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Purpose The impact of rurality and socioeconomic deprivation on end-of-life (EOL) care for patients with heart failure (HF) is unknown. We analyzed claims to describe the prevalence and predictors of EOL health care utilization for patients dying with HF in a predominantly rural state. Methods We used the MaineHealth Data Organization's All-Payer Claims Data to identify 15,168 patients ≥35 who died with HF between 2012 and 2017. The primary outcome was health care utilization during the last 180 days of life (EOL definition for this analysis), including emergency department (ED) visits, hospitalizations, intensive care unit (ICU) admissions, and hospice utilization. Patient characteristics analyzed included age, gender, comorbidities, area deprivation index (ADI), and rurality. Findings Among 15,168 patients ≥35 who died with HF, 48% had ≥2 hospitalizations, 72% had ≥2 ED visit, 29% had an ICU stay, 2% initiated dialysis during EOL, and 64% received hospice. Rural patients were more likely to have an ICU admission and have ≥2 hospitalizations. Patients residing in areas with higher ADI were more likely to be hospitalized, admitted to the ICU, and started on dialysis. Both rural patients and those living in higher ADI areas were less likely to receive hospice. After multivariable adjustment, rurality and ADI were independently associated with a decreased likelihood of receiving hospice (OR 0.62 [95% CI: 0.53-0.72] for the most rural patients and OR 0.64 [95% CI: 0.57-0.72] for the highest ADI). Conclusion Both rurality and local area deprivation drive disparities in EOL care for patients dying with heart failure.

Positron emission tomography (PET) using 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter-1 (hGLUT-1) in FaDu and GIST-1 cells by measuring [3 H]2-deoxy-d-glucose ([3 H]2-DG) and [3 H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3 H]2-DG uptake. In GIST-1 cells, [3 H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H-pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT-1. We hypothesize that inhibition of hGLUT-1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18 F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT-1 inhibition by TKIs may have implications for routine [18 F]FDG-PET monitoring of tumor response in patients.

BACKGROUND AND AIMS: Cardiac and vascular growth factors (GF) may influence myocardial remodeling through cardiac growth and angiogenic effects. We hypothesized that concentrations of circulating GF are associated with cardiac remodeling traits. METHODS: We related blood concentrations of vascular endothelial GF (VEGF), VEGFR-1 (sFlt1), angiopoietin 2 (Ang-2), soluble angiopoietin type-2 receptor (sTie2), hepatocyte GF (HGF), insulin-like GF (IGF)-1, IGF binding protein (IGFBP)-3, and growth differentiation factor-15 (GDF-15) to echocardiographic traits in 3151 Framingham Study participants (mean age 40 years, 55% women). We evaluated the following measures: left ventricular (LV) mass index (LVMi), LV ejection fraction (LVEF), global longitudinal strain (GLS), mitral E/e’, and aortic root diameter (AoR). All biomarker values were sex-standardized. RESULTS: In multivariable-adjusted analyses, higher GDF-15 concentrations were associated with higher log-LVMi (β=0.009 per SD, P =0.01). Similarly, sTie2 concentrations were positively associated with log-E/e’ (β=0.011 per SD, P =0.04). IGF-1 and Ang-2 concentrations were positively and negatively associated with GLS, respectively (β(IGF-1) =0.16 per SD and β(Ang-2) =−0.15 per SD, both P

While immunotherapy agents have improved outcomes in metastatic melanoma (MM), predictive biomarkers in these patients are lacking. Parameters identified from body composition analysis, such as low SMD (also termed myosteatosis), may prognosticate MM patients on immunotherapy.In this retrospective study, 44 MM patients received nivolumab, either as monotherapy or in combination with ipilimumab. Pre-treatment computed tomography (CT) scans were analyzed to determine skeletal muscle density (SMD) in Hounsfield units (HU) and muscle surface area (MSA) in cmLow SMD was associated with worse overall survival (OS) by log rank test (median 12.03 vs. 34.96 months, p = 0.001) and in multivariate analysis when accounting for age, sex, performance status, and number of prior lines of therapy (HR 4.40, 95% CI 1.44-13.42, p = 0.009). Lower nivolumab dosing by MSA was significantly associated with improved OS (median 42.9 vs. 12.3 months, p 0.001). This association remained significant in multivariate analysis with age, sex, performance status, and number of prior lines of therapy (HR 0.05, 95% CI 0.01-0.30, p = 0.001). Neither SMD nor higher nivolumab dose per MSA were associated with increased incidence of treatment toxicity.Low SMD is prognostic in MM treated with nivolumab immunotherapy. Presence of myosteatosis or higher nivolumab dose based on body composition did not predict treatment toxicity.

