Intra- and Intertumoral Microglia/Macrophage Infiltration and Their Associated Molecular Signature Is Highly Variable in Canine Oligodendroglioma: A Preliminary Evaluation.

The goal of this study was to define the glioma-associated microglia/macrophage (GAM) response and associated molecular landscape in canine oligodendrogliomas. Here, we quantified the intratumoral GAM density of low- and high-grade oligodendrogliomas compared to that of a normal brain, as well as the intratumoral concentration of several known GAM-derived pro-tumorigenic molecules in high-grade oligodendrogliomas compared to that in a normal brain. Our analysis demonstrated marked intra- and intertumoral heterogeneity of GAM infiltration. Correspondingly, we observed significant variability in the intratumoral concentrations of several GAM-associated molecules, unlike what we previously observed in high-grade astrocytomas. However, high-grade oligodendroglioma tumor homogenates (n = 6) exhibited an increase in the pro-tumorigenic molecules hepatocyte growth factor receptor (HGFR) and vascular endothelial growth factor (VEGF), as we observed in high-grade astrocytomas. Moreover, neoplastic oligodendrocytes displayed robust expression of GAL-3, a chimeric galectin implicated in driving immunosuppression in human glioblastoma. While this work identifies shared putative therapeutic targets across canine glioma subtypes (HGFR, GAL-3), it highlights several key differences in the immune landscape. Therefore, a continued effort to develop a comprehensive understanding of the immune microenvironment within each subtype is necessary to inform therapeutic strategies going forward.

Lipoprotein(a) and diet-a challenge for a role of saturated fat in cardiovascular disease risk reduction?

In this perspective, we discuss new evidence relating to current dietary recommendations to reduce SFA intake to modulate an individual's global risk of CVD. Although it is well established that lowering dietary SFA intake has a beneficial effect on LDL cholesterol concentrations, findings increasingly indicate an opposite effect on lipoprotein(a) [Lp(a)] concentrations. In recent years, many studies have firmly established a role for an elevated Lp(a) concentration as a genetically regulated, causal, and prevalent risk factor for CVD. However, there is less awareness of the effect of dietary SFA intake on Lp(a) concentrations. This study discusses this issue and highlights the contrasting effect of reducing dietary SFA intake on LDL cholesterol and Lp(a), 2 highly atherogenic lipoproteins. This calls attention to the need for precision nutrition approaches that move beyond a "one-size-fits-all" approach. To illustrate the contrast, we describe the dynamic contributions of Lp(a) and LDL cholesterol concentrations to CVD risk during interventions with a low-SFA diet, with the hope that this will stimulate further studies and discussions regarding dietary management of CVD risk.

Accessing and utilizing clinical and genomic data from an electronic health record data warehouse.

Electronic health records (EHRs) and linked biobanks have tremendous potential to advance biomedical research and ultimately improve the health of future generations. Repurposing EHR data for research is not without challenges, however. In this paper, we describe the processes and considerations necessary to successfully access and utilize a data warehouse for research. Although imperfect, data warehouses are a powerful tool for harnessing a large amount of data to phenotype disease. They will have increasing relevance and applications in clinical research with growing sophistication in processes for EHR data abstraction, biobank integration, and cross-institutional linkage.

Microglia-Derived Olfactomedin-like 3 Is a Potent Angiogenic Factor in Primary Mouse Brain Endothelial Cells: A Novel Target for Glioblastoma.

Neoangiogenesis, a hallmark feature of all malignancies, is robust in glioblastoma (GBM). Vascular endothelial growth factor (VEGF) has long been regarded as the primary pro-angiogenic molecule in GBM. However, anti-VEGF therapies have had little clinical efficacy, highlighting the need to explore VEGF-independent mechanisms of neoangiogenesis. Olfactomedin-like 3 (OLFML3), a secreted glycoprotein, is an established proangiogenic factor in many cancers, but its role in GBM neoangiogenesis is unknown. To gain insight into the role of OLFML3 in microglia-mediated angiogenesis, we assessed endothelial cell (EC) viability, migration and differentiation following (1) siRNA knockdown targeting endogenous EC Olfml3 and (2) EC exposure to human recombinant OLFML3 (rhOLFML3; 10 ng/mL, 48 h), and conditioned medium (CM) from isogenic control and Olfml3−/− microglia (48 h). Despite a 70% reduction in Olfml3 mRNA levels, EC angiogenic parameters were not affected. However, exposure to both rhOLFML3 and isogenic control microglial CM increased EC viability (p < 0.01), migration (p < 0.05) and differentiation (p < 0.05). Strikingly, these increases were abolished, or markedly attenuated, following exposure to Olfml3−/− microglial CM despite corresponding increased microglial secretion of VEGF-A (p < 0.0001). Consistent with reports in non-CNS malignancies, we have demonstrated that OLFML3, specifically microglia-derived OLFML3, promotes VEGF-independent angiogenesis in primary brain microvascular ECs and may provide a complementary target to mitigate neovascularization in GBM.

