Willingness of older people living with dementia and mild cognitive impairment and their caregivers to have medications deprescribed.

BACKGROUND: people living with cognitive impairment commonly take multiple medications including potentially inappropriate medications (PIMs), which puts them at risk of medication related harms. AIMS: to explore willingness to have a medication deprescribed of older people living with cognitive impairment (dementia or mild cognitive impairment) and multiple chronic conditions and assess the relationship between willingness, patient characteristics and belief about medications. METHODS: cross-sectional study using results from the revised Patients' Attitudes Towards Deprescribing questionnaire (rPATDcog) collected as baseline data in the OPTIMIZE study, a pragmatic, cluster-randomised trial educating patients and clinicians about deprescribing. Eligible participants were 65+, diagnosed with dementia or mild cognitive impairment, and prescribed at least five-long-term medications. RESULTS: the questionnaire was mailed to 1,409 intervention patients and 553 (39%) were returned and included in analysis. Participants had a mean age of 80.1 (SD 7.4) and 52.4% were female. About 78.5% (431/549) of participants said that they would be willing to have one of their medications stopped if their doctor said it was possible. Willingness to deprescribe was negatively associated with getting stressed when changes are made and with previously having a bad experience with stopping a medication (P < 0.001 for both). CONCLUSION: most older people living with cognitive impairment are willing to deprescribe. Addressing previous bad experiences with stopping a medication and stress when changes are made to medications may be key points to discuss during deprescribing conversations.

Structured Outpatient Diabetes Education and Telehealth Follow-up to Improve HbA 1c.

BACKGROUND: More than 10% of Americans have diabetes, with higher rates in Hispanics and African Americans. National Healthy People 2030 goals for expected decrease in HbA 1c levels have not been met. LOCAL PROBLEM: No standardized diabetes education or follow-up existed at a free clinic. Patients exhibited diabetic self-management inadequacies and elevated HbA 1c levels. METHODS: A pre/postimplementation study design was used to evaluate changes in HbA 1c levels, medication adherence, missed appointments, and emergency department visits. INTERVENTIONS: Structured diabetes education and follow-up text/phone messages for patients with HbA 1c levels 8% or higher were implemented over 3 months. RESULTS: Outcome data were available for 27 of the 34 participants. Postimplementation, there was a significant 1.7% decrease in mean HbA 1c levels ( P < .001). No significant differences were found for the other outcome measures. CONCLUSIONS: Structured diabetes education and follow-up text/phone messages in a free clinic improved patients' HbA 1c levels.

Design of BET Inhibitor Bottlebrush Prodrugs with Superior Efficacy and Devoid of Systemic Toxicities.

Prodrugs engineered for preferential activation in diseased versus normal tissues offer immense potential to improve the therapeutic indexes (TIs) of preclinical and clinical-stage active pharmaceutical ingredients that either cannot be developed otherwise or whose efficacy or tolerability it is highly desirable to improve. Such approaches, however, often suffer from trial-and-error design, precluding predictive synthesis and optimization. Here, using bromodomain and extra-terminal (BET) protein inhibitors (BETi)-a class of epigenetic regulators with proven anticancer potential but clinical development hindered in large part by narrow TIs-we introduce a macromolecular prodrug platform that overcomes these challenges. Through tuning of traceless linkers appended to a "bottlebrush prodrug" scaffold, we demonstrate correlation of in vitro prodrug activation kinetics with in vivo tumor pharmacokinetics, enabling the predictive design of novel BETi prodrugs with enhanced antitumor efficacies and devoid of dose-limiting toxicities in a syngeneic triple-negative breast cancer murine model. This work may have immediate clinical implications, introducing a platform for predictive prodrug design and potentially overcoming hurdles in drug development.

The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma.

(18) F-labelled-fluorodeoxyglucose positron emission tomography (FDG-PET) findings are challenging to interpret for residual disease versus complete response in paediatric patients with non-Hodgkin lymphoma (NHL). A biopsy is often warranted to confirm the presence or absence of viable tumour if there is clinical or radiographic evidence of residual disease. In this study, we compared conventional imaging and FDG-PET/computerized tomography (CT) findings with biopsy results in 18 children with NHL. Our goal was to provide additional data to establish more reliable criteria for response evaluation. Residual disease was suspected after conventional imaging alone in eight patients, after FDG-PET/CT alone in three and after both modalities in seven patients. Biopsy confirmed the presence of viable tumour in two patients. Two additional patients experienced progressive disease or relapse. The sensitivity and negative predictive value of FDG-PET/CT using the London criteria to indicate residual tumour detectable by biopsy were 100%, but specificity was low (60%), as was the positive predictive value (25%). Thus, in this study, a negative FDG-PET/CT finding was a good indicator of complete remission. However, because false-positive FDG-PET/CT findings are common, biopsy and close monitoring are required for accurate determination of residual disease in individual patients.

