Identifying research priorities and essential elements of palliative care services for people facing malignant brain tumors: A participatory co-design approach.

Background: Primary malignant brain tumors (ie, brain cancer) impact the quality of life (QoL) for patients and care partners in disease-specific ways involving cognition and communication. Palliative care (PC) addresses patient/care partner QoL, but it is not known how PC may address the unique needs of brain cancer patients. The purpose of this project was to identify brain cancer PC research priorities using participatory co-design methods. Methods: Participatory co-design included the formation of a longitudinal, collaborative advisory group, engagement frameworks, design-thinking processes, and social media-based engagement over a 1-year period. Community-identified brain cancer QoL needs and research priorities were mapped to proposed "essential elements" of brain cancer PC services. Results: We engaged an estimated 500 patients, care partners, healthcare professionals, and others with an interest in QoL and PC services for people with malignant brain tumors. Research priorities included testing the early introduction of PC services designed to address the unique QoL needs of brain cancer patients and care partners. Essential elements of brain cancer PC include: (1) addressing brain cancer patients' unique range of QoL needs and concerns, which change over time, (2) tailoring existing services and approaches to patient needs and concerns, (3) enhancing the involvement of interprofessional care team members, and (4) optimizing timing for PC services. This was the first participatory research effort exploring brain cancer patient and care partner QoL needs and PC services. Conclusions: The brain tumor community calls for research testing PC service models for patients that incorporate the "essential elements" of palliative care.

Amorphous Solid Dispersion Formation for Enhanced Release Performance of Racemic and Enantiopure Praziquantel.

Praziquantel (PZQ) is the treatment of choice for schistosomiasis, which affects more than 250 million people globally. Commercial tablets contain the crystalline racemic compound (RS-PZQ) which limits drug dissolution and oral bioavailability and can lead to unwanted side effects and poor patient compliance due to the presence of the S-enantiomer. While many approaches have been explored for improving PZQ's dissolution and oral bioavailability, studies focusing on investigating its release from amorphous solid dispersions (ASDs) have been limited. In this work, nucleation induction time experiments were performed to identify suitable polymers for preparing ASDs using RS-PZQ and R-PZQ, the therapeutically active enantiomer. Cellulose-based polymers, hydroxypropyl methylcellulose acetate succinate (HPMCAS, MF grade) and hydroxypropyl methylcellulose (HPMC, E5 LV grade), were the best crystallization inhibitors for RS-PZQ in aqueous media and were selected for ASD preparation using solvent evaporation (SE) and hot-melt extrusion (HME). ASDs prepared experimentally were subjected to X-ray powder diffraction to verify their amorphous nature and a selected number of ASDs were monitored and found to remain physically stable following several months of storage under accelerated-stability testing conditions. SE HPMCAS-MF ASDs of RS-PZQ and R-PZQ showed faster release than HPMC E5 LV ASDs and maintained good performance with an increase in drug loading (DL). HME ASDs of RS-PZQ formulated using HPMCAS-MF exhibited slightly enhanced release compared to that of SE ASDs. SE HPMCAS-MF ASDs showed a maximum release increase of the order of 6 times compared to generic and branded (Biltricide) PZQ tablets. More importantly, SE R-PZQ ASDs with HPMCAS-MF released the drug as effectively as RS-PZQ or better, depending on the DL used. These findings have significant implications for the development of commercial PZQ formulations comprised solely of the R-enantiomer, which can result in mitigation of the biopharmaceutical and compliance issues associated with current commercial tablets.

Chemistry and Ionization of HPMCAS Influences the Dissolution and Solution-Mediated Crystallization of Posaconazole Amorphous Solid Dispersions.