Prevalence and Clinicopathologic Features of Canine Metastatic Melanoma Involving the Central Nervous System: A Retrospective Analysis and Comparative Review.

Background: Central nervous system (CNS) involvement is the leading cause of death in malignant melanoma. Rodent models, while vital to mechanistic investigation, have had limited success identifying effective therapies for melanoma brain metastases. The companion dog with de novo melanoma is a promising complementary model for developmental therapeutic investigation, as these tumors occur in an immunologically outbred host that has shared environmental exposures with humans. However, relatively little is known regarding the prevalence and clinicopathological features of canine melanoma metastasis to the CNS. To further validate the dog as an appropriate model for human metastatic melanoma, the aims of this study were to determine the rate of CNS metastasis and associated clinicopathologic features in canine malignant melanoma. Methods: Medical records of dogs diagnosed with malignant melanoma from 1985-2019 at the University of California Davis Veterinary Medical Teaching Hospital were assessed retrospectively. Clinicopathologic features were compared between dogs with CNS metastasis (CNS+) and dogs without CNS metastasis (CNS-). Site of CNS involvement and associated neurological signs were analyzed via Wilcoxon-Mann-Whitney rank sum and Fisher's exact tests. Survival data were analyzed via Kaplan-Meier estimates. Results: CNS metastasis was identified in 38% of dogs in this study (20/53). The oral cavity was the most common site of primary melanoma in both groups [CNS+: n=12 (60%) vs. CNS-: n=22 (67%); p>0.99]. The total burden of metastatic disease was higher in the CNS+ group (CNS+: 4, 95% CI 3-5 vs. CNS-: 3, 95% CI 1-3; p<0.001). The cerebrum was the most common site of CNS metastasis (n=15, 75%) and seizures were the most observed neurological sign (n=9, 64%). There was no difference in overall survival between CNS+ and CNS- groups. However, the median survival time following onset of neurological signs was 9.5 days (95% CI 1-43), with 5 dogs euthanized within 24 hours of the onset of neurological signs. Conclusions: Canine and human MM patients share similar rates of CNS metastasis and clinical presentation. This study will guide clinical management of canines with malignant melanoma and inform future studies using dogs with spontaneously occurring melanoma as a preclinical model for human melanoma brain metastases.

The transition from in-person to virtual museum programing for individuals living with chronic pain - A formative evaluation.

Museum engagement may be an effective approach for decreasing social disconnection and pain among individuals living with chronic pain. In October 2019, we launched a randomized controlled trial to assess the feasibility of museum engagement for individuals living with chronic pain; the study was halted in March, 2020 due to Covid-19-related safety concerns. This paper describes the process of transitioning from in-person to virtual museum programing in order to continue the study. Virtual museum programing is a feasible option for individuals living with chronic pain that is amenable to research and which may improve accessibility, inclusivity, and scalability relative to in-person programing.

Dietary Management of Heart Failure: DASH Diet and Precision Nutrition Perspectives.