Evaluating the Safety of an Educational Deprescribing Intervention: Lessons from the Optimize Trial.

BACKGROUND: Patients, family members, and clinicians express concerns about potential adverse drug withdrawal events (ADWEs) following medication discontinuation or fears of upsetting a stable medical equilibrium as key barriers to deprescribing. Currently, there are limited methods to pragmatically assess the safety of deprescribing and ascertain ADWEs. We report the methods and results of safety monitoring for the OPTIMIZE trial of deprescribing education for patients, family members, and clinicians. METHODS: This was a pragmatic cluster randomized trial with multivariable Poisson regression comparing outcome rates between study arms. We conducted clinical record review and adjudication of sampled records to assess potential causal relationships between medication discontinuation and outcomes. This study included adults aged 65+ with dementia or mild cognitive impairment, one or more additional chronic conditions, and prescribed 5+ chronic medications. The intervention included an educational brochure on deprescribing that was mailed to patients prior to primary care visits, a clinician notification about individual brochure mailings, and an educational tip sheets was provided monthly to primary care clinicians. The outcomes of the safety monitoring were rates of hospitalizations and mortality during the 4 months following brochure mailings and results of record review and adjudication. The adjudication process was conducted throughout the trial and included classifications: likely, possibly, and unlikely. RESULTS: There was a total of 3012 (1433 intervention and 1579 control) participants. There were 420 total hospitalizations involving 269 (18.8%) people in the intervention versus 517 total hospitalizations involving 317 (20.1%) people in the control groups. Adjusted risk ratios comparing intervention to control groups were 0.92 [95% confidence interval (CI) 0.72, 1.16] for hospitalization and 1.19 (95% CI 0.67, 2.11) for mortality. Both groups had zero deaths "likely" attributed to a medication change prior to the event. A total of 3 out of 30 (10%) intervention group hospitalizations and 7 out of 35 (20%) control group hospitalizations were considered "likely" due to a medication change. CONCLUSIONS: Population-based deprescribing education is safe in the older adult population with cognitive impairment in our study. Pragmatic methods for safety monitoring are needed to further inform deprescribing interventions. TRIAL REGISTRATION: NCT03984396. Registered on 13 June 2019.

Late Holocene relative sea-level records from coral microatolls in Singapore.

Late Holocene relative sea-level (RSL) data are important to understand the drivers of RSL change, but there is a lack of precise RSL records from the Sunda Shelf. Here, we produced a Late Holocene RSL reconstruction from coral microatolls in Singapore, demonstrating for the first time the utility of Diploastrea heliopora microatolls as sea-level indicators. We produced 12 sea-level index points and three marine limiting data with a precision of < ± 0.2 m (2σ) and < ± 26 years uncertainties (95% highest density region). The data show a RSL fall of 0.31 ± 0.18 m between 2.8 and 0.6 thousand years before present (kyr BP), at rates between - 0.1 ± 0.3 and - 0.2 ± 0.7 mm/year. Surface profiles of the fossil coral microatolls suggest fluctuations in the rate of RSL fall: (1) stable between 2.8 and 2.5 kyr BP; (2) rising at ~ 1.8 kyr BP; and (3) stable from 0.8 to 0.6 kyr BP. The microatoll record shows general agreement with published, high-quality RSL data within the Sunda Shelf. Comparison to a suite of glacial isostatic adjustment (GIA) models indicate preference for lower viscosities in the mantle. However, more high quality and precise Late Holocene RSL data are needed to further evaluate the drivers of RSL change in the region and better constrain GIA model parameters.

Intervention design in cognitively impaired populations-Lessons learned from the OPTIMIZE deprescribing pragmatic trial.