Background Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy. Methods and results TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3MyeKO) and control animals (ErbB3MyeWT). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3MyeKO mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3MyeKO male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3MyeKO male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3MyeKO male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3MyeKO male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3MyeKO and ErbB3MyeWT female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3MyeKO mice hearts compared to control animals after TAC. Conclusion Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.

This article reviews Dolmetscherinnen und Dolmetscher im Netz der Macht: Autobiographisch konstruierte Lebenswege in autoritaren Regimen 978-3-7329-0336-8978-3-7329-9698-8

Summary Background Severe muscle mass (MM) loss is a defining feature of cancer observed across all types and stages of disease and is an independent predictor of poor clinical outcomes including higher incidences of chemotherapy toxicity and decreased survival. Protein is essential to build MM, yet the optimal amount for preventing or treating muscle loss in patients with cancer remains undefined. Methods The Protein Recommendation to Increase Muscle (PRIMe) study is a single-center, two-armed, parallel, randomized, controlled pilot trial that assesses the feasibility of utilizing a high protein (HP) diet to positively impact clinical outcomes in people undergoing chemotherapy to treat colorectal cancer. Forty patients with newly diagnosed stage II-IV colorectal cancer who are scheduled to receive chemotherapy will be included. Participants are randomly assigned to a HP or normal protein (NP) diet for twelve weeks. The HP and NP groups receive nutrition recommendations to achieve 2.0 g of protein per kilogram of body weight per day (g∙kg−1∙d−1) and 1.0 g⋅kg−1⋅d−1, respectively. These values refer to the upper and lower recommended range of protein intake for people with cancer. Energy recommendations are based on measured energy expenditure. Assessments are completed within two weeks of starting chemotherapy (baseline), at week 6, and at week 12. Changes to skeletal MM, physical function, anthropometrics, body composition, muscle strength, physical activity, energy metabolism, metabolic markers, nutritional status, quality of life, readiness to change and psychosocial determinants of behavioural change are assessed between the HP and NP groups. Feasibility of the nutritional intervention is assessed by change in MM as a surrogate marker. Conclusions This evidence-based study investigates the feasibility of increasing protein intake following a diagnosis of cancer on clinical outcomes during treatment for colorectal cancer. This study will inform larger trials assessing the impact of increasing protein intake in cancer to determine their importance and integration into standard clinical care for people with cancer.

Aims We sought to clarify the role of ventriculo–arterial (V–A) coupling in the treatment of nonischemic dilated cardiomyopathy (NIDCM) by adding a mineralocorticoid receptor antagonist (MRA) to conventional anti‐failure therapy. Methods and results We employed cardiac magnetic resonance imaging to quantify left ventricular (LV) contractility and V–A coupling in normal subjects at rest (n = 11) and in patients with NIDCM (n = 12) before and after long term anti‐failure therapy, in which MRA was added to conventional anti‐failure therapy. After ≥6 months' treatment in NIDCM patients, LV volumes and mass decreased, and the LV ejection fraction increased from a median of 24% (17, 27) (interquartile range IQR) to 47 (42, 52) (P 0.05). The V–A coupling ratio, Ea/end‐systolic elastance (single‐beat method), decreased by −1.08 (−1.96, −0.55), (P = 0.003), as did Ea/end‐systolic pressure/end‐systolic pressure ratio, −0.54 (0.35, 0.87), (P = 0.002). The preload recruitable stroke work (PRSW) increased as did PRSW indexed for Ea (both P = 0.002), which reflected ‘total circulatory performance’. Conclusions In NIDCM, adding MRA to conventional anti‐failure therapy markedly improved LV ejection fraction and reduced peripheral vascular resistance, due to both improved LV contractility and especially to enhanced V–A coupling, as Ea decreased to normal. Total circulatory performance was a sensitive indicator of both LV pump performance and the arterial loading conditions.

