe traumatic injury without intracranial hemorrhage.

OBJECTIVES: To determine whether delirium during the hospital stay predicted health-related quality of life (HRQOL) at 1 year after injury in trauma intensive care unit (ICU) survivors without intracranial hemorrhage, and to examine the association between depressive and posttraumatic stress disorder (PTSD) symptoms and each of the HRQOL domains at 1-year follow-up. DESIGN: Prognostic cohort with a 1-year follow-up. SETTING: Level 1 trauma ICU. PARTICIPANTS: Adult patients without intracranial hemorrhage (N=173) admitted to a level 1 trauma ICU. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: HRQOL was measured with the Medical Outcomes Study 36-Item Short-Form Health Survey at 1 year after traumatic injury. RESULTS: Average delirium duration ± SD was .51±1.1 days. Hierarchical multivariable linear regression analyses did not find a statistical relationship between delirium and HRQOL at 1-year follow-up. However, increased levels of depressive symptoms at 1 year were statistically associated with poorer functioning in all physical and mental health HRQOL domains, whereas PTSD at 1 year was statistically associated with all HRQOL domains except role-physical (P<.05). CONCLUSIONS: There was no statistical association between delirium during the hospital stay and HRQOL at 1 year, which may be due to the short time spent in delirium by our study population. Depressive symptoms demonstrated a stronger relationship with mental and physical HRQOL domains at 1 year than PTSD, indicating their own unique pathway after trauma. Findings lend support for the separate assessment and management of depression and PTSD. Additional research on the duration and subtypes of delirium is needed within the trauma ICU population, as the effects are not widely known.

A prospective investigation of long-term cognitive impairment and psychological distress in moderately versus severely injured trauma intensive care unit survivors without intracranial hemorrhage.

BACKGROUND: The primary objective was to prospectively determine the 12-month prevalence of cognitive impairment and psychologic difficulties in moderately versus severely injured adult trauma intensive care unit (TICU) survivors without intracranial hemorrhage. METHODS: We conducted a prospective cohort study in which patients were followed for 1 year after hospital discharge. A total of 173 patients from the Vanderbilt TICU who had an Injury Severity Score (ISS) of >15 (indicative of moderately severe trauma) were enrolled between July 2006 and June 2007. Patients were screened for delirium on a daily basis in the TICU by study personnel via the confusion assessment method of the ICU, and preexisting cognitive impairment was assessed through a surrogate-based evaluation using the short form of the Informant Questionnaire for Cognitive Decline in the Elderly. Of these patients, 108 were evaluated 1 year after hospital discharge with a comprehensive battery of neuropsychological tests and depression and posttraumatic stress disorder (PTSD) instruments. Cognitive impairment was defined as having two neuropsychological test scores 1.5 SD below the mean or one neuropsychological test score 2 SD below the mean. RESULTS: Fifty-nine patients (55%) demonstrated cognitive impairment at 12-month follow-up, with three of these patients (5.5%) having preexisting impairment. Clinically significant symptoms of depression and PTSD occurred in 40% and 26% of patients, respectively. No significant differences in cognitive impairment (59% vs. 50%), depressive symptoms (35% vs. 44%), and symptoms of PTSD (22% vs. 28%) were identified between moderately (ISS 15-25) and severely (ISS>25) injured TICU survivors, respectively (all p>0.05). In addition, multivariate logistic regression analysis found that moderately injured trauma patients had a similar rate of cognitive impairment when compared with those with severe injury at 12-month follow-up (p=0.25). CONCLUSION: Long-term cognitive impairment is highly prevalent in TICU survivors without intracranial hemorrhage as are psychologic difficulties. Injury severity, concussion status, and delirium duration were not risk factors for the development of neuropsychological deficits in this cohort. Individuals with moderately severe injuries seem to be as likely as their more severely injured counterparts to experience marked cognitive impairment and psychologic difficulties; thus, screening efforts should focus on this potentially overlooked patient group.

Clinical Significance of Pain at Hospital Discharge Following Traumatic Orthopedic Injury: General Health, Depression, and PTSD Outcomes at 1 Year.