BACKGROUND: Polypharmacy is common in older adults with cognitive impairment and multiple chronic conditions, increasing risks of adverse drug events, hospitalization, and death. Deprescribing, the process of reducing or stopping potentially inappropriate medications, may improve outcomes. The OPTIMIZE pragmatic trial examined whether educating and activating patients, family members and clinicians about deprescribing reduces number of chronic medications and potentially inappropriate medications. Acceptability and challenges of intervention delivery in cognitively impaired older adults are not well understood. METHODS: We explored mechanisms of intervention implementation through post hoc qualitative interviews and surveys with stakeholder groups of 15 patients, 7 caregivers, and 28 clinicians. We assessed the context in which the intervention was delivered, its implementation, and mechanisms of impact. RESULTS: Acceptance of the intervention was affected by contextual factors including cognition, prior knowledge of deprescribing, communication, and time constraints. All stakeholder groups endorsed the acceptability, importance, and delivery of the intervention. Positive mechanisms of impact included patients scheduling specific appointments to discuss deprescribing and providers being prompted to consider deprescribing. Recollection of intervention materials was inconsistent but most likely shortly after intervention delivery. Short visit times remained the largest provider barrier to deprescribing. CONCLUSIONS: Our work identifies key learnings in intervention delivery that can guide future scaling of deprescribing interventions in this population. We highlight the critical roles of timing and repetition in intervention delivery to cognitively impaired populations and the barrier posed by short consultation times. The acceptability of the intervention to patients and family members highlights the potential to incorporate deprescribing education into routine clinical practice and expand proven interventions to other vulnerable populations.

Optimization of stability, encapsulation, release, and cross-priming of tumor antigen-containing PLGA nanoparticles.

PURPOSE: In order to investigate Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) as potential vehicles for efficient tumor antigen (TA) delivery to dendritic cells (DC), this study aimed to optimize encapsulation/release kinetics before determining immunogenicity of antigen-containing NP. METHODS: Various techniques were used to liberate TA from cell lines. Single (gp100) and multiple (B16-tumor lysate containing gp100) antigens were encapsulated within differing molecular weight PLGA co-polymers. Differences in morphology, encapsulation/release and biologic potency were studied. Findings were adopted to encapsulate fresh tumor lysate from patients with advanced tumors and compare stimulation of tumor infiltrating lymphocytes (TIL) against that achieved by soluble lysate. RESULTS: Four cycles of freeze-thaw + 15 s sonication resulted in antigen-rich lysates without the need for toxic detergents or protease inhibitors. The 80 KDa polymer resulted in maximal release of payload and favorable production of immunostimulatory IL-2 and IFN-γ. NP-mediated antigen delivery led to increased IFN-γ and decreased immunoinhibitory IL-10 synthesis when compared to soluble lysate. CONCLUSIONS: Four cycles of freeze-thaw followed by 15 s sonication is the ideal technique to obtain complex TA for encapsulation. The 80 KDa polymer has the most promising combination of release kinetics and biologic potency. Encapsulated antigens are immunogenic and evoke favorable TIL-mediated anti-tumor responses.

An experimental investigation of the impact of rapport on Stroop test performance.

Rapport in the context of neuropsychological testing refers to the level of interpersonal ease between examiner and examinee. However, scant research has examined the impact of rapport on neuropsychological test performance. The purpose of this between-subjects experiment was to investigate the impact of rapport on Stroop test performance. College students (N = 114) were randomly assigned to either a high or a low rapport condition and administered the D-KEFS Color-Word Interference Test. Individuals in the low rapport condition took longer to complete the Inhibition Trial of the Stroop test but did not vary on the Inhibition/Switching Trial. Low rapport may distract examinees, sapping attentional resources on the Inhibition Trial.

Deprescribing Education vs Usual Care for Patients With Cognitive Impairment and Primary Care Clinicians: The OPTIMIZE Pragmatic Cluster Randomized Trial.

