Improving Access and Timeliness of Early Palliative Care Specialist Assessment for Patients With Advanced Lung Cancer in a Rapid Assessment Clinic.

Background: Integrating palliative care in the management of patients with lung cancer improves quality of life, patient satisfaction, and overall survival. However, few patients receive timely palliative care consultation. The Lung Diagnostic Assessment Program (LDAP) in Southeastern Ontario is a multidisciplinary rapid assessment clinic that expedites the diagnosis and management of patients with suspected lung cancer. Objectives: We sought to increase the percentage of LDAP patients with stage IV lung cancer receiving palliative care consultation within three months of diagnosis. Design: We integrated a palliative care specialist in LDAP to facilitate in-person, same-visit consultation for patients with a new lung cancer diagnosis. Setting/Subjects: Five hundred fifty patients in a Canadian academic center (154 initial baseline, 104 COVID baseline, 292 post-palliative care integration). Measurements: Baseline data were established using retrospective chart review (February-June 2020 and December 2020-March 2021 due to COVID-19 pandemic). Data were collected prospectively to assess improvement (March-August 2021). Statistical Process Control charts assessed for special cause variation; chi-square tests assessed for differences between groups. Results: The percentage of patients with stage IV lung cancer seen by palliative care within three months increased from 21.8% (12/55) during early-COVID baseline to 49.2% (32/65) after palliative care integration (p < 0.006). Palliative care integration in LDAP reduced mean time from referral to consultation from 24.8 to 12.3 days, including same-day consultation for 15/32 (46.8%) patients with stage IV disease. Conclusions: Integrating palliative care specialists into LDAP improved the timeliness of palliative care assessment for patients with stage IV lung cancer.

A systematic review of randomized controlled trial characteristics for interventions to improve upper extremity motor recovery post stroke.

INTRODUCTION: Given the prevalence of motor deficits post-stroke, a large proportion of stroke rehabilitation interventions are directed toward motor recovery. OBJECTIVES: The purpose of this study is to present a detailed investigation of the methodological characteristics in the stroke rehabilitation literature with respect to randomized controlled trials (RCTs) designed to facilitate upper extremity motor recovery. METHODS: This review was conducted following guidelines from the Preferred Reporting Items for Systematic reviews and Meta Analyses (PRISMA) statement. English articles of RCTs were eligible if they were published before April 1, 2021 and applied an intervention to the hemiparetic upper extremity of individuals post stroke as the primary objective of the study, or recorded at least one upper extremity related outcome measure. RESULTS: The number of RCTs for upper extremity rehabilitation interventions post stroke has been increasing, with over three quarters of RCTs published in the last decade. In total, 1,307 RCTs met inclusion criteria for which the mean sample size (start/finish) was 45.8 (SD 55.4)/41.8 (SD 49.7). The median sample size (start/finish) was 30 (IQR 20-48)/29 (IQR 19-44). The mean PEDro score was 6.12 (SD 1.55). 251 RCTs (19%) were multi-centered trials. Key methodological measures of quality remain low including the blinding of assessors (59%), intention to treat analyses (42%) and concealed allocation (37%). CONCLUSIONS: There is a large number of RCTs evaluating stroke rehabilitation upper extremity interventions. Research quality continues to be a challenge (low percentage of key quality indicators, small percentage of multicentred trials, small sample sizes) but is slowly improving.

Network Meta-Analysis of Non-Conventional Therapies for Improving Upper Limb Motor Impairment Poststroke.

BACKGROUND: Network meta-analysis is a method that can estimate relative efficacy between treatments that may not have been compared directly within the literature. The purpose of this study is to present a network meta-analysis of non-conventional interventions to improve upper extremity motor impairment after stroke. METHODS: A literature search was conducted in 5 databases from their inception until April 1, 2021. Terms were used to narrow down articles related to stroke, the upper extremity, and interventional therapies. Randomized controlled trials written in English were eligible if; 50% poststroke patients; ≥18 years old; applied an intervention for the upper extremity, and/or used the Fugl-Meyer upper extremity scale as an outcome measure; the intervention had ≥3 randomized controlled trials with comparisons against a conventional care group; conventional care groups were dose matched for therapy time. A Bayesian network meta-analysis approach was taken to estimate mean difference (MD) and 95% CI. RESULTS: One hundred seventy-six randomized controlled trials containing 6781 participants examining 20 non-conventional interventions were identified for inclusion within the final model. Eight of the identified interventions proved significantly better than conventional care, with modified constraint induced movement therapy (MD, 6.7 [95% CI, 4.3-8.9]), high frequency repetitive transcranial magnetic stimulation (MD, 5.4 [95% CI, 1.9-8.9]), mental imagery (MD, 5.4 [95% CI, 1.8-8.9]), bilateral arm training (MD, 5.2 [95% CI, 2.2-8.1]), and intermittent theta-burst stimulation (MD, 5.1 [95% CI, 0.62-9.5]) occupying the top 5 spots according to the surface under the cumulative ranking curve. CONCLUSIONS: Overall, it would seem that modified constraint induced movement therapy has the greatest probability of being the most effective intervention, with high-frequency repetitive transcranial magnetic stimulation, mental imagery, and bilateral arm training all having similar probabilities of occupying the next spot in the rankings. We think this analysis can provide a guide for where future resources and clinical trials should be directed, and where a clinician may begin when considering alternative therapeutic interventions.