Well-differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal (GI) tract and pancreas are relatively rare; however, the annual incidence has been increasing. Carcinoid syndrome (CS) is a constellation of symptoms that occur when a GI NET metastasizes to the liver and releases high levels of vasoactive substances into the systemic circulation. CS occurs in 19% of NETs patients at diagnosis and is associated with shorter survival. Carcinoid heart disease (CHD) occurs in over 50% of patients with CS and is associated with poor long-term prognosis. NET-induced valvular fibrosis is a significant cause of mortality and morbidity in these patients. Somatostatin analogs relieve CS symptoms, but they have never been shown to reverse CHD progression or improve overall survival. Surgical therapy for right-sided valve disease is associated with improved symptoms and quality of life and possibly improved survival, despite relatively high morbidity and mortality associated with cardiac intervention. A 65-year-old woman with a metastatic pancreatic NET had typical signs and symptoms of CS. She presented in congestive heart failure and was found to have severe tricuspid regurgitation with characteristic features of CHD on transthoracic echocardiogram (TTE). Following octreotide monotherapy, serial TTEs demonstrated regression of tricuspid valve involvement. The patient improved clinically and remained asymptomatic on subsequent visits. This is the first case of CHD regression with medical therapy supported by serial TTEs. Developing a deeper understanding of cases like this will help us unlock new intervention targets and strategies for treatments in the future.

Background Body composition is minimally investigated in an immunotherapy era. Specific body composition signals such as myosteatosis may reflect aspects of patients' immunology and thereby their ability to respond to immunotherapies. Ipilimumab is a key checkpoint inhibitor in metastatic melanoma. As an antibody, it may also be more accurately dosed using body composition parameters rather than weight alone. This retrospective study aimed to investigate body composition‐based dosing and outcomes. Methods Pretreatment computed tomography images from metastatic melanoma, ipilimumab‐treated patients from 2009 to 2014 were used to measure myosteatosis [skeletal muscle radiographic density or SMD, in Hounsfield units (HU)] and surface area (cm2) as previously described. Cut point analysis determined whether a level of ipilimumab dose and myosteatosis demonstrated differences in progression‐free (PFS) and overall survival (OS). Secondary endpoints included objective response rates and toxicities. Results Of 121 identified, 97 patients were evaluable. Baseline demographics included 56 years median age, 60% male participants, and 23.7% with BRAF mutations. SMD analysis identified cut‐offs of SMD < 42 in those with BMI < 25 kg/m2 and 2.03 mg/cm2 are prognostic of poorer melanoma outcomes post ipilimumab. SMD may identify patients with flawed immunology and predict who may better respond to such therapy. Ipilimumab dosing by skeletal muscle index stands in contrast to weight‐based dosing and may demonstrate a more accurate method of antibody dosing.

We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105

The metastatic pancreatic adenocarcinoma clinical trial (MPACT) trial established gemcitabine (gem) and nab-paclitaxel (nab) as a standard treatment for pancreatic cancer utilizing granulocyte colony-stimulating factors to manage neutropenia. This was a challenge for jurisdictions that do not use granulocyte colony-stimulating factors in palliative settings. We developed dosage guidelines to dose modify gem and nab without granulocyte colony-stimulating factors. We undertook a retrospective review to determine the efficacy and safety of these dose adjustment guidelines in the real world.A multi-centered, retrospective chart review was performed on pancreatic patients between December 1, 2014, and August 21, 2018. Provincial electronic medical health records were reviewed. Using Log-rank statistics we determined the patient's progression-free survival and overall survival.Of 248 patients, 209 met patient selection criteria. Patients were excluded if they were lost to follow-up, on gem alone prior to nab/gem combination therapy or did not receive nab or gem. Patients who received nab/gem as first-line therapy had a median progression-free survival of 6.3 months (95% CI, 5.1-7.4), and median overall survival of 11.1 months (95% CI, 9.5-12.8). Those who received gem/nab in the second line had a median progression-free survival of 4.6 months (95% CI, 2.8-6.5), and median overall survival of 19.3 months (95% CI, 12.6-26.0).The patient's progression-free survival and overall survival taking nab/gem using our dose modification algorithm were equivalent or superior to the MPACT trial's progression-free survival and overall survival. Gem/nab can be given by our dose modification scheme without granulocyte colony-stimulating factor.

Background We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105+ cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Methods Endothelial cells and CD105+ non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB recepotrs was examined using multiparametric flow cytometry. Human microvascular endothelial cells (HMEC-1) and LV epicardial CD105+ non-endothelial cells were used to determine the effect of high glucose on ADAM10-dependent cleavage of ErbB receptors. Results We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2 on both endothelial cells and CD105+ non-endothelial cells. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high glucose in HMEC-1 and LV epicardial CD105+ non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM D-glucose resulted in decreased cell surface expression of ErbB2. We also found high expression of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) on both endothelial cells and CD105+ non-endothelial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. Conclusions We suggest that high glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.