Heart failure (HF) is a major health care burden increasing in prevalence over time. Effective, evidence-based interventions for HF prevention and management are needed to improve patient longevity, symptom control, and quality of life. Dietary Approaches to Stop Hypertension (DASH) diet interventions can have a positive impact for HF patients. However, the absence of a consensus for comprehensive dietary guidelines and for pragmatic evidence limits the ability of health care providers to implement clinical recommendations. The refinement of medical nutrition therapy through precision nutrition approaches has the potential to reduce the burden of HF, improve clinical care, and meet the needs of diverse patients. The aim of this review is to summarize current evidence related to HF dietary recommendations including DASH diet nutritional interventions and to develop initial recommendations for DASH diet implementation in outpatient HF management. Articles involving human studies were obtained using the following search terms: Dietary Approaches to Stop Hypertension (DASH diet), diet pattern, diet, metabolism, and heart failure. Only full-text articles written in English were included in this review. As DASH nutritional interventions have been proposed, limitations of these studies are the small sample size and non-randomization of interventions, leading to less reliable evidence. Randomized controlled interventions are needed to offer definitive evidence related to the use of the DASH diet in HF management.

Chemotherapy After Diagnosis of Malignant Bowel Obstruction is Associated with Superior Survival for Medicare Patients with Advanced Malignancy.

BACKGROUND: Although malignant bowel obstruction (MBO) often is a terminal event, systemic therapies are advocated for select patients to extend survival. This study aimed to evaluate factors associated with receipt of chemotherapy after MBO and to determine whether chemotherapy after MBO is associated with survival. METHODS: This retrospective cohort study investigated patients 65 years of age or older with metastatic gastrointestinal, gynecologic, or genitourinary cancers who were hospitalized with MBO from 2008 to 2012 using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Fine and Gray models were used to identify factors associated with receipt of chemotherapy accounting for the competing risk of death. Cox models identified factors associated with overall survival. RESULTS: Of the 2983 MBO patients, 39% (n = 1169) were treated with chemotherapy after MBO. No differences in receipt of chemotherapy between the surgical and medical patients were found in the univariable analysis (subdistribution hazard ratio [SHR], 0.96; 95% confidence interval [CI], 0.86-1.07; p = 0.47) or multivariable analysis (SHR, 1.12; 95% CI, 1.00-1.26; p = 0.06). Older age, African American race, medical comorbidities, non-colorectal and non-ovarian cancer diagnoses, sepsis, ascites, and intensive care unit stays were inversely associated with receipt of chemotherapy after MBO (p < 0.05). Chemotherapy with surgery was associated with longer survival than surgery (adjusted hazard ratio [aHR], 2.97; 95% CI, 2.65-3.34; p < 0.01) or medical management without chemotherapy (aHR, 4.56; 95% CI, 4.04-5.14; p < 0.01). Subgroup analyses of biologically diverse cancers (colorectal, pancreatic, and ovarian) showed similar results, with greater survival related to chemotherapy (p < 0.05). CONCLUSIONS: Chemotherapy plays an integral role in maximizing oncologic outcome for select patients with MBO. The data from this study are critical to optimizing multimodality care for these complex patients.

High Versus Low Volume Fluid Resuscitation Strategies in a Porcine Model (Sus scrofa) of Combined Thermal and Traumatic Brain Injury.

BACKGROUND: Combined burn and traumatic brain injury (TBI) treatment priorities may not align due to opposing fluid resuscitation paradigms used in treating burns and TBI. We developed a porcine model of combined thermal injury/TBI and compared an "aggressive" fluid resuscitation strategy using the Parkland formula and a "restrictive" resuscitation strategy using the modified Brooke formula. METHODS: Twenty-eight swine were deeply anesthetized and received a 40% total body surface area full-thickness burn injury and TBI. Swine were then randomized to receive restrictive or aggressive resuscitation for 8 h after which time animals were euthanized and necropsy was performed. Volume of brain injury was assessed after analyzing segmental slices of brain tissue. RESULTS: There were no differences between the restrictive and aggressive resuscitation groups in blood pressure, heart rate, central venous pressure, intra-cranial pressure (ICP), or serum lactate levels after 8 h of resuscitation. Urine output was higher in the aggressive resuscitation group. The restrictive group had a significantly higher serum blood urea nitrogen (BUN) compared with baseline and compared with the aggressive group. There was no significant difference in size of brain injury between groups. CONCLUSIONS: Both restrictive and aggressive resuscitation demonstrated adequate resuscitation at 8 h postinjury. Increased serum BUN in the restrictive group may be an indicator of early acute kidney injury, despite adequate urine output. Resuscitation strategy did not appear to affect ICP or the size of brain injury.

