Socioeconomic Predictors of Pituitary Surgery.

BACKGROUND: There exists a lack of data on the effect of socioeconomic status (SES) on outcomes for pituitary tumors, which have been associated with significant morbidity. The goal of this population-level study is to investigate the role of SES on receiving treatment and survival in patients with pituitary tumors. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program database from the National Cancer Institute was used to identify patients diagnosed with pituitary tumors between 2003 and 2012. SES was determined using a validated composite index. Race was categorized as Caucasian and non-Caucasian. Treatment received included surgery, radiation, and radiation with surgery. Odds of receiving surgery and survival probability were analyzed using multivariate logistic regression and Cox proportional hazards model, respectively. RESULTS: A total of 25,802 patients with pituitary tumors were identified for analysis. High SES tertile (odds ratio (OR) = 1.095; 95% confidence interval (CI) [1.059, 1.132]) and quintile (OR = 1.052; 95% CI [1.031, 1.072]) were associated with higher odds of receiving surgery (p<0.0001). Caucasian patients had higher odds of receiving surgery when compared to non-Caucasian patients (OR = 1.064; 95% CI [1.000, 1.133]; p<0.05). Neither SES nor race were significant predictors of survival probability. CONCLUSION: Socioeconomic status and race were found to be associated with higher odds of receiving surgery for pituitary tumors, and thus serve as independent predictors of surgical management. Further studies are required to investigate possible causes for these findings.

Microglia are effector cells of CD47-SIRPα antiphagocytic axis disruption against glioblastoma.

Glioblastoma multiforme (GBM) is a highly aggressive malignant brain tumor with fatal outcome. Tumor-associated macrophages and microglia (TAMs) have been found to be major tumor-promoting immune cells in the tumor microenvironment. Hence, modulation and reeducation of tumor-associated macrophages and microglia in GBM is considered a promising antitumor strategy. Resident microglia and invading macrophages have been shown to have distinct origin and function. Whereas yolk sac-derived microglia reside in the brain, blood-derived monocytes invade the central nervous system only under pathological conditions like tumor formation. We recently showed that disruption of the SIRPα-CD47 signaling axis is efficacious against various brain tumors including GBM primarily by inducing tumor phagocytosis. However, most effects are attributed to macrophages recruited from the periphery but the role of the brain resident microglia is unknown. Here, we sought to utilize a model to distinguish resident microglia and peripheral macrophages within the GBM-TAM pool, using orthotopically xenografted, immunodeficient, and syngeneic mouse models with genetically color-coded macrophages (Ccr2RFP) and microglia (Cx3cr1GFP). We show that even in the absence of phagocytizing macrophages (Ccr2RFP/RFP), microglia are effector cells of tumor cell phagocytosis in response to anti-CD47 blockade. Additionally, macrophages and microglia show distinct morphological and transcriptional changes. Importantly, the transcriptional profile of microglia shows less of an inflammatory response which makes them a promising target for clinical applications.

A Three-Step Letter Advance Directive Procedure to Facilitate Patient-Proxy Alignment in Advance Care Planning.

Background: Little is known about the extent of alignment between hematopoietic stem cell transplant (HSCT) patients and their healthcare proxies with respect to advance care planning (ACP). Aim: To determine if a structured three-step process using the letter advance directive (LAD) could (1) allow for the differences in opinion between patient-proxy dyads to surface and (2) help bridge preexisting discordance about specific treatment choices. Design: Blinded to each other, the HSCT patient (LAD-1) and proxy (LAD-2) each completed the LAD (step 1). They unmasked, compared LAD-1 and LAD-2, and discussed their choices (step 2). They completed a final letter directive (LAD-3) by consensus (step 3). Settings/Participants: Convenience sample of eighty dyads (patient and proxy) at a regional HSCT referral center. Results: The mean patient-proxy concordance was 72.9% for the 12 questions in the LAD. Wanting to be pain free at the end of life was the statement with the most amount of agreement (88.75% in LAD-1, 91.25% in LAD-2, and 90% in LAD-3). Patient-proxy dyads had notable discordance related to specific treatments. The highest discordance was related to ventilator support (46.3% of patients refused it, while 58.8% of proxies refused on behalf of the patient). Overall, proxies were more likely than patients to opt in for dialyses and hospice care but more likely to opt out for cardiac resuscitation and sedation to palliate refractory symptoms. On open discussion, patient-proxy discordance mostly resolved in favor of the patient. Conclusions: The ACP process should allow for patient-proxy differences to surface, facilitate a discussion about the granular details with the goal of reaching consensus. Our three-step approach using the LAD is an effective way to identify areas of patient-proxy concordance and discordance about specific treatment preferences. A structured patient-proxy discussion using the LAD helped reconcile discordance and most often in favor of a patient's original wishes.

Nationwide Assessment of Factors Associated with Nonoperative Management of Pediatric Splenic Injury.