BACKGROUND Our purpose was to assess the accuracy of resting energy expenditure (REE) equations in patients with newly diagnosed stage I-IV non-small cell lung, rectal, colon, renal, or pancreatic cancer. METHODS In this cross-sectional study, REE was measured using indirect calorimetry and compared with 23 equations. Agreement between measured and predicted REE was assessed via paired t-tests, Bland-Altman analysis, and percent of estimations ≤ 10% of measured values. Accuracy was measured among subgroups of body mass index (BMI), stage (I-III vs IV), and cancer type (lung, rectal, and colon) categories. Fat mass (FM) and fat-free mass (FFM) were assessed using dual x-ray absorptiometry. RESULTS Among 125 patients, most had lung, colon, or rectal cancer (92%, BMI: 27.5 ± 5.6 kg/m2 , age: 61 ± 11 years, REE: 1629 ± 321 kcal/d). Thirteen (56.5%) equations yielded REE values different than measured (P

Anthracycline-associated cardiomyopathy and peripartum cardiomyopathy are nonischemic cardiomyopathies that often afflict previously healthy young patients; both diseases have been well described since at least the 1970s and both occur in the settings of predictable stressors (ie, cancer treatment and pregnancy). Despite this, the precise mechanisms and the ability to reliably predict who exactly will go on to develop cardiomyopathy and heart failure in the face of anthracycline exposure or childbirth have proven elusive. For both cardiomyopathies, recent advances in basic and molecular sciences have illuminated the complex balance between cardiomyocyte and endothelial homeostasis via 3 broad pathways: reactive oxidative stress, interference in apoptosis/growth/metabolism, and angiogenic imbalance. These advances have already shown potential for specific, disease-altering therapies, and as our mechanistic knowledge continues to evolve, further clinical successes are expected to follow.

Background Anthracycline chemotherapy is an effective and widely used treatment for solid tumors and hematological malignancies regardless of its known cardiotoxicity. The mechanisms of the cardiotoxicity are not fully understood and methods to protect the heart during or following anthracycline chemotherapy are currently unclear. In order to examine the efficacy of human cell based therapy in anthracycline-induced injury, we characterized a mouse model using an immune compromised strain of mice capable of accepting human cells. Methods Immune compromised mice (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) were repeatedly exposed to pharmaceutical grade doxorubicin (0.5 mg/kg – 4 mg/kg). Cardiotoxicity was assessed by echocardiography and μCT imaging of the coronary vascular bed as well as by flow cytometry and by histological assessments of anthracycline-induced cardiac tissue damage. Results The immune compromised mice were highly susceptible to doxorubicin treatment. Doxorubicin induced both systemic and cardiac toxicities. Gastrointestinal and hepatic injury occurred at 4 mg/kg and 1.5 mg/kg dosing while mice receiving 0.5 mg/kg weekly only displayed hepatic damage. Repeated exposure to 0.5 mg/kg anthracyclines resulted in cardiac toxicity. Flow cytometric analysis of hearts indicated a loss in endothelial and cardiac progenitor cells after doxorubicin treatment. This endothelial loss is corroborated by the lack of small vessels detected by μCT in the hearts of mice exposed to doxorubicin. Histological assessment shows no overt cardiomyocyte injury but livers from mice treated with doxorubicin show marked hepatic plate atrophy with intracytoplasmic and canalicular cholestasis, rare pericentral hepatocellular necrosis and significant zone 3 iron accumulation, likely an indication of metabolic injury due to doxorubicin toxicity. Conclusions Immune compromised mice are sensitive to doxorubicin therapy resulting in systemic complications in addition to cardiovascular toxicity. Anthracycline-induced cardiotoxicity is observed at very low doses in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice.