Building a comprehensive mentoring academy for schools of health.

Formal mentoring programs are increasingly recognized as critical for faculty career development. We describe a mentoring academy (MA) developed for faculty across tracks (i.e., researchers, clinicians, educators) within a "school of health" encompassing schools of medicine and nursing. The program is anchored dually in a clinical and translational science center and a school of health. The structure includes the involvement of departmental and center mentoring directors to achieve widespread uptake and oversight. A fundamental resource provided by the MA includes providing workshops to enhance mentoring skills. Initiatives for junior faculty emphasize establishing and maintaining strong mentoring relationships and implementing individual development plans (IDPs) for career planning. We present self-report data on competency improvement from mentor workshops and data on resources and barriers identified by junior faculty (n = 222) in their IDPs. Mentors reported statistically significantly improved mentoring competency after workshop participation. Junior faculty most frequently identified mentors (61%) and collaborators (23%) as resources for goal attainment. Top barriers included insufficient time and time-management issues (57%), funding limitations (18%), work-life balance issues (18%), including inadequate time for self-care and career development activities. Our MA can serve as a model and roadmap for providing resources to faculty across traditional tracks within medical schools.

Hospital utilization and disposition among patients with malignant bowel obstruction: a population-based comparison of surgical to medical management.

BACKGROUND: Malignant bowel obstruction (MBO) is often a terminal event in end-stage cancer patients. The decision to intervene surgically is complex, given the risk of harm in patients with a limited lifespan. Therefore, we sought to compare clinically meaningful outcomes in MBO patients treated with surgical versus medical management using population-based data. METHODS: We performed a retrospective analysis of hospitalized patients with MBO from 2006 to 2010 using the California Office of Statewide Health Planning and Development dataset. Hospital-free days (HFDs) at 30-, 90-, and 180-days were calculated accounting for all hospitalization, emergency department visit, and skilled nursing facility lengths of stay. Adjusted regression models were used to compare HFDs, disposition, complications, in-hospital death, and survival for surgical versus medical MBO cohorts, using inverse probability of treatment weighting with propensity scores. RESULTS: Of 4576 MBO patients, 3421 (74.8%) were treated medically and 1155 (25.2%) were treated surgically. Surgical patients had higher rates of complications (44.0% vs. 21.3%, p < 0.0001) and in-hospital death (9.5% vs. 3.9%, p < 0.0001) with lower rates of disposition to home (76.3% vs. 89.8%, p < 0.0001). Surgical patients had fewer 30- and 90-day HFDs compared to medical patients (p < 0.01). However, at 180-days, there were no differences in HFDs between treatment groups. There was no difference in overall survival between surgical and medical patients (median 6.5 vs. 6.4 months). CONCLUSION: In this population-based analysis, medical management was associated with less hospital utilization at 30- and 90-days, fewer in-hospital deaths, and more frequent discharges to home. These data underscore the potential benefits of medical management for MBO patients at the end-of-life.

Palliative Care Training and Decision-Making for Patients with Advanced Cancer: A Comparison of Surgeons and Medical Physicians.

BACKGROUND: Surgical decision-making in patients with advanced cancer requires careful thought and deliberation to balance the high risks with the potential palliative benefits. We sought to compare surgical decision-making and palliative care training among surgeons and medical physicians who commonly treat advanced cancer patients. We hypothesized that surgeons will report less palliative care training compared with medical physicians, and deficits in palliative care training will be associated with more aggressive treatment recommendations in clinical scenarios of advanced cancer patients with symptomatic surgical conditions. STUDY DESIGN: Practicing surgeons, medical oncologists, intensivists, and palliative care physicians from a large urban city and its surrounding areas were surveyed with a 32-item questionnaire consisting of a survey addressing palliative care training and 4 clinical vignettes depicting patients with advanced cancer and symptomatic surgical conditions. RESULTS: Of the 299 physicians surveyed, 102 responded (response rate 34.1%). Surgeons reported fewer hours of palliative care training during residency, fellowship, and continuing medical education combined (median 10, IQR 2-15) compared with medical oncologists (median 30, IQR 20-80) and medical intensivists (median 50 IQR 30-100), P < .05. Additionally, 20% of surgeons reported no history of any palliative care training. Analysis of physician recommendations for treatment of the 4 clinical vignettes showed minimal consensus regardless of physician specialty. Absence of palliative care training was associated with recommending major operative intervention more frequently compared with physicians with ≥40 hours of palliative care training (0.7 ± 0.7 vs 1.6 ± 0.8, P =.01). CONCLUSION: Substantial deficiencies in palliative care training persist among surgeons and are associated with more aggressive recommendations for treatment for the selected scenarios presented in patients with advanced cancer. These findings highlight the need for greater efforts systemwide in palliative care education among surgeons, including incorporation of a structured palliative care training curriculum in graduate and continuing surgical education.