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is one of the polymers of choice in formulating amorphous solid dispersions (ASDs) and helps to sustain high levels of drug supersaturation by delaying drug crystallization. Herein, the impact of HPMCAS chemistry on the solution crystallization kinetics of a fast-crystallizing lipophilic drug, posaconazole (PCZ), from the aqueous bulk phase and the drug-rich phase generated by liquid-liquid phase separation (LLPS), was studied. Three grades of HPMCAS: L, M, and H, which differ in the degree of acetyl and succinoyl substitution (A/S ratio), were compared. The influence of the polymers on the nucleation induction time, and LLPS concentration of PCZ, as well as the size, ζ-potential and composition of the nano-sized drug-rich phase was determined. An increase in the nucleation induction time was observed with an increase in the polymer A/S ratio. A blue shift in the fluorescence emission spectrum of PCZ suggested a greater extent of interaction between PCZ and HPMCAS with an increase in the A/S ratio. More polymer partitioning into the drug-rich phase was also observed with an increase in the A/S ratio, resulting in smaller droplets. A greater extent of ionization of HPMCAS upon increasing the pH from 5.5 to 7.5 decreased the hydrophobicity of the polymer resulting in shorter nucleation induction times. The phase behavior of PCZ in ASD release studies was consistent with these observations, where the shortest duration of supersaturation was observed with the L grade. Although the H grade provided the best inhibition of crystallization, complete release was only observed at higher pH. HPMCAS grade thus influences the kinetics of PCZ crystallization following release from an ASD, as well as the extent of release at physiologically relevant pH conditions. This study provides insights into the role of HPMCAS chemistry and ionization as factors influencing its ability to act as a crystallization inhibitor.

Amorphous Solubility Advantage: Theoretical Considerations, Experimental Methods, and Contemporary Relevance.

Twenty-five years ago, Hancock and Parks asked a provocative question: "what is the true solubility advantage for amorphous pharmaceuticals?" Difficulties in determining the amorphous solubility have since been overcome due to significant advances in theoretical understanding and experimental methods. The amorphous solubility is now understood to be the concentration after the drug undergoes liquid-liquid or liquid-glass phase separation, forming a water-saturated drug-rich phase in metastable equilibrium with an aqueous phase containing molecularly dissolved drug. While crystalline solubility is an essential parameter impacting the absorption of crystalline drug formulations, amorphous solubility is a vital factor for considering absorption from supersaturating formulations. However, the amorphous solubility of drugs is complex, especially in the presence of formulation additives and gastrointestinal components, and concentration-based measurements may not indicate the maximum drug thermodynamic activity. This review discusses the concept of the amorphous solubility advantage, including a historical perspective, theoretical considerations, experimental methods for amorphous solubility measurement, and the contribution of supersaturation and amorphous solubility to drug absorption. Leveraging amorphous solubility and understanding the associated physicochemical principles can lead to more effective development strategies for poorly water-soluble drugs, ultimately benefiting therapeutic outcomes.

Exploring biorelevant conditions and release profiles of ritonavir from HPMCAS-based amorphous solid dispersions.

Development of a release test for amorphous solid dispersions (ASDs) that is in vivo predictive is essential to identify optimally performing formulations early in development. For ASDs containing an enteric polymer, consideration of buffer properties is essential. Herein, release rates of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and ritonavir from ASDs with a 20% drug loading were compared in phosphate and bicarbonate buffers with different molarities, at pH 6.5. The bioaccessibility of ritonavir from the ASD in the tiny-TIM apparatus was also evaluated and compared to that of the crystalline drug. The surface pH at the dissolving solid: solution interface was evaluated using a pH-sensitive fluorescence probe for HPMCAS and ASD compacts in phosphate and bicarbonate buffers. Drug and polymer were found to release congruently in all buffer systems, indicating that the polymer controlled the drug release. Release was slowest in 10 mM bicarbonate buffer, and much faster in phosphate buffers with molarities typically used in release testing (20-50 mM). Release from the 10 mM bicarbonate buffer was matched in a 5 mM phosphate buffer. The surface pH of HPMCAS and HPMCAS:ritonavir ASDs was found to be lower than the bulk solution pH, where surface pH differences largely explained release rate differences seen in the different buffer systems. Ritonavir was highly bioaccessible from the ASD, as assessed by the tiny-TIM system, and much less bioaccessible when crystalline drug was used. The observations highlight the need for continued development of biorelevant assays tailored for ASD formulation assessment.