Supplemental Digital Content is available in the text., Background: Heart failure, which is a major global health problem, is often preceded by pathological cardiac hypertrophy. The expansion of the cardiac vasculature, to maintain adequate supply of oxygen and nutrients, is a key determinant of whether the heart grows in a physiological compensated manner or a pathological decompensated manner. Bidirectional endothelial cell (EC)–cardiomyocyte (CMC) cross talk via cardiokine and angiocrine signaling plays an essential role in the regulation of cardiac growth and homeostasis. Currently, the mechanisms involved in the EC-CMC interaction are not fully understood, and very little is known about the EC-derived signals involved. Understanding how an excess of angiogenesis induces cardiac hypertrophy and how ECs regulate CMC homeostasis could provide novel therapeutic targets for heart failure. Methods: Genetic mouse models were used to delete vascular endothelial growth factor (VEGF) receptors, adeno-associated viral vectors to transduce the myocardium, and pharmacological inhibitors to block VEGF and ErbB signaling in vivo. Cell culture experiments were used for mechanistic studies, and quantitative polymerase chain reaction, microarrays, ELISA, and immunohistochemistry were used to analyze the cardiac phenotypes. Results: Both EC deletion of VEGF receptor (VEGFR)-1 and adeno-associated viral vector–mediated delivery of the VEGFR1-specific ligands VEGF-B or placental growth factor into the myocardium increased the coronary vasculature and induced CMC hypertrophy in adult mice. The resulting cardiac hypertrophy was physiological, as indicated by preserved cardiac function and exercise capacity and lack of pathological gene activation. These changes were mediated by increased VEGF signaling via endothelial VEGFR2, because the effects of VEGF-B and placental growth factor on both angiogenesis and CMC growth were fully inhibited by treatment with antibodies blocking VEGFR2 or by endothelial deletion of VEGFR2. To identify activated pathways downstream of VEGFR2, whole-genome transcriptomics and secretome analyses were performed, and the Notch and ErbB pathways were shown to be involved in transducing signals for EC-CMC cross talk in response to angiogenesis. Pharmacological or genetic blocking of ErbB signaling also inhibited part of the VEGF-B–induced effects in the heart. Conclusions: This study reveals that cross talk between the EC VEGFR2 and CMC ErbB signaling pathways coordinates CMC hypertrophy with angiogenesis, contributing to physiological cardiac growth.

Background First-line adjuvant chemotherapy options for early-stage colorectal cancer (CRC) include CapeOx (capecitabine, intravenous oxaliplatin) and FOLFOX (intravenous 5-fluorouracil, leucovorin, oxaliplatin). Capecitabine is an oral prodrug analog of 5-fluorouracil, and recent studies have suggested that proton pump inhibitors (PPIs) may detrimentally affect capecitabine efficacy. Conversely, some literature suggests that PPIs may negatively affect CRC itself. To gain insight into the nature of PPIs’ effect on capecitabine and CRC, we investigated their effects on effectiveness of CapeOx versus FOLFOX chemotherapy. Patients and Methods We conducted a retrospective chart review of 389 patients with stage II-III CRC who received adjuvant CapeOx or FOLFOX from 2004 to 2013. Information regarding PPI receipt, chemotherapy, and patient outcomes from medical records was analyzed. Results Three-year recurrence-free survival was significantly lower in CapeOx-treated PPI recipients than non-PPI recipients (69.5 vs. 82.6%; P = .029). Unadjusted analysis showed that CapeOx-treated PPI recipients were twice as likely to experience cancer recurrence or death as CapeOx-treated non-PPI recipients (hazard ratio = 2.03; 95% confidence interval, 1.06-3.88; P = .033). FOLFOX-treated PPI recipients had a non–statistically significant difference in 3-year recurrence-free survival versus non-PPI recipients (82.9 vs. 61.7%; P = .066) and a non–statistically significant difference in recurrence/death (hazard ratio = 0.51; 95% confidence interval, 0.25-1.06; P = .071). No significant differences were seen in overall survival between groups. Conclusion Our results suggest PPIs negatively affected recurrence-free survival in CapeOx-treated CRC patients and yielded no significant effects among FOLFOX-treated patients, potentially implicating a pharmacokinetic interaction between PPIs and capecitabine. No overall survival effects were seen. Given PPIs’ widespread use, further studies are required to corroborate our findings.

We examine the concept of personal knowledge management using data drawn from our study of digital nomads. We make two contributions: an empirical and conceptual development of knowledge management as it relates to independent workers and an advancement of social informatics that builds on Gibson's ecological perspective. Digital nomads provide an empirical basis to better understand how knowledge management is shifting from organization‐centric, with its concomitant emphasis on organizational information systems, to worker‐centric, which relies on personal knowledge ecologies. We advance this concept as a combination of personal knowledge management activities and the digital technologies that support them. Our data make clear that individuals are the locus of personal knowledge ecologies, but these ecologies are embedded in a larger community of collaborators, clients, and peers who are often extensively mediated by digital technologies. This embedding and mediation are at the core of the sociotechnical arrangements that define the personal knowledge ecologies that we document.