To evaluate variation in care nationwide for children with splenic injuries at pediatric trauma, adult trauma, and nontrauma centers. We used the National Inpatient Sample from 2001 to 2010 to identify pediatric patients with splenic injury. We analyzed demographic, clinical, and hospital status characteristics. The primary objective was comparison of splenectomy rates at pediatric, adult, and nontrauma centers. We identified 34,599 patients with splenic injury. Throughout the study, 3,979 (11.5%) patients underwent splenectomy: 8.2 per cent of patients at pediatric trauma, 17.6 per cent at adult trauma, and 14.5 per cent at nontrauma centers. Multivariate regression analysis demonstrated patients had decreased odds of splenectomy at pediatric trauma centers compared with adult and nontrauma centers (OR = 0.42, P < 0.001). In addition, children aged 14 to 17 years (OR = 2.5) with injury severity score > 14 (OR = 5.8) had increased odds of undergoing splenectomy. In this nationwide sample, children with splenic injury treated at adult trauma and nontrauma centers had significantly higher rates of splenectomy compared with children treated at pediatric trauma centers. We highlight the need for interventions that ensure all injured children receive appropriate and high quality trauma care.

Brainstem Dose Constraints in Nonisometric Radiosurgical Treatment Planning of Trigeminal Neuralgia: A Single-Institution Experience.

BACKGROUND: CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia. METHODS: We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression. RESULTS: After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P < 0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control. CONCLUSIONS: These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.

Temporal variation in HIV-specific IgG subclass antibodies during acute infection differentiates spontaneous controllers from chronic progressors.

OBJECTIVE: Given the emerging appreciation for the role of antibody-dependent effector functions and IgG subclass distribution among spontaneous controllers of HIV, we sought to determine whether antibody-associated features diverged in early HIV infection between patients who ultimately became controllers versus those who became progressors. METHODS: IgG was purified from plasma from nine acutely infected patients who subsequently controlled HIV spontaneously (controllers) and 10 acutely infected individuals who did not control viremia (progressors). Antibody profiles were compared at weeks 4, 12, 24 and 48 postinfection. Levels of clade B gp120-specific, gp140-specific and gp41-specific IgG antibody subclasses were measured. In addition, gp120-specific antibody-dependent cellular phagocytosis, rapid fluorescent antibody-dependent cellular cytotoxicity and antibody-dependent cellular viral inhibition were all assessed. RESULTS: Although no single antibody-related measurement was significantly associated with long-term HIV control, combinations of antibody-associated variables were able to accurately differentiate controllers and progressors. In contrast to controllers, progressors showed greater dynamic changes in gp120-specific subclass selection profiles, with increasing levels of Env-specific IgG2 antibodies and losses in Env-specific IgG3 antibodies. Moreover, progressors, but not controllers, lost antibody-dependent cellular viral inhibition function over time. Together, these results highlight changes in IgG subclass selection profiles in progressive, but not controlled, HIV infection. CONCLUSION: This study suggests that the temporal variation and maintenance of Env-specific IgG subclasses during acute HIV infection are predictive of eventual disease control. The maintenance of gp120-specific and gp140-specific IgG3 may contribute to control of disease in spontaneous controllers. Thus, strategies to induce stable IgG3 responses may preserve control of the viral reservoir.

The effect of socioeconomic status on gross total resection, radiation therapy and overall survival in patients with gliomas.

Socioeconomic status (SES) is associated with survival in many cancers but the effect of socioeconomic status on survival and access to care for patients with gliomas has not been well studied. This study included 50,170 patients from the Surveillance, Epidemiology, and End Results Program at the National Cancer Institute database diagnosed with gliomas of the brain from 2003 to 2012. Patient SES was divided into tertiles and quintiles. Treatment options included radiation, surgery (gross total resection (GTR)/other surgery), and radiation with surgery. Multivariable logistic regression and Cox proportional hazards model were used to analyze data with SAS v9.4. The results were adjusted for age at diagnosis, race, sex, tumor type, and tumor grade. Kaplan-Meier survival curves were constructed according to SES tertiles and quintiles. Patients from a higher SES tertile were significantly more likely to receive surgery, radiation, GTR, and radiation with surgery (OR 1.092, 1.116, 1.103, 1.150 respectively, all p < 0.0001). This correlation was also true when patients were divided into quintiles (OR 1.054, 1.072, 1.062, 1.089 respectively, all p < 0.0001). Furthermore, the lowest SES tertiles (HR 1.258, 1.146) and the lowest SES quintiles (HR 1.301, 1.273, 1.194, 1.119) were associated with significantly shorter survival times (all p for trend <0.0001). Surgery, radiation therapy, surgery with radiation therapy, and GTR were also found to be associated with improved overall survival in glioma patients (HR 0.553, 0.849, 0.666, 0.491 respectively, all p < 0.0001). The findings from this national study suggest an effect of SES on access to treatment, and survival in patients with gliomas.

A Functional Role for Antibodies in Tuberculosis.

