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.

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.

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.

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.

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.

Current perioperative outcomes for patients with disseminated cancer.

BACKGROUND: Surgical morbidity and mortality (M&M) for patients with disseminated malignancy (DMa) is high, and some have questioned the role of surgery. Therefore, we sought to characterize temporal trends in M&M among DMa patients, hypothesizing that surgical intervention would remain prevalent. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program from 2006-2010. Excluding patients undergoing a primary hepatic operation, we identified 21,755 patients with DMa. Parametric and/or nonparametric statistics and logistic regression were used to evaluate temporal trends and predictors of M&M. RESULTS: The prevalence of surgical intervention for DMa declined slightly over the time period, from 1.9%-1.6% of all procedures (P < 0.01). Among DMa patients, the most frequent operations performed were bowel resection, other gastrointestinal procedures, and multivisceral resections, these all showed small statistically significant decreases over time (P < 0.01). The rate of emergency operations also decreased (P < 0.01). In contrast, the rate of preoperative independent functional status rose, whereas the rate of preoperative weight loss and sepsis decreased (P < 0.01). Rates of 30-d morbidity (33.7 versus 26.6%), serious morbidity (19.8 versus 14.2%), and mortality (10.4 versus 9.3%) all decreased over the study period (P < 0.05). Multivariate analysis identified standard predictors (e.g., impaired functional status, preoperative weight loss, preoperative sepsis, and hypoalbuminemia) of worse 30-d M&M. CONCLUSIONS: Thirty-day morbidity, serious morbidity, and mortality have decreased incrementally for patients with DMa undergoing surgical intervention, but surgical intervention remains prevalent. These data further highlight the importance of careful patient selection and goal-directed therapy in patients with incurable malignancy.

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.

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.

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.

Nomogram to predict risk of 30-day morbidity and mortality for patients with disseminated malignancy undergoing surgical intervention.

OBJECTIVE: To estimate individual risk of 30-day surgical morbidity and mortality after surgical intervention for patients with disseminated malignancy (DMa). BACKGROUND: Patients with DMa frequently require surgical consultation for palliative operations. Although these patients are at high risk for surgical morbidity and mortality, limited data exist allowing individual risk stratification. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) from 2005 to 2007, we identified 7447 patients with DMa. Each of the 53 preoperative ACS NSQIP variables was analyzed to assess risk of morbidity and mortality. Logistic regression models were developed using stepwise model selection and generalized additive models. Covariates were evaluated for nonlinearity and interactions among variables. We constructed nomograms utilizing clinically and statistically significant covariates to predict 30-day risk of morbidity and mortality. RESULTS: Overall 30-day unadjusted morbidity and mortality rates were 28.3% and 8.9%, respectively. Mortality rates reached 18.4% for vascular procedures and 27.9% for emergent operations. Increasing age, impaired functional status, Do-Not-Resuscitate status, impaired respiratory function, ascites, hypoalbuminema, elevated creatinine, and abnormal WBC were all significant predictors (P < 0.0001) of increased morbidity and mortality on multivariate analysis. Nomograms to predict individual 30-day risk of complications and death based on preoperative factors were developed and validated by bootstrapping. Concordance indices were 0.704 and 0.861 for morbidity and mortality, respectively. CONCLUSIONS: Surgical intervention among patients with DMa is associated with substantial morbidity and mortality. We have constructed nomograms to predict individual risk of 30-day morbidity and mortality. These have significant implications for surgical decision-making in this group of 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.

Probiotics and immunity.

Probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, including the gastrointestinal tract. While this beneficial effect was originally thought to stem from improvements in the intestinal microbial balance, there is now substantial evidence that probiotics can also provide benefits by modulating immune functions. In animal models, probiotic supplementation is able to provide protection from spontaneous and chemically induced colitis by downregulating inflammatory cytokines or inducing regulatory mechanisms in a strain-specific manner. In animal models of allergen sensitization and murine models of asthma and allergic rhinitis, orally administered probiotics can strain-dependently decrease allergen-specific IgE production, in part by modulating systemic cytokine production. Certain probiotics have been shown to decrease airway hyperresponsiveness and inflammation by inducing regulatory mechanisms. Promising results have been obtained with probiotics in the treatment of human inflammatory diseases of the intestine and in the prevention and treatment of atopic eczema in neonates and infants. However, the findings are too variable to allow firm conclusions as to the effectiveness of specific probiotics in these conditions.