6-Carboxycellulose Acetate Butyrate: Effectiveness as an Amorphous Solid Dispersion Polymer.

Amorphous solid dispersion (ASD) in a polymer matrix is a powerful method for enhancing the solubility and bioavailability of otherwise crystalline, poorly water-soluble drugs. 6-Carboxycellulose acetate butyrate (CCAB) is a relatively new commercial cellulose derivative that was introduced for use in waterborne coating applications. As CCAB is an amphiphilic, carboxyl-containing, high glass transition temperature (Tg) polymer, characteristics essential to excellent ASD polymer performance, we chose to explore its ASD potential. Structurally diverse drugs quercetin, ibuprofen, ritonavir, loratadine, and clarithromycin were dispersed in CCAB matrices. We evaluated the ability of CCAB to create ASDs with these drugs and its ability to provide solubility enhancement and effective drug release. CCAB/drug dispersions prepared by spray drying were amorphous up to 25 wt % drug, with loratadine remaining amorphous up to 50% drug. CCAB formulations with 10% drug proved effective at providing in vitro solubility enhancement for the crystalline flavonoid drug quercetin as well as ritonavir, but not for the more soluble APIs ibuprofen and clarithromycin and the more hydrophobic loratadine. CCAB did provide slow and controlled release of ibuprofen, offering a simple and promising Long-duration ibuprofen formulation. Formulation with clarithromycin showed the ability of the polymer to protect against degradation of the drug at stomach pH. Furthermore, CCAB ASDs with both loratadine and ibuprofen could be improved by the addition of the water-soluble polymer poly(vinylpyrrolidone) (PVP), with which CCAB shows good miscibility. CCAB provided solubility enhancement in some cases, and the slower drug release exhibited by CCAB, especially in the stomach, could be especially beneficial, for example, in formulations containing known stomach irritants like ibuprofen.

Characterizing Walking Behaviors in Aged Residential Care Using Accelerometry, With Comparison Across Care Levels, Cognitive Status, and Physical Function: Cross-Sectional Study.

Background: Walking is important for maintaining physical and mental well-being in aged residential care (ARC). Walking behaviors are not well characterized in ARC due to inconsistencies in assessment methods and metrics as well as limited research regarding the impact of care environment, cognition, or physical function on these behaviors. It is recommended that walking behaviors in ARC are assessed using validated digital methods that can capture low volumes of walking activity. Objective: This study aims to characterize and compare accelerometry-derived walking behaviors in ARC residents across different care levels, cognitive abilities, and physical capacities. Methods: A total of 306 ARC residents were recruited from the Staying UpRight randomized controlled trial from 3 care levels: rest home (n=164), hospital (n=117), and dementia care (n=25). Participants' cognitive status was classified as mild (n=87), moderate (n=128), or severe impairment (n=61); physical function was classified as high-moderate (n=74) and low-very low (n=222) using the Montreal Cognitive Assessment and the Short Physical Performance Battery cutoff scores, respectively. To assess walking, participants wore an accelerometer (Axivity AX3; dimensions: 23×32.5×7.6 mm; weight: 11 g; sampling rate: 100 Hz; range: ±8 g; and memory: 512 MB) on their lower back for 7 days. Outcomes included volume (ie, daily time spent walking, steps, and bouts), pattern (ie, mean walking bout duration and alpha), and variability (of bout length) of walking. Analysis of covariance was used to assess differences in walking behaviors between groups categorized by level of care, cognition, or physical function while controlling for age and sex. Tukey honest significant difference tests for multiple comparisons were used to determine where significant differences occurred. The effect sizes of group differences were calculated using Hedges g (0.2-0.4: small, 0.5-0.7: medium, and 0.8: large). Results: Dementia care residents showed greater volumes of walking (P<.001; Hedges g=1.0-2.0), with longer (P<.001; Hedges g=0.7-0.8), more variable (P=.008 vs hospital; P<.001 vs rest home; Hedges g=0.6-0.9) bouts compared to other care levels with a lower alpha score (vs hospital: P<.001; Hedges g=0.9, vs rest home: P=.004; Hedges g=0.8). Residents with severe cognitive impairment took longer (P<.001; Hedges g=0.5-0.6), more variable (P<.001; Hedges g=0.4-0.6) bouts, compared to those with mild and moderate cognitive impairment. Residents with low-very low physical function had lower walking volumes (total walk time and bouts per day: P<.001; steps per day: P=.005; Hedges g=0.4-0.5) and higher variability (P=.04; Hedges g=0.2) compared to those with high-moderate capacity. Conclusions: ARC residents across different levels of care, cognition, and physical function demonstrate different walking behaviors. However, ARC residents often present with varying levels of both cognitive and physical abilities, reflecting their complex multimorbid nature, which should be considered in further work. This work has demonstrated the importance of considering a nuanced framework of digital outcomes relating to volume, pattern, and variability of walking behaviors among ARC residents.