Comparison of common risk stratification indices to predict outcomes among stage IV cancer patients with bowel obstruction undergoing surgery.

BACKGROUND AND OBJECTIVES: Among patients with disseminated malignancy (DMa), bowel obstruction is common with high operative morbidity. Since preoperative risk stratification is critical, we sought to compare three standard risk indices, the American Society of Anesthesiology (ASA) classification, Charlson comorbidity index (CCI), and modified frailty index (mFI). METHODS: We identified 1928 DMa patients with bowel obstruction who underwent an abdominal operation from 2007 to 2012 American College of Surgeons National Surgical Quality Improvement Program. Multivariate analyses assessed predictors of prolonged length of stay (LOS), 30-day serious morbidity and mortality. Receiver operating characteristics' areas under the curves (AUCs) for risk indices scores and 30-day mortality were assessed. RESULTS: Serious morbidity and mortality rates were 20.4% and 14.8%. ASA and CCI did not predict serious morbidity or prolonged LOS, but were predictors of mortality. The mFI did not predict prolonged LOS, but did predict serious morbidity and mortality. Subgroup analyses showed similar results. There were no significant differences between ASA, CCI, and mFI AUCs for mortality. CONCLUSIONS: ASA, CCI, and mFI are limited in their ability to predict postoperative adverse events among DMa patients undergoing surgery for bowel obstruction. These data suggest that a more tailored preoperative risk stratification tool would improve treatment planning.

Lung resection is safe and feasible among stage IV cancer patients: An American College of Surgeons National Surgical Quality Improvement Program analysis.

BACKGROUND: Operative resection can be associated with improved survival for selected patients with stage IV malignancies but may also be associated with prohibitive acute morbidity and mortality. We sought to evaluate rates of acute morbidity and mortality after lung resection in patients with disseminated malignancy with primary lung cancer and non-lung cancer pulmonary metastatic disease. METHODS: For 2011-2012, 6,360 patients were identified from the American College of Surgeons National Surgical Quality Improvement Program undergoing lung resections, including 603 patients with disseminated malignancy. Logistic regression analyses were used to compare outcomes between patients with and without disseminated malignancy. RESULTS: After controlling for preoperative and intraoperative differences, we observed no statistically significant differences in rates of 30-day overall and serious morbidity or mortality between disseminated malignancy and non-disseminated malignancy patients (P > .05). Disseminated malignancy patients were less likely to have a prolonged duration of stay and be discharged to a facility compared to non-disseminated malignancy patients (P < .05). Subgroup analyses by procedure type and diagnosis showed similar results. CONCLUSION: Disseminated malignancy patients undergoing lung resections experienced low rates of overall morbidity, serious morbidity, and mortality comparable to non-disseminated malignancy patients. These data suggest that lung resections may be performed safely on carefully selected, disseminated malignancy patients with both primary lung cancer and pulmonary metastatic disease, with important implications for multimodality care.

Increased Rates of Prolonged Length of Stay, Readmissions, and Discharge to Care Facilities among Postoperative Patients with Disseminated Malignancy: Implications for Clinical Practice.