Summary Background Body composition is increasingly being studied as a method of predicting chemotherapy toxicity. Our study aimed to evaluate associations of body composition with treatment toxicity in a group of pancreatic cancer patients treated with gemcitabine plus nab-paclitaxel. Methods A retrospective review was performed for all patients who received first-line gemcitabine plus nab-paclitaxel for metastatic pancreatic cancer at a northern Alberta cancer institute (Canada) from 2014 to 2017. Total lean body mass (LBM) was derived from measurements of muscle surface area at L3 on baseline computed tomography (CT) scans. Optimal stratification, or minimal p-value analysis, was used to assess for a threshold of nab-paclitaxel dose per LBM (mg/kg) associated with a higher risk of dose-limiting toxicity (DLT). Results 152 patients were included in the study, of whom 62 (40.8%) experienced DLT. nab-Paclitaxel dose/LBM ranged from 0.98 to 8.76 mg/kg. A threshold for nab-paclitaxel dose/LBM that optimally predicted risk of DLT was identified at 5.83 mg/kg. Above this cut-off, 18/31 (58.1%) patients experienced DLT, compared to 44/121 (36.4%) patients below (p = 0.028). Patients above this cut-off had a higher incidence of peripheral neuropathy compared to those below, though this was not statistically significant based on an adjusted p-value threshold (48.4 vs. 29.8% respectively, p = 0.050). Body mass index, body surface area, and absolute initial doses of nab-paclitaxel or gemcitabine did not significantly impact likelihood of DLT. Conclusions nab-Paclitaxel dose normalized to LBM, based on CT-derived measures of skeletal muscle, has potential to predict risk of chemotherapy toxicity. Chemotherapy dosing based on body composition, rather than conventional anthropometric measures, may be effective in reducing treatment toxicity.

Background/objectives Sarcopenia (low skeletal muscle index) and myosteatosis (low skeletal radiodensity) have been associated with poor outcomes in melanoma. This systematic review was performed to summarize and critically evaluate current literature surrounding body composition in melanoma. Methods MEDLINE and Embase databases were searched for studies of melanoma patients with computed tomography (CT) based body composition analysis from 2000 to 2020. Outcomes of interest were survival, including overall survival (OS), progression-free survival (PFS), and disease-free survival (DFS), as well as treatment-related adverse events (AEs). Results Nine studies of 914 patients were included in the final review. The majority of studies were of metastatic melanoma patients treated with immunotherapy. Studies demonstrated a variety of CT analysis techniques and cut-offs to define sarcopenia and myosteatosis. Associations of sarcopenia or myosteatosis with survival (OS, PFS, DFS) or risk of treatment-related AEs were conflicting. Multiple studies had low quality of evidence due to small sample sizes, use of non-validated CT measures, and lack of multivariable analyses. Conclusions Due to methodologic heterogeneity and low quality of evidence, impacts of CT-derived body composition parameters on outcomes in melanoma are unclear. Further research should be conducted to elucidate impacts of body composition in melanoma.