Diffusion Mapping with Diffractive Optical Elements for Periodically Patterned Photobleaching.

Fourier transform-fluorescence recovery after photobleaching (FT-FRAP) using a diffractive optical element (DOE) is shown to support distance-dependent diffusion analysis in biologically relevant media. Integration of DOEs enables patterning of a dot array for parallel acquisition of point-bleach FRAP measurements at multiple locations across the field of view. In homogeneous media, the spatial harmonics of the dot array analyzed in the spatial Fourier transform domain yield diffusion recovery curves evaluated over specific well-defined distances. Relative distances for diffusive recovery in the spatial Fourier transform domain are directly connected to the 2D (h,k) Miller indices of the corresponding lattice lines. The distribution of the photobleach power across the entire field of view using a multidot array pattern greatly increases the overall signal power in the spatial FT-domain for signal-to-noise improvements. Derivations are presented for the mathematical underpinnings of FT-FRAP performed with 2D periodicity in the photobleach patterns. Retrofitting of FT-FRAP into instrumentation for high-throughput FRAP analysis (Formulatrix) supports automated analysis of robotically prepared 96-well plates for precise quantification of molecular mobility. Figures of merit are evaluated for FT-FRAP in analysis for both slow diffusion of fluorescent dyes in glassy polymer matrices spanning several days and model proteins and monoclonal antibodies within aqueous solutions recovering in matters of seconds.

Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors.

PURPOSE: Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. METHODS: We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. RESULTS: Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CONCLUSIONS: CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

Threading the needle: Achieving simplicity and performance in cellulose alkanoate ω-carboxyalkanoates for amorphous solid dispersion.

Most active pharmaceutical ingredients (APIs) suffer from poor water solubility, often keeping them from reaching patients. To overcome the issues of poor drug solubility and subsequent low bioavailability, amorphous solid dispersions (ASDs) have garnered much attention. Cellulose ester derivatives are of interest for ASD applications as they are benign, sustainable-based, and successful in commercial drug delivery systems, e.g. in osmotic pump systems and as commercial ASD polymers. Synthesis of carboxy-pendant cellulose esters is a challenge, due in part to competing reactions between carboxyls and hydroxyls, forming ester crosslinks. Herein we demonstrate proof-of-concept for a scalable synthetic route to simple, yet highly promising ASD polymers by esterifying cellulose polymers through ring-opening of cyclic succinic or glutaric anhydride. We describe the complexity of such ring-opening reactions, not previously well-described, and report ways to avoid gelation. We report synthesis, characterization, and preliminary in vitro ASD evaluations of fifteen such derivatives. Synthetic routes were designed to accommodate these criteria: no protecting groups, no metal catalysts, mild conditions with standard reagents, simple purification, and one-pot synthesis. Finally, these designed ASD polymers included members that maintained fast-crystallizing felodipine in solution and release it from an ASD at rather high 20 % drug loading (DL).

Dissolution Mechanisms of Amorphous Solid Dispersions: Application of Ternary Phase Diagrams To Explain Release Behavior.