Radical palliative surgery: new limits to pursue.

This case report describes the radical subtotal palliative resection of a massive recurrent desmoid tumor encompassing the abdomen, pelvis, and groin in a child who was 13 years old at the time of initial resection. Given the extensive distribution of the tumor en bloc resection, which is the standard treatment of desmoid tumors, would have meant performing a hemipelvectomy and repair of a large abdominal wall defect, likely with skin grafts and mesh. The patient's personal goals however were to alleviate the pain and limited mobility that would allow her to re-attend high school and appear normal to her peers. Therefore, palliative surgery was pursued and currently the patient is 5 years out from her last surgery doing well. We believe that the option of surgical palliation in this case was warranted and should be an option for similar cases in the future.

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.

The utility of the model for end-stage liver disease score: a reliable guide for liver transplant candidacy and, for select patients, simultaneous hospice referral.

Patients with chronic liver disease are referred late to hospice or never referred. There are several barriers to timely referral. First, liver transplantation (LT) and hospice care have always been perceived as mutually exclusive. Yet the criteria for hospice referral and for LT are more similar than different (for example, advanced liver disease and imminent death). Second, physicians, patients, and families have not had a reliable metric to guide referral. However, many patients wait for transplantation but never receive an organ. We hypothesized that the Model for End-Stage Liver Disease (MELD) score already in use to prioritize LT could be used in selected patients for concurrent hospice referral. Furthermore, we hypothesized that patients awaiting LT can receive hospice care and remain eligible for transplantation. Patients with advanced or end-stage liver disease were referred to the University of California Davis Health System hospice program. We correlated the MELD score at admission to length of stay (LOS) in hospice. A total of 157 end-stage liver disease patients were admitted to the hospice service. At the time of hospice admission the mean MELD score was 21 (range, 6-45). The mean length of hospice stay was 38 days (range, 1-329 days). A significant correlation was observed between hospice LOS and MELD score at hospice admission (P < 0.01). Six patients were offered a liver graft while on the combined (LT and hospice) program. MELD can be used to guide clinician recommendation to families about hospice care, achieving one of the national benchmark goals of increasing hospice care duration beyond the current median of 2-3 weeks. A higher MELD score might augment physician judgment as to hospice referral. Hospice care for selected patients may be an effective strategy to improve the care of end-stage liver disease patients waiting for LT.

The immunobiology of mushrooms.

There has been enormous interest in the biologic activity of mushrooms and innumerable claims have been made that mushrooms have beneficial effects on immune function with subsequent implications for inhibition of tumor growth. The majority of these observations are anecdotal and often lack standardization. However, there remains considerable data on both in vitro and in vivo effects that reflect on the potential of mushroom compounds to influence human immunity. A number of these effects are beneficial but, unfortunately, many responses are still characterized based on phenomenology and there is more speculation than substance. With respect to tumor biology, although many neoplastic lesions are immunogenic, tumor antigens frequently are self antigens and induce tolerance and many patients with cancer exhibit suppressed immune responses, including defective antigen presentation. Therefore, if and when mushroom extracts are effective, they more likely function as a result of improved antigen presentation by dendritic cells than by a direct cytopathic effect. In this review we attempt to place these data in perspective, with a particular focus on dendritic cell populations and the ability of mushroom extracts to modulate immunity. There is, at present, no scientific basis for the use of either mushrooms or mushroom extracts in the treatment of human patients but there is significant potential for rigorous research to understand the potential of mushrooms in human disease and thence to focus on appropriate clinical trials to demonstrate effectiveness and/ or potential toxicity.