OBJECTIVES: The purpose of this study was to determine whether pain at hospital discharge is associated with general health and depression and posttraumatic stress disorder (PTSD) at 1 year following traumatic orthopedic injury. MATERIALS AND METHODS: This study prospectively enrolled 213 patients, 19 to 86 years of age, admitted to an academic level 1 trauma center for surgical treatment of a traumatic lower-extremity or upper-extremity orthopedic injury. Pain at hospital discharge was measured with the Brief Pain Inventory. At 1-year follow-up, physical and mental health was assessed with the SF-12 and depressive and PTSD symptoms with the 9-item Patient Health Questionnaire (PHQ-9) and PTSD Checklist-Civilian Version (PCL-C), respectively. Cut-off scores of 10 on the PHQ-9 and 44 on the PCL-C classified patients as having depression or PTSD. RESULTS: A total of 133 patients (62%) completed follow-up at 1 year. Responders and nonresponders did not differ significantly on baseline characteristics. Multivariable regression found that increased pain at discharge was significantly associated with depression (odds ratio=3.3; P<0.001) and PTSD (odds ratio=1.4; P=0.03) at 1 year, after controlling for age, education, injury severity score, and either depressive or PTSD symptoms at hospital discharge. Early postoperative pain was not a significant risk factor for long-term physical and mental health. DISCUSSION: Findings highlight the importance of early screening for uncontrolled postoperative pain to identify patients at high risk for poor psychological outcomes and who could benefit from more aggressive pain management. Results suggest early interventions are needed to address pain severity in patients with orthopedic trauma.

Telephone-based goal management training for adults with mild traumatic brain injury: study protocol for a randomized controlled trial.

BACKGROUND: Approximately 1 million individuals experience a mild traumatic brain injury (TBI) and cost the United States nearly $17 billion each year. Many trauma survivors with mild TBI have debilitating and long-term physical, emotional, and cognitive impairments that are unrecognized at trauma centers. Early intervention studies are needed to address these impairments, especially cognitive deficits in executive functioning. Goal management training (GMT) is a structured cognitive rehabilitation program that has been found to improve executive functioning in patients with moderate to severe TBI. The current study adapted the GMT program for telephone delivery in order to improve the accessibility of rehabilitation services in a patient population with multiple barriers to care and significant yet unrecognized cognitive impairment. The primary objective of this study is to examine the efficacy of telephone-based GMT for improving executive functioning, functional status, and psychological health in trauma survivors with mild TBI. METHODS/DESIGN: This study is a three-group randomized controlled trial being conducted at a Level I trauma center. Ninety trauma survivors with mild TBI and cognitive deficits in executive functioning will be randomized to receive telephone-based GMT, telephone-based education, or usual care. GMT and education programs will be delivered by a physical therapist. The first in-person session is 1 h and the remaining six telephone sessions are 30 min. A battery of well-established cognitive tests will be conducted and validated questionnaires will be collected that measure executive functioning, functional status, and depressive and posttraumatic stress disorder symptoms at 6 weeks, 4 months, and 7 months following hospital discharge. DISCUSSION: This study supports a telephone-delivery approach to rehabilitation services in order to broaden the availability of evidence-based cognitive strategies. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov on 10 October 2012, registration number: NCT01714531.

Cognitive-behavioral-based physical therapy to improve surgical spine outcomes: a case series.

BACKGROUND AND PURPOSE: Fear of movement is a risk factor for poor postoperative outcomes in patients following spine surgery. The purposes of this case series were: (1) to describe the effects of a cognitive-behavioral-based physical therapy (CBPT) intervention in patients with high fear of movement following lumbar spine surgery and (2) to assess the feasibility of physical therapists delivering cognitive-behavioral techniques over the telephone. CASE DESCRIPTION: Eight patients who underwent surgery for a lumbar degenerative condition completed the 6-session CBPT intervention. The intervention included empirically supported behavioral self-management, problem solving, and cognitive restructuring and relaxation strategies and was conducted in person and then weekly over the phone. Patient-reported outcomes of pain and disability were assessed at baseline (6 weeks after surgery), postintervention (3 months after surgery), and at follow-up (6 months after surgery). Performance-based outcomes were tested at baseline and postintervention. The outcome measures were the Brief Pain Inventory, Oswestry Disability Index, 5-Chair Stand Test, and 10-Meter Walk Test. OUTCOMES: Seven of the patients demonstrated a clinically significant reduction in pain, and all 8 of the patients had a clinically significant reduction in disability at 6-month follow-up. Improvement on the performance-based tests also was noted postintervention, with 5 patients demonstrating clinically meaningful change on the 10-Meter Walk Test. DISCUSSION: The findings suggest that physical therapists can feasibly implement cognitive-behavioral skills over the telephone and may positively affect outcomes after spine surgery. However, a randomized clinical trial is needed to confirm the results of this case series and the efficacy of the CBPT intervention. Clinical implications include broadening the availability of well-accepted cognitive-behavioral strategies by expanding implementation to physical therapists and through a telephone delivery model.