The use of amorphous solid dispersions (ASDs) in commercial drug products has increased in recent years due to the large number of poorly soluble drugs in the pharmaceutical pipeline. However, the release behavior of ASDs is complex and remains not well understood. Often, the drug release from ASDs is rapid and complete at lower drug loadings (DLs) but becomes slow and incomplete at higher DLs. The DL where release becomes hindered is termed the limit of congruency (LoC). Currently, there are no approaches to predict the LoC. However, recent findings show that one potential cause leading to the LoC is a change in phase morphology after water-induced phase separation at the ASD/solution interface. In this study, the phase behavior of ASDs in contact with aqueous solutions was described thermodynamically by constructing experimental and computational ternary phase diagrams, and these were used to predict morphology changes and ultimately the LoC. Experimental ternary phase diagrams were obtained by equilibrating ASD/water mixtures over time. Computational ternary phase diagrams were obtained by Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT). The morphology of the hydrophobic phase was studied with fluorescence confocal microscopy. It was demonstrated that critical point (plait point) composition approximately corresponded to the ASD DL, where the hydrophobic phase, formed during phase separation, became interconnected and hindered ASD release. This work provides mechanistic insights into the ASD release behavior and highlights the potential of in silico ASD design using phase diagrams.

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma.

PURPOSE: Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS: Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS: The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION: ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.

Interplay of Drug-Polymer Interactions and Release Performance for HPMCAS-Based Amorphous Solid Dispersions.

The interplay between drug and polymer chemistry and its impact on drug release from an amorphous solid dispersion (ASD) is a relatively underexplored area. Herein, the release rates of several drugs of diverse chemistry from hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based ASDs were explored using surface area normalized dissolution. The tendency of the drug to form an insoluble complex with HPMCAS was determined through coprecipitation experiments. The role of pH and the extent of drug ionization were probed to evaluate the role of electrostatic interactions in complex formation. Relationships between the extent of complexation and the drug release rate from an ASD were observed, whereby the drugs could be divided into two groups. Drugs with a low extent of insoluble complex formation with HPMCAS tended to be neutral or anionic and showed reasonable release at pH 6.8 even at higher drug loadings. Cationic drugs formed insoluble complexes with HPMCAS and showed poor release when formulated as an ASD. Thus, and somewhat counterintuitively, a weakly basic drug showed a reduced release rate from an ASD at a bulk solution pH where it was ionized, relative to when unionized. The opposite trend was observed in the absence of polymer for the neat amorphous drug. In conclusion, electrostatic interactions between HPMCAS and lipophilic cationic drugs led to insoluble complex formation, which in turn resulted in ASDs with poor release performance.

Esophageal Remodeling Correlates With Eating Behaviors in Pediatric Eosinophilic Esophagitis.

INTRODUCTION: There are limited data characterizing eating habits among pediatric patients with eosinophilic esophagitis (EoE). We compared eating behaviors in pediatric patients with EoE with healthy controls and assessed the degree of correlation with symptomatology, endoscopic and histologic findings, and esophageal distensibility. METHODS: We conducted a prospective, observational study where subjects consumed 4 food textures (puree, soft solid, chewable, and hard solid) and were scored for eating behaviors including number of chews per bite, sips of fluid per food, and consumption time. Symptomatic, endoscopic, histologic, and esophageal distensibility data were collected for case subjects. RESULTS: Twenty-seven case subjects and 25 healthy controls were enrolled in our study (mean age 11.0 years, 63.5% male). Compared with healthy controls, pediatric patients with EoE demonstrated more chews per bite with soft solid (13.6 vs 9.1, P = 0.031), chewable (14.7 vs 10.7, P = 0.047), and hard solid foods (19.0 vs 12.8, P = 0.037). Patients with EoE also demonstrated increased consumption time with soft solid (94.7 vs 58.3 seconds, P = 0.002), chewable (90.0 vs 65.1 seconds, P = 0.005), and hard solid foods (114.1 vs 76.4 seconds, P = 0.034) when compared with healthy controls. Subgroup analysis based on disease status showed no statistically significant differences in eating behaviors between active and inactive EoE. Total endoscopic reference score positively correlated with consumption time ( r = 0.53, P = 0.008) and number of chews ( r = 0.45, P = 0.027) for chewable foods and with number of chews ( r = 0.44, P = 0.043) for hard solid foods. Increased consumption time correlated with increased eosinophil count ( r = 0.42, P = 0.050) and decreased esophageal distensibility ( r = -0.82, P < 0.0001). DISCUSSION: Altered eating behaviors including increased chewing and increased consumption time can be seen in pediatric patients with EoE, can persist despite histologic remission, and may be driven by changes in esophageal distensibility.