While a third of the world carries the burden of tuberculosis, disease control has been hindered by a lack of tools, including a rapid, point-of-care diagnostic and a protective vaccine. In many infectious diseases, antibodies (Abs) are powerful biomarkers and important immune mediators. However, in Mycobacterium tuberculosis (Mtb) infection, a discriminatory or protective role for humoral immunity remains unclear. Using an unbiased antibody profiling approach, we show that individuals with latent tuberculosis infection (Ltb) and active tuberculosis disease (Atb) have distinct Mtb-specific humoral responses, such that Ltb infection is associated with unique Ab Fc functional profiles, selective binding to FcγRIII, and distinct Ab glycosylation patterns. Moreover, compared to Abs from Atb, Abs from Ltb drove enhanced phagolysosomal maturation, inflammasome activation, and, most importantly, macrophage killing of intracellular Mtb. Combined, these data point to a potential role for Fc-mediated Ab effector functions, tuned via differential glycosylation, in Mtb control.

Increased risk for complications following diagnostic cerebral angiography in older patients: Trends from the Nationwide Inpatient Sample (1999-2009).

The full utility of diagnostic cerebral angiography, an invasive cerebrovascular imaging technique, is currently debated. Our goal was to determine trends in diagnostic cerebral angiography utilization and associated complications from 1999 through 2009. The National Inpatient Sample (NIS) was used to identify patients who received primary cerebral angiography from 1999-2009 in the United States. We observed trends in discharge volume, total mean charge, and post-procedural complications for this population. Data was based on sample projections and analyzed using univariate and multivariate regression. There were a total of 424,105 discharges indicating primary cerebral angiography nationwide from 1999-2009. The majority of these cases (65%) were in patients older than 55years. Embolic stroke was the most frequent complication, particularly in the oldest age bracket, occurring in 16,304 patients. The risk for complications increased with age (p<0.0001) and with other underlying health conditions. Pulmonary, deep vein thrombosis, and renal associated comorbidities resulted in the greatest risk for developing post-procedural complications. Throughout the study period case volume for cerebral angiography remained constant while total charge per patient increased from $17,365 in 1999 to $45,339 in 2009 (p<0.001). While the overall complication rate for this invasive procedure is relatively low, the potential risk for embolic stroke in older patients is significant. It is worth considering less invasive diagnostic techniques for an older and at risk patient population.

Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo.

Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

Dissecting Polyclonal Vaccine-Induced Humoral Immunity against HIV Using Systems Serology.

While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine trials. Each vaccine regimen induced a unique humoral "Fc fingerprint." Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive.

Polyfunctional Fc-effector profiles mediated by IgG subclass selection distinguish RV144 and VAX003 vaccines.

The human phase 2B RV144 ALVAC-HIV vCP1521/AIDSVAX B/E vaccine trial, held in Thailand, resulted in an estimated 31.2% efficacy against HIV infection. By contrast, vaccination with VAX003 (consisting of only AIDSVAX B/E) was not protective. Because protection within RV144 was observed in the absence of neutralizing antibody activity or cytotoxic T cell responses, we speculated that the specificity or qualitative differences in Fc-effector profiles of nonneutralizing antibodies may have accounted for the efficacy differences observed between the two trials. We show that the RV144 regimen elicited nonneutralizing antibodies with highly coordinated Fc-mediated effector responses through the selective induction of highly functional immunoglobulin G3 (IgG3). By contrast, VAX003 elicited monofunctional antibody responses influenced by IgG4 selection, which was promoted by repeated AIDSVAX B/E protein boosts. Moreover, only RV144 induced IgG1 and IgG3 antibodies targeting the crown of the HIV envelope V2 loop, albeit with limited coverage of breakthrough viral sequences. These data suggest that subclass selection differences associated with coordinated humoral functional responses targeting strain-specific protective V2 loop epitopes may underlie differences in vaccine efficacy observed between these two vaccine trials.

Accelerated maternal responding following intra-VTA pertussis toxin treatment.

Prior studies have supported a role for mesolimbic dopaminergic mechanisms in the regulation of maternal behavior. Accordingly, the ventral tegmental area (VTA) and its dopaminergic projections to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in both the onset and maintenance of normal maternal behavior. To date, studies of direct manipulation of VTA neurochemistry at the onset of maternal behavior have been limited. The current study was undertaken to directly test the hypothesis that enhancement of dopaminergic transmission in the mesolimbic dopamine system can stimulate maternal activity using a pup-induced virgin model. Nulliparous female rats were stereotaxically infused with pertussis toxin (PTX 0, 0.1, or 0.3 µg/hemisphere) into the VTA to chronically stimulate the activity of dopaminergic projection neurons. After 3 days of recovery, maternal responding to donor pups was tested daily, and latency (in days) to full maternal behavior was recorded. Intra-VTA PTX treatment produced a robust dose-dependent decrease in maternal behavior latency, and a long-lasting increase in locomotor activity. These effects were associated with significantly decreased dopamine D1 receptor mRNA expression in the NAc. No effects of PTX treatment on mesolimbic dopamine utilization or mPFC receptor expression were observed. The findings indicate that chronic neural activation in the VTA accelerates the onset of maternal behavior in virgin female rats via modification of the NAc dopamine D1 receptor.