Background: Individuals with dementia or mild cognitive impairment frequently have multiple chronic conditions (defined as ≥2 chronic medical conditions) and take multiple medications, increasing their risk for adverse outcomes. Deprescribing (reducing or stopping medications for which potential harms outweigh potential benefits) may decrease their risk of adverse outcomes. Objective: To examine the effectiveness of increasing patient and clinician awareness about the potential to deprescribe unnecessary or risky medications among patients with dementia or mild cognitive impairment. Design, Setting, and Participants: This pragmatic, patient-centered, 12-month cluster randomized clinical trial was conducted from April 1, 2019, to March 31, 2020, at 18 primary care clinics in a not-for-profit integrated health care delivery system. The study included 3012 adults aged 65 years or older with dementia or mild cognitive impairment who had 1 or more additional chronic medical conditions and were taking 5 or more long-term medications. Interventions: An educational brochure and a questionnaire on attitudes toward deprescribing were mailed to patients prior to a primary care visit, clinicians were notified about the mailing, and deprescribing tip sheets were distributed to clinicians at monthly clinic meetings. Main Outcomes and Measures: The number of prescribed long-term medications and the percentage of individuals prescribed 1 or more potentially inappropriate medications (PIMs). Analysis was performed on an intention-to-treat basis. Results: This study comprised 1433 individuals (806 women [56.2%]; mean [SD] age, 80.1 [7.2] years) in 9 intervention clinics and 1579 individuals (874 women [55.4%]; mean [SD] age, 79.9 [7.5] years) in 9 control clinics who met the eligibility criteria. At baseline, both groups were prescribed a similar mean (SD) number of long-term medications (7.0 [2.1] in the intervention group and 7.0 [2.2] in the control group), and a similar proportion of individuals in both groups were taking 1 or more PIMs (437 of 1433 individuals [30.5%] in the intervention group and 467 of 1579 individuals [29.6%] in the control group). At 6 months, the adjusted mean number of long-term medications was similar in the intervention and control groups (6.4 [95% CI, 6.3-6.5] vs 6.5 [95% CI, 6.4-6.6]; P = .14). The estimated percentages of patients in the intervention and control groups taking 1 or more PIMs were similar (17.8% [95% CI, 15.4%-20.5%] vs 20.9% [95% CI, 18.4%-23.6%]; P = .08). In preplanned subgroup analyses, adjusted differences between the intervention and control groups were -0.16 (95% CI, -0.34 to 0.01) for individuals prescribed 7 or more long-term medications at baseline (n = 1434) and -0.03 (95% CI, -0.20 to 0.13) for those prescribed 5 to 6 medications (n = 1578) (P = .28 for interaction; P = .19 for subgroup interaction for PIMs). Conclusions and Relevance: This large-scale educational deprescribing intervention for older adults with cognitive impairment taking 5 or more long-term medications and their primary care clinicians demonstrated small effect sizes and did not significantly reduce the number of long-term medications and PIMs. Such interventions should target older adults taking relatively more medications. Trial Registration: ClinicalTrials.gov Identifier: NCT03984396.

Developing an algorithm across integrated healthcare systems to identify a history of cancer using electronic medical records.

OBJECTIVE: Tumor registries in integrated healthcare systems (IHCS) have high precision for identifying incident cancer but often miss recently diagnosed cancers or those diagnosed outside of the IHCS. We developed an algorithm using the electronic medical record (EMR) to identify people with a history of cancer not captured in the tumor registry to identify adults, aged 40-65 years, with no history of cancer. MATERIALS AND METHODS: The algorithm was developed at Kaiser Permanente Colorado, and then applied to 7 other IHCS. We included tumor registry data, diagnosis and procedure codes, chemotherapy files, oncology encounters, and revenue data to develop the algorithm. Each IHCS adapted the algorithm to their EMR data and calculated sensitivity and specificity to evaluate the algorithm's performance after iterative chart review. RESULTS: We included data from over 1.26 million eligible people across 8 IHCS; 55 601 (4.4%) were in a tumor registry, and 44848 (3.5%) had a reported cancer not captured in a registry. The common attributes of the final algorithm at each site were diagnosis and procedure codes. The sensitivity of the algorithm at each IHCS was 90.65%-100%, and the specificity was 87.91%-100%. DISCUSSION: Relying only on tumor registry data would miss nearly half of the identified cancers. Our algorithm was robust and required only minor modifications to adapt to other EMR systems. CONCLUSION: This algorithm can identify cancer cases regardless of when the diagnosis occurred and may be useful for a variety of research applications or quality improvement projects around cancer care.

Polymer nanoparticles containing tumor lysates as antigen delivery vehicles for dendritic cell-based antitumor immunotherapy.