BACKGROUND: The impact of surgery on end of life care for patients with disseminated malignancy (DMa) is incompletely characterized. The purpose of this study was to evaluate postoperative outcomes impacting quality of care among DMa patients, specifically prolonged length of hospital stay, readmission, and disposition. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was queried for years 2011-2012. DMa patients were matched to non-DMa patients with comparable clinical characteristics and operation types. Primary hepatic operations were excluded, leaving a final cohort of 17,972 DMa patients. The primary outcomes were analyzed using multivariate Cox regression models. RESULTS: DMa patients represented 2.1% of all ACS-NSQIP procedures during the study period. The most frequent operations were bowel resections (25.3%). Compared to non-DMa matched controls, DMa patients had higher rates of postoperative overall morbidity (24.4% vs. 18.7%, p<0.001), serious morbidity (14.9% vs. 12.0%, p<0.001), mortality (7.6% vs. 2.5%, p<0.001), prolonged length of stay (32.2% vs. 19.8%, p<0.001), readmission (15.7% vs. 9.6%, p<0.001), and discharges to facilities (16.2% vs. 12.9%, p<0.001). Subgroup analyses of patients by procedure type showed similar results. Importantly, DMa patients who did not experience any postoperative complication experienced significantly higher rates of prolonged length of stay (23.0% vs. 11.8%, p<0.001), readmissions (10.0% vs. 5.2%, p<0.001), discharges to a facility (13.2% vs. 9.5%, p<0.001), and 30-day mortality (4.7% vs. 0.8%, p<0.001) compared to matched non-DMa patients. CONCLUSION: Surgical interventions among DMa patients are associated with poorer postoperative outcomes including greater postoperative complications, prolonged length of hospital stay, readmissions, disposition to facilities, and death compared to non-DMa patients. These data reinforce the importance of clarifying goals of care for DMa patients, especially when acute changes in health status potentially requiring surgery occur.

The origin and implementation of the Broadening Experiences in Scientific Training programs: an NIH common fund initiative.

Recent national reports and commentaries on the current status and needs of the U.S. biomedical research workforce have highlighted the limited career development opportunities for predoctoral and postdoctoral trainees in academia, yet little attention is paid to preparation for career pathways outside of the traditional faculty path. Recognizing this issue, in 2013, the U.S. National Institutes of Health (NIH) Common Fund issued a request for application titled "NIH Director's Biomedical Research Workforce Innovation Award: Broadening Experiences in Scientific Training (BEST)." These 5-yr 1-time grants, awarded to 17 single or partnering institutions, were designed to develop sustainable approaches to broaden graduate and postgraduate training, aimed at creating training programs that reflect the range of career options that trainees may ultimately pursue. These institutions have formed a consortium in order to work together to develop, evaluate, share, and disseminate best practices and challenges. This is a first report on the early experiences of the consortium and the scope of participating BEST programs. In this report, we describe the state of the U.S. biomedical workforce and development of the BEST award, variations of programmatic approaches to assist with program design without BEST funding, and novel approaches to engage faculty in career development programs. To test the effectiveness of these BEST programs, external evaluators will assess their outcomes not only over the 5 yr grant period but also for an additional 10 yr beyond award completion.

Three Dimensional Culture of Human Renal Cell Carcinoma Organoids.

Renal cell carcinomas arise from the nephron but are heterogeneous in disease biology, clinical behavior, prognosis, and response to systemic therapy. Development of patient-specific in vitro models that efficiently and faithfully reproduce the in vivo phenotype may provide a means to develop personalized therapies for this diverse carcinoma. Studies to maintain and model tumor phenotypes in vitro were conducted with emerging three-dimensional culture techniques and natural scaffolding materials. Human renal cell carcinomas were individually characterized by histology, immunohistochemistry, and quantitative PCR to establish the characteristics of each tumor. Isolated cells were cultured on renal extracellular matrix and compared to a novel polysaccharide scaffold to assess cell-scaffold interactions, development of organoids, and maintenance of gene expression signatures over time in culture. Renal cell carcinomas cultured on renal extracellular matrix repopulated tubules or vessel lumens in renal pyramids and medullary rays, but cells were not observed in glomeruli or outer cortical regions of the scaffold. In the polysaccharide scaffold, renal cell carcinomas formed aggregates that were loosely attached to the scaffold or free-floating within the matrix. Molecular analysis of cell-scaffold constructs including immunohistochemistry and quantitative PCR demonstrated that individual tumor phenotypes could be sustained for up to 21 days in culture on both scaffolds, and in comparison to outcomes in two-dimensional monolayer cultures. The use of three-dimensional scaffolds to engineer a personalized in vitro renal cell carcinoma model provides opportunities to advance understanding of this disease.