3573 Background: Response to antiPD-1 monotherapy is poor in microsatellite stable (MSS)/mismatch-repair proficient (pMMR) mCRC; the combination of antiPD-1 pembro + anti-MEK bini, with or without chemo, may improve upon this limited response. KEYNOTE-651 (NCT03374254) is an open-label phase 1b multicenter trial of pembro + bini (cohort A) or pembro + bini + chemo (mFOLFOX7 in cohort C, FOLFIRI in cohort E) in MSS/pMMR mCRC. Preliminary results from the dose-finding phase at 2 dose levels (DL) of bini are presented. Methods: Patients (pts) had MSS/pMMR mCRC and must have been previously treated with fluoropyrimidine, irinotecan, and oxaliplatin in cohort A, or with fluoropyrimidine + oxaliplatin-based regimen in cohort E; pts were previously untreated in cohort C. Pts received pembro 200 mg Q3W + bini 30 mg BID (cohort A, DL1), pembro 200 mg Q3W+ bini 30 mg BID + mFOLFOX7 Q2W (cohort C, DL1) or pembro 200 mg Q3W + bini 30 mg BID + FOLFIRI Q2W (cohort E, DL1). Bini dose escalation to 45 mg BID (DL2) was planned in cohorts A, C, and E, with a target dose-limiting toxicity (DLT) of 30%. Primary end point was safety (DLT). Secondary end point was ORR. DCR, PFS, and OS were exploratory. ORR, DCR, and PFS were assessed by investigator per RECIST v1.1. Results: Median study follow-up at data cutoff (Oct 15, 2021) was 36 mo (range, 32-43) for cohort A, 17 mo (2-24) for cohort C, and 11 mo (2-25) for cohort E. In cohort A, 1/6 pts (17%) had DLT at DL1; no DLT occurred in 14 pts (0%) at DL2. In cohort A, gr 3/4 TRAEs occurred in 3/6 pts (50%) at DL1 and 8/14 pts (57%) at DL2. In cohort C, 3/9 evaluable pts (33%) had DLT at DL1; thus, bini dose was not escalated to DL2. In cohort C, gr 3/4 TRAEs occurred in 9/11 total pts (82%). In cohort E, 1/5 evaluable pts (20%) had DLT at DL1 and 5/10 evaluable pts (50%) had DLT at DL2. Enrollment was stopped in cohort E, DL2 and bini dose was de-escalated to DL1; 2/4 additional pts (50%) had DLT at DL1 (total 3/9 pts [33%] had DLT in cohort E, DL1). In cohort E, gr 3/4 TRAEs occurred in 5/9 pts (56%) at DL1 and 10/11 total pts (91%) at DL2. No gr 5 TRAEs occurred in any cohort. ORR was 0% in cohort A; limited efficacy was seen in cohorts C and E (Table). Conclusions: Bini could be safely combined with pembro in cohort A. However, with bini + pembro + chemo, the 45-mg dose of bini was not well tolerated and required dose reduction to 30 mg. Addition of bini to pembro + chemo did not improve efficacy; therefore, enrollment was prematurely closed in cohorts C and E. Efficacy by KRAS mutation status will be shown. Clinical trial information: NCT03374254. [Table: see text]

3614 Background: Sarcopenia and myosteatosis affect survival in colorectal cancer (CRC). The role of adiposity is not yet fully elucidated. This study explores visceral and subcutaneous adipose tissue (VAT/SAT) distributions, and how they affect overall (OS), disease-free (DFS) and cancer specific survival (CSS). Methods: This retrospective cohort study, included resected stage I-III CRC in Alberta from January 2007 to December 2009. We excluded recurrent/metastatic disease or no CT scan. This study was approved by the Health Research Ethics Board at the University of Alberta. Body composition parameters were measured from CT scans. Sarcopenia and myosteatosis were defined by cohort-specific cut-off values. Total and visceral fat areas were indexed by height, and cohort-specific cut-offs defined total and visceral obesity (VO). SAT (SC:TFR) and VAT (V:TFR) to total adipose ratios were compared by gender, as described by Fleming. SAT and VAT fat radiodensity (Hounsfield units, HU) was measured and divided into quartiles. Differences between groups were compared with student’s t-test and Fisher Exact test. Cox proportional hazard models were created, adjusting for important covariates, to assess adiposity effects on OS, DFS and CSS. Results: Our cohort included 968 patients with a median follow up of 63.5 months. The majority were stage II (38.6%) and III (51.0%). In total, 67.9% had total obesity and 51.0% had visceral obesity. In males, there was no difference in the incidence of myosteatosis or sarcopenia, regardless of V:TFR or SC:TFR. In women, those with a high V:TFR or SC:TFR had significantly higher incidence of myosteatosis, but not sarcopenia. Men and women with elevated V:TFR had significantly lower VAT and SAT HU (p

