Extracellular Vesicles Promote Arteriogenesis in Chronically Ischemic Myocardium in the Setting of Metabolic Syndrome.

Background Ischemic heart disease continues to be a leading cause of mortality in patients. Extracellular vesicles (EVs) provide a potential for treatment that may induce collateral vessel growth to increase myocardial perfusion. Methods and Results Nineteen male Yorkshire pigs were given a high-fat diet for 4 weeks, then underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, the pigs received either intramyocardial vehicle (n=6), EVs (high-fat diet with myocardial EV injection [HVM]; n=8), or HVM and calpain inhibition (n=5). Five weeks later, myocardial function, perfusion, coronary vascular density, and cell signaling were examined. Perfusion in the collateral-dependent myocardium was increased during rapid ventricular pacing in the HVM group in both nonischemic (P=0.04) and ischemic areas of the ventricle (P=0.05). Cardiac output and stroke volume were significantly improved in the HVM group compared with the control group during ventricular pacing (P=0.006). Increased arteriolar density was seen in the HVM group in both nonischemic and ischemic myocardium (P=0.003 for both). However, no significant changes in the capillary density were observed between the control, HVM, and HVM and calpain inhibition groups (P=0.07). The group that received EVs with oral calpain inhibition had neither increased vessel density (P>0.99) nor improvement in blood flow or cardiac function (P=0.48) when compared with the control group. Conclusions These findings suggest that EVs promote angiogenesis in areas of chronic myocardial ischemia and improve cardiac function under conditions of diet-induced metabolic syndrome.

Germline and Somatic DNA Damage Repair Gene Mutations and Overall Survival in Metastatic Pancreatic Adenocarcinoma Patients Treated with FOLFIRINOX.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with lack of predictive biomarkers. We conducted a study to assess DNA damage repair (DDR) gene mutations as a predictive biomarker in PDAC patients treated with FOLFIRINOX. EXPERIMENTAL DESIGN: Indiana University Simon Cancer Center pancreatic cancer database was used to identify patients with metastatic PDAC, treated with FOLFIRINOX and had tissue available for DNA sequencing. Baseline demographic, clinical, and pathologic information was gathered. DNA isolation and targeted sequencing was performed using the Ion AmpliSeq protocol. Overall survival (OS) analysis was conducted using Kaplan-Meier, logistic regression and Cox proportional hazard methods. Multivariate models were adjusted for age, gender, margin status, CA 19-9, adjuvant chemotherapy, tumor and nodal stage. RESULTS: Overall, 36 patients were sequenced. DDR gene mutations were found in 12 patients. Mutations were seen in BRCA1 (N = 7), BRCA2 (N = 5), PALB2 (N = 3), MSH2 (N = 1), and FANCF (N = 1) of all the DDR genes sequenced. Median age was 65.5 years, 58% were male, 97.2% were Caucasian and 51.4% had any family history of cancer. The median OS was near significantly superior in those with DDR gene mutations present vs. absent [14 vs. 5 months; HR, 0.58; 95% confidence interval (CI), 0.29-1.14; log-rank P = 0.08]. Multivariate logistic (OR, 1.47; 95% CI, 1.04-2.06; P = 0.04) and Cox regression (HR, 0.37; 95% CI, 0.15-0.94; P = 0.04) showed presence of DDR gene mutations was associated with improved OS. CONCLUSIONS: In a single institution, retrospective study, we found that the presence of DDR gene mutations are associated with improved OS in PDAC patients treated with FOLFIRINOX.

Three cachexia phenotypes and the impact of fat-only loss on survival in FOLFIRINOX therapy for pancreatic cancer.