Palliative Care in Neuro-oncology.

Historically, the practice of neurology as an independent subspecialty from internal medicine began in Europe and the United States in the 1930s. The American Academy of Neurology (AAN) was founded 75 years ago in 1948, solidifying its emergence as a stand-alone discipline of medicine. In 1967, St. Christopher's Hospice, the first free standing hospice home, was opened in London by Dame Cicely Saunders. Dame Saunders is considered a pioneer in the development of the hospice movement, and she embodies the importance of the multi-disciplinary team in the care of the patient, as she began her career as a nurse, then became a social worker and, finally, a physician. A decade later, in 1978, Dr. Balfour Mount, a Canadian urologic cancer surgeon, coined the term "palliative care" ("to improve the quality of life") after having spent time with Dr. Saunders at St. Christopher's some years earlier. The field of palliative care continued to develop as a distinct subspecialty focused on improving quality of life for patients at any age and in any stage of serious illness. In a 1996 position statement, the AAN made clear that the practice of primary palliative care is the responsibility of all neurologists to their patients. Finally, coming full circle, the specialty of neuro-palliative care, a subspecialty not just of neurology but of palliative medicine, became established around 2018. Neuro-palliative care can be seen as a specialty focusing on the holistic approach to symptom management in patients suffering from neurologic disease with the aim of improved symptom control and attention to the psychologic and spiritual aspects of illness.

Management of Neurologic Complications in Patients with Brain and Spine Tumors.

Patients with brain and spine tumors represent a distinct population with unique needs. We provide a practical review of neurologic care in this group with an emphasis on familiarizing the general neurologist to the nuances of neuro-oncologic supportive care. We review the management of cerebral edema, steroid dosing, and pertinent side effects. We discuss seizure management, including choice of anticonvulsants, putative antitumor effects, and important seizure mimics like drop attacks. We review the presentation and symptomatology of stroke-like migraine attack after radiation therapy (SMART syndrome). We describe the signs and symptoms that should prompt concern for metastatic spinal cord compression, as well as both acute and definitive treatment options. Finally, we discuss the underappreciated incidence of venous thromboembolic events, particularly in patients with gliomas, and review the data on management.

Reductive amination of oxidized hydroxypropyl cellulose with ω-aminoalkanoic acids as an efficient route to zwitterionic derivatives.

Zwitterionic polymers, with their equal amounts of cationic and anionic functional groups, have found widespread utility including as non-fouling coatings, hydrogel materials, stabilizers, antifreeze materials, and drug carriers. Polysaccharide-derived zwitterionic polymers are attractive because of their sustainable origin, potential for lower toxicity, and possible biodegradability, but previous methods for synthesis of zwitterionic polysaccharide derivatives have been limited in terms of flexibility and attainable degree of substitution (DS) of charged entities. We report herein successful design and synthesis of zwitterionic polysaccharide derivatives, in this case based on cellulose, by reductive amination of oxidized 2-hydroxypropyl cellulose (Ox-HPC) with ω-aminoalkanoic acids. Reductive amination products could be readily obtained with DS(cation) (= DS(anion)) up to 1.6. Adduct hydrophilic/hydrophobic balance (amphiphilicity) can be influenced by selecting the appropriate chain length of the ω-aminoalkanoic acid. This strategy is shown to produce a range of amphiphilic, water-soluble, moderately high glass transition temperature (Tg) polysaccharide derivatives in just a couple of efficient steps from commercially available building blocks. The adducts were evaluated as crystallization inhibitors. They are strong inhibitors of crystallization even for the challenging, poorly soluble, fast-crystallizing prostate cancer drug enzalutamide, as supported by surface tension and Flory-Huggins interaction parameter results.