Background Epirubicin is metabolized by uridine glucuronosyltransferase 2B7 (UGT2B7). Patients homozygous for the minor allele (CC) in the UGT2B7 -161 promoter polymorphism have lower clearance and significantly higher rates of leukopenia compared to wild-type homozygote (TT) or heterozygote (CT) patients. This study was designed to determine if TT and CT genotype patients could tolerate a higher epirubicin dose compared to CC genotype patients. Patients and Methods We studied women with histologically confirmed non-metastatic, invasive breast cancer who were scheduled to receive at least three cycles of FE100C in the (neo)adjuvant setting. Patients received standard-dose FE100C during the first 21-day cycle. Based on genotype, the epirubicin dose was escalated in the second and third cycles to 115 and 130 mg/m2 or to 120 and 140 mg/m2 for CT and TT genotype patients, respectively. The main outcome measurements were myelosuppression and dose-limiting toxicity. These were analyzed for relationships with the three genotypes. Results Forty-five patients were enrolled (10 CC, 21 CT, and 14 TT genotypes) and received 100 mg/m2 of epirubicin in the first cycle. Twelve and 10 TT patients were dose escalated at the second and third cycles, respectively; 16 CT patients were dose escalated at the second and third cycles. Leukopenia, but not febrile neutropenia, was genotype and dose dependent and increased in patients with CT and TT genotypes as their dose was increased. However, the third-cycle leukopenia rates were comparable to patients with the CC genotype receiving standard-dose epirubicin. Conclusion Pharmacogenetically guided epirubicin dosing is well tolerated and allowed dose escalation without increased toxicity.

Positron emission tomography (PET) using 2‐deoxy‐2‐[18F]fluoro‐d‐glucose ([18F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter‐1 (hGLUT‐1) in FaDu and GIST‐1 cells by measuring [3H]2‐deoxy‐d‐glucose ([3H]2‐DG) and [3H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3H]2‐DG uptake. In GIST‐1 cells, [3H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H‐pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT‐1. We hypothesize that inhibition of hGLUT‐1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT‐1 inhibition by TKIs may have implications for routine [18F]FDG‐PET monitoring of tumor response in patients.

BackgroundAdvanced heart failure (AHF) carries a morbidity and mortality that are similar or worse than many advanced cancers. Despite this, there are no accepted quality metrics for end‐of‐life (EOL) care for patients with AHF.Methods and ResultsAs a first step toward identifying quality measures, we performed a qualitative study with 23 physicians who care for patients with AHF. Individual, in‐depth, semistructured interviews explored physicians' perceptions of characteristics of high‐quality EOL care and the barriers encountered. Interviews were analyzed using software‐assisted line‐by‐line coding in order to identify emergent themes. Although some elements and barriers of high‐quality EOL care for AHF were similar to those described for other diseases, we identified several unique features. We found a competing desire to avoid overly aggressive care at EOL alongside a need to ensure that life‐prolonging interventions were exhausted. We also identified several barriers related to identifying EOL including greater prognostic uncertainty, inadequate recognition of AHF as a terminal disease and dependence of symptom control on disease‐modifying therapies.ConclusionsOur findings support quality metrics that prioritize receipt of goal‐concordant care over utilization measures as well as a need for more inclusive payment models that appropriately reflect the dual nature of many AHF therapies.

Introduction: Understanding molecular mechanisms underlying cardiac hypertrophy is crucial for protecting against cardiac remodeling, or slowing down its destined pathway to heart failure. Recent studies revealed that myeloid cells play an important role in the regulation of hypertrophic remodeling. Neuregulin-1 (NRG-1) has been shown to play an essential role in the regulation of tissue-protective and pro-survival processes in response to tissue injury in the cardiovascular system. We find that NRG-1 receptors, including ErbB2 and ErbB3, are expressed and functionally active in cardiac myeloid cells. We hypothesized that the NRG-1/ErbB3 signaling in myeloid cells plays a protective role in cardiac hypertrophic remodeling. To test this hypothesis, we examined the effect of Erbb3 gene ablation in mouse myeloid cells on cardiac hypertrophic remodeling induced by pressure overload. Methods and results: Myeloid-specific ErbB3-deficient mice (ErbB3 MyeKO ) were generated by crossing Erbb3 -floxed mice with LysM-Cre transgenic mice. Cardiac hypertrophic remodeling was established in mice by transverse aortic constriction (TAC). Five days after TAC, survival was dramatically reduced in male ErbB3 MyeKO mice (20% vs. 90%, p=0.021 , MyeKO vs. MyeWT). The post-mortem examination of lung weight to body weight ratio suggested that acute pulmonary edema was developed in ERBB3 MyeKO mice. In order to determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3 MyeKO males, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. A significant accumulation of myeloid cells was found in control but not in ErbB3 MyeKO males. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and cardiac progenitors) in control but not ErbB3 MyeKO males. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3 MyeKO males after TAC. Conclusion: Our data highlight the important role of myeloid cell-specific ErbB3 signaling in the accumulation of myeloid cells that contributes to the development of compensatory hypertrophy and the prevention of acute heart failure in male mice.