BACKGROUND: By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy. METHODS: We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed. RESULTS: Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%. CONCLUSIONS: Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Impact of Nab-Paclitaxel-based Second-line Chemotherapy in Metastatic Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with median survival of 20% at 1 year. We conducted a retrospective study to assess the efficacy and tolerability of nab-paclitaxel (NP)-based second-line chemotherapy in metastatic PDAC. PATIENTS AND METHODS: The Indiana University Simon Cancer Center pancreatic cancer program was used to identify patients with metastatic PDAC who received any second-line chemotherapy. Demographic, clinical and outcomes data were collected by manual chart abstraction. Patients were divided into two groups: a NP-based treatment group and a non- NP-based treatment group. Overall (OS) and progression-free (PFS) survival were estimated using Kaplan-Meier method. Cox proportional hazards regression was used for multivariate analyses. RESULTS: A total of 120 patients received second-line chemotherapy. There were 47 (39%) patients in the NP group and 73 (61%) in the non-NP group. As compared to the non-NP group, the NP group showed improved median PFS [2.8 vs. 2.1 months; hazard ratio (HR)=0.62, 95% confidence interval (CI)=0.38-1.02; p=0.06] and median OS (7.5 vs. 4.7 months; HR=0.67, 95% CI=0.45-1.00; p=0.05). Multivariate analyses adjusted for age showed a significantly improved PFS (adjusted HR=0.60, 95% CI=0.36-0.98; p=0.04) and a suggestion of improved OS (adjusted HR=0.67, 95% CI=0.44-1.01, p=0.05) in the NP group as compared to non-NP group. Serious adverse events were seen in 13.3% of patients in the non-NP group and 17.1% patients in the NP group. CONCLUSION: In a single-institution retrospective cohort study, we report a significant improvement in the PFS and suggestion of improvement in the OS with NP-based second-line chemotherapy with an acceptable toxicity rate.

Assessment of an established dialysis nurse practitioner model of care using mixed methods research.

AIMS AND OBJECTIVES: To assess a dialysis nurse practitioner (NP) model of care by examining satisfaction, quality of life (QOL) and clinical outcomes of haemodialysis patients and explore experiences of dialysis nurses. DESIGN: Mixed methods. METHODS: Database analyses of dialysis indices amongst a sample (n = 45) of haemodialysis patients; a survey (n = 27) examining patient experience, satisfaction and QOL; and in-depth interviews with a sample (n = 10) of nurses. RESULTS: Nurses commended the NP role, with five themes emerging: "managing and co-ordinating", "streamlining and alleviating", "developing capability", "supporting innovation and quality" and "connecting rurally". Patients' average age was 66 years and 71% were male. Patients' satisfaction with the care they received was rated 3.5/4 or higher across seven parameters and the average QOL score was 7.9/10. CONCLUSION: The NP model of care is effective in enhancing patient care within a collaborative framework. The challenge is to sustain, and enhance the model, through mentorship programs for potential candidates.

Acceptance onto dialysis - CARI guidelines.

The Caring for Australasians with Renal Impairment (CARI) guidelines initiative is an Australia/New Zealand evidence based project that aims to provide high quality, evidence based clinical practice guidelines for the management of all stages of kidney disease. This article summarises CARI guidelines on Acceptance onto dialysis and forms part of a series on aspects of assessment and management of patients with chronic kidney disease.

Impulsivity, suicidality and alcohol use disorders in adolescents and young adults with borderline personality disorder.

Borderline Personality Disorder (BPD) is a severe and disabling psychiatric condition that typically emerges in late adolescence or early adulthood. Nearly 50% of individuals with BPD have a co-occurring Alcohol Use Disorder (AUD) at some point in the course of their illness. This study explores clinical characteristics of adolescents and young adults (age 30 years and younger) with BPD and AUD (N=21) compared to BPD without any history of substance use disorders (N=17). Based on theoretical considerations and previous findings, we hypothesized that adolescents and young adults with BPD and AUDs would be more impulsive and exhibit higher rates of suicidal behavior than individuals with BPD and no substance use disorders. Consistent with our first hypothesis, the BPD/AUD group was more impulsive than the BPD only group. However, the two groups did not differ on measures of suicidal behavior. Overall, impulsivity was correlated with total number of suicide attempts in the adolescent/young adult group. When older BPD participants were included in the comparison (up to age 55), the BPD/AUD group exhibited more lifetime suicide attempts that were higher in medical lethality than the BPD only group, suggesting an overall increased lifetime suicide risk in the BPD/AUD group. The relationship between impulsivity, AUD, and suicidal behavior and lifetime suicide risk in adolescent and young adults with BPD is discussed.