Cognitive-behavioral determinants of pain and disability two years after traumatic injury: A cross-sectional survey study.

BACKGROUND: Approximately, 2.5 million trauma survivors are hospitalized each year, with the majority experiencing prolonged and profound pain-related disability. The present study investigated the association between fear of movement and pain catastrophizing and pain and physical health 2 years after high-energy trauma. METHODS: One hundred eight adult patients admitted to a Level I trauma intensive care unit, between July 2006 and July 2007, were contacted by phone 2 years after multiple trauma. Eighty-four (78%) participants completed measures of fear of movement, pain catastrophizing, pain intensity and interference with activity, and physical health. Patient and injury characteristics were abstracted from the medical record and a research database. Hierarchical multivariable linear regression analyses examined the unique contribution of fear of movement and pain catastrophizing to pain and physical health outcomes. RESULTS: Fear of movement and catastrophizing explained a significant proportion of variance in pain intensity (29%), pain interference (34%), and physical health (19%), after controlling for age, sex, intensive care unit stay, and depression. Fear of movement and pain catastrophizing were independently associated with pain intensity and physical health, but only pain catastrophizing was associated with pain interference (p < 0.05). CONCLUSIONS: Results suggest that fear of movement and catastrophizing are risk factors for poor long-term outcomes after traumatic injury. Prospective studies are warranted to test the fear-avoidance model and determine whether the model may be relevant for explaining the development of chronic pain and disability in trauma survivors. The identification of subgroups based on negative pain beliefs may have the potential to improve outcomes after traumatic injury.

Pain and satisfaction in hospitalized trauma patients: the importance of self-efficacy and psychological distress.

BACKGROUND: Unmanaged pain has been found to predict delayed return to work, psychologic distress, and chronic pain and disability in patients with traumatic injury. However, little is known about the pain experience during hospitalization. The primary objective of this study was to determine pain intensity, pain interference, and satisfaction with pain treatment in orthopedic trauma patients at hospital discharge. A secondary objective was to examine whether patient self-efficacy and psychologic distress were associated with pain and satisfaction. METHODS: Two hundred thirty-three orthopedic trauma patients were enrolled and completed a discharge assessment at a Level I trauma center. Pain was measured with the Brief Pain Inventory and satisfaction with the American Pain Society Patient Outcome Questionnaire. RESULTS: Ninety-seven percent of patients reported pain at the time of hospital discharge, with 59% and 73% reporting moderate to severe pain intensity and interference, respectively. Overall, 86% of patients were satisfied with pain treatment. Multivariable regression analyses demonstrated that decreased self-efficacy was associated with moderate to severe pain intensity, increased depression was associated with moderate to severe pain intensity and interference, and increased pain intensity was associated with decreased satisfaction (p < 0.05). CONCLUSIONS: Results suggest that orthopedic trauma patients have a significant pain burden but are satisfied with pain treatment during the hospital stay. Efforts are needed to improve pain assessment and management and findings imply that addressing self-efficacy and depressive symptoms may decrease pain and increase satisfaction at hospital discharge. Brief educational interventions that incorporate pain coping skills and self-management techniques may be a feasible approach to improving self-efficacy in the acute care setting. Additional recommendations include routine hospital screening for depression and increased communication between surgeons and mental health providers to identify patients at high risk for unmanaged pain and facilitate provision of early mental health services.