Encapsulation of tumor-associated antigens in polymer nanoparticles (NP) is a promising approach to enhance efficiency of antigen delivery for anti-tumor vaccines. Head and neck squamous carcinoma (HNSCC) cell lines were initially used to generate tumor-associated antigens (TAA)-containing poly (lactic-co-glycolic acid) (PLGA) NP; encapsulation efficiency and release kinetics were profiled. Findings were adopted to entrap fresh tumor lysate from five patients with advanced HNSCC. To test the hypothesis that NP enhance antigen presentation, dendritic cell (DC) produced from patient blood monocyte precursors were loaded with either the un-encapsulated or NP-encapsulated versions of tumor lysates. These were used to stimulate freshly-isolated autologous CD8+ T cells. In four of five patients, anti-tumor CD8+ T cells showed significantly increased immunostimulatory IFN-γ (p=0.071) or decreased immmunoinhibitory IL-10 production (p=0.0004) associated with NP-mediated antigen delivery. The observations represent an enabling step in the production of clinically-translatable, inexpensive, highly-efficient, and personalized polymer-based immunotherapy for solid organ malignancies. FROM THE CLINICAL EDITOR: Enhancing the antigen presentation may be a viable approach to increase the efficiency of tumor cell directed cytotoxicity via immune mechanisms. This study presents an example for this using head and neck cancer cell lines and nanotechnology-based encapsulated antigen presentation to dendritic cells. The observed CD8+ T-cell response was significantly enhanced. This method may pave the way to a highly efficient cancer cell elimination method with minimal to no toxicity.

Feasibility of a Traceback Approach for Using Pathology Specimens to Facilitate Genetic Testing in the Genetic Risk Analysis in Ovarian Cancer (GRACE) Study Protocol.

Guidelines currently state that genetic testing is clinically indicated for all individuals diagnosed with ovarian cancer. Individuals with a prior diagnosis of ovarian cancer who have not received genetic testing represent missed opportunities to identify individuals with inherited high-risk cancer variants. For deceased individuals, post-mortem genetic testing of pathology specimens allows surviving family members to receive important genetic risk information. The Genetic Risk Assessment in Ovarian Cancer (GRACE) study aims to address this significant healthcare gap using a "traceback testing" approach to identify individuals with a prior diagnosis of ovarian cancer and offer genetic risk information to them and their family members. This study will assess the potential ethical and privacy concerns related to an ovarian cancer traceback testing approach in the context of patients who are deceased, followed by implementation and evaluation of the feasibility of an ovarian cancer traceback testing approach using tumor registries and archived pathology tissue. Descriptive and statistical analyses will assess health system and patient characteristics associated with the availability of pathology tissue and compare the ability to contact and uptake of genetic testing between patients who are living and deceased. The results of this study will inform the implementation of future traceback programs.

Intravaginal gene silencing using biodegradable polymer nanoparticles densely loaded with small-interfering RNA.

Vaginal instillation of small-interfering RNA (siRNA) using liposomes has led to silencing of endogenous genes in the genital tract and protection against challenge from infectious disease. Although siRNA lipoplexes are easily formulated, several of the most effective transfection agents available commercially may be toxic to the mucosal epithelia and none are able to provide controlled or sustained release. Here, we demonstrate an alternative approach using nanoparticles composed entirely of FDA-approved materials. To render these materials effective for gene silencing, we developed novel approaches to load them with high amounts of siRNA. A single dose of siRNA-loaded nanoparticles to the mouse female reproductive tract caused efficient and sustained gene silencing. Knockdown of gene expression was observed proximal (in the vaginal lumen) and distal (in the uterine horns) to the site of topical delivery. In addition, nanoparticles penetrated deep into the epithelial tissue. This is the first report demonstrating that biodegradable polymer nanoparticles are effective delivery vehicles for siRNA to the vaginal mucosa.

Building a better methane generation model: Validating models with methane recovery rates from 35 Canadian landfills.

The German EPER, TNO, Belgium, LandGEM, and Scholl Canyon models for estimating methane production were compared to methane recovery rates for 35 Canadian landfills, assuming that 20% of emissions were not recovered. Two different fractions of degradable organic carbon (DOC(f)) were applied in all models. Most models performed better when the DOC(f) was 0.5 compared to 0.77. The Belgium, Scholl Canyon, and LandGEM version 2.01 models produced the best results of the existing models with respective mean absolute errors compared to methane generation rates (recovery rates + 20%) of 91%, 71%, and 89% at 0.50 DOC(f) and 171%, 115%, and 81% at 0.77 DOC(f). The Scholl Canyon model typically overestimated methane recovery rates and the LandGEM version 2.01 model, which modifies the Scholl Canyon model by dividing waste by 10, consistently underestimated methane recovery rates; this comparison suggested that modifying the divisor for waste in the Scholl Canyon model between one and ten could improve its accuracy. At 0.50 DOC(f) and 0.77 DOC(f) the modified model had the lowest absolute mean error when divided by 1.5 yielding 63 +/- 45% and 2.3 yielding 57 +/- 47%, respectively. These modified models reduced error and variability substantially and both have a strong correlation of r = 0.92.

Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

At present there are no drugs for the treatment of chronic liver fibrosis that have been approved by the Food and Drug administration of the United States. Telmisartan, a small-molecule antihypertensive drug, displays antifibrotic activity, but its clinical use is limited because it causes systemic hypotension. Here, we report the scalable and convergent synthesis of macromolecular telmisartan prodrugs optimized for preferential release in diseased liver tissue. We optimized the release of active telmisartan in fibrotic liver to be depot-like (that is, a constant therapeutic concentration) through the molecular design of telmisartan brush-arm star polymers, and show that these lead to improved efficacy and to the avoidance of dose-limiting hypotension in both metabolically and chemically induced mouse models of hepatic fibrosis, as determined by histopathology, enzyme levels in the liver, intact-tissue protein markers, hepatocyte necrosis protection, and gene-expression analyses. In rats and dogs, the prodrugs are retained long-term in liver tissue and have a well-tolerated safety profile. Our findings support the further development of telmisartan prodrugs that enable infrequent dosing in the treatment of liver fibrosis.

Publisher Correction: Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs.

In the version of this Article originally published, the author Peter Blume-Jensen was not denoted as a corresponding author; this has now been amended and the author's email address has been added. The 'Correspondence and requests for materials' statement was similarly affected and has now been updated with the author's initials 'P.B-J.'

Nanoparticle delivery of miR-223 to attenuate macrophage fusion.

The foreign body response (FBR) begins with injury acquired during implantation of a biomaterial (BM) and is detrimental due to the eventual encapsulation of the implant. Fusion of macrophages to form foreign body giant cells (FBGC), a hallmark of the FBR, is the consequence of a multistep mechanism induced by interleukin (IL)-4 that includes the acquisition of a fusion competent state and subsequent cytoskeletal rearrangements. However, the precise mechanism, regulation, and interplay among molecular mediators to generate FBGCs are insufficiently understood. Seeking novel mediators of fusion that might be regulated at the post-transcriptional level, we examined the role of microRNAs (miRs) in this process. A miR microarray was screened and identified miR-223 as a negative regulator of macrophage fusion. In addition, transfection of primary macrophages with a mir-223 mimic attenuated IL-4-induced fusion. Furthermore, miR-223 KO mice and mir-223 deficient cells displayed increased fusion in vivo and in vitro, respectively. Finally, we developed a method for in vivo delivery of miR-223 mimic utilizing PLGA nanoparticles, which inhibited FBGC formation in a biomaterial implant model. Our results identify miR-223 as a negative regulator of fusion and demonstrate miR-223 mimic-loaded nanoparticles as a therapeutic inhibitor of macrophage fusion.

Distribution of polymer nanoparticles by convection-enhanced delivery to brain tumors.

Glioblastoma multiforme (GBM) is a fatal brain tumor characterized by infiltration beyond the margins of the main tumor mass and local recurrence after surgery. The blood-brain barrier (BBB) poses the most significant hurdle to brain tumor treatment. Convection-enhanced delivery (CED) allows for local administration of agents, overcoming the restrictions of the BBB. Recently, polymer nanoparticles have been demonstrated to penetrate readily through the healthy brain when delivered by CED, and size has been shown to be a critical factor for nanoparticle penetration. Because these brain-penetrating nanoparticles (BPNPs) have high potential for treatment of intracranial tumors since they offer the potential for cell targeting and controlled drug release after administration, here we investigated the intratumoral CED infusions of PLGA BPNPs in animals bearing either U87 or RG2 intracranial tumors. We demonstrate that the overall volume of distribution of these BPNPs was similar to that observed in healthy brains; however, the presence of tumors resulted in asymmetric and heterogeneous distribution patterns, with substantial leakage into the peritumoral tissue. Together, our results suggest that CED of BPNPs should be optimized by accounting for tumor geometry, in terms of location, size and presence of necrotic regions, to determine the ideal infusion site and parameters for individual tumors.