Simultaneous Chromatographic Quantitation of Drug Substance and Excipients in Nanoformulations Using a Combination of Evaporative Light Scattering and Absorbance Detectors.

Nanomedicines including lipid- and polymer-based nanoparticles and polymer-drug conjugates enable targeted drug delivery for the treatment of numerous diseases. Quantitative analysis of components in nanomedicines is routinely performed to characterize the products to ensure quality and property consistency but has been mainly focused on the active pharmaceutical ingredients (APIs) in academic publications. It has been increasingly recognized that excipients in nanomedicines are critical in determining the product quality, stability, consistency, and safety. APIs are often analyzed by high-performance liquid chromatography (HPLC), and it would be convenient if the same method can be applied to excipients to robustly quantify all components in nanomedicines. Here, we report the development of a HPLC method that combined an evaporative light scattering (ELS) detector with an UV-vis detector to simultaneously analyze drugs and excipients in nanomedicines. This method was tested on diverse nanodrug delivery systems, including a niosomal nanoparticle encapsulating a phytotherapeutic, a liposome encapsulating an immune boosting agent, and a PEGylated peptide. This method can be utilized for a variety of applications, such as monitoring drug loading, studying drug release, and storage stability. The information obtained from the analyses is of importance for nanomedicine formulation development.

Liposomal Resiquimod for Enhanced Immunotherapy of Peritoneal Metastases of Colorectal Cancer.

Colorectal cancer with peritoneal metastases is currently treated by cytoreductive surgery and locoregional chemotherapeutics. This standard treatment is associated with high morbidity, mortality, and recurrence rate. To augment the existing therapy, we developed a liposome-based delivery system containing 1,2-stearoyl-3-trimethylammonium-propane chloride (DSTAP), a cationic lipid, to localize a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity (PerC) for enhancing the immune response against cancer that had spread to the PerC. The liposomes delivered by intraperitoneal injection increased peritoneal retention of R848 by 14-fold while retarding its systemic absorption, leading to a 5-fold decreased peak plasma concentration compared to free R848 in mice. Within the PerC, the DSTAP-liposomes were found in ~40% of the dendritic cells by flow cytometry. DSTAP-R848 significantly upregulated interferon α (IFN-α) in the peritoneal fluid by 2-fold compared to free R848, without increasing the systemic level. Combined with oxaliplatin, a cytotoxic agent inducing immunogenic cell death, DSTAP-R848 effectively inhibited the progression of CT26 murine colorectal tumor in the PerC, while the combination with free R848 only showed a mild effect. Moreover, the combination of oxaliplatin and DSTAP-R848 significantly increased infiltration of CD8+ T cells in the PerC compared to oxaliplatin combined with free R848, indicating enhanced immune response against the tumor. The results suggest that DSTAP-R848 exhibits potential in augmenting existing therapies for treating colorectal cancer with peritoneal metastases via immune activation.

Lipid-based nanoparticle technologies for liver targeting.

Liver diseases such as hepatitis, cirrhosis, and hepatocellular carcinoma are global health problems accounting for approximately 800 million cases and over 2 million deaths per year worldwide. Major drawbacks of standard pharmacological therapies are the inability to deliver a sufficient concentration of a therapeutic agent to the diseased liver, and nonspecific drug delivery leading to undesirable systemic side effects. Additionally, depending on the specific liver disease, drug delivery to a subset of liver cells is required. In recent years, lipid nanoparticles have been developed to passively and actively target drugs to the liver. The success of this approach has been highlighted by the FDA-approval of the first liver-targeting lipid nanoparticle, ONPATTRO, in 2018 and many other promising candidate technologies are expected to follow. This review summarizes recent developments of various lipid-based liver-targeting technologies, namely solid-lipid nanoparticles, liposomes, niosomes and micelles, and discusses the challenges and future perspectives in this field.

Development and Characterization of the Solvent-Assisted Active Loading Technology (SALT) for Liposomal Loading of Poorly Water-Soluble Compounds.

A large proportion of pharmaceutical compounds exhibit poor water solubility, impacting their delivery. These compounds can be passively encapsulated in the lipid bilayer of liposomes to improve their water solubility, but the loading capacity and stability are poor, leading to burst drug leakage. The solvent-assisted active loading technology (SALT) was developed to promote active loading of poorly soluble drugs in the liposomal core to improve the encapsulation efficiency and formulation stability. By adding a small volume (~5 vol%) of a water miscible solvent to the liposomal loading mixture, we achieved complete, rapid loading of a range of poorly soluble compounds and attained a high drug-to-lipid ratio with stable drug retention. This led to improvements in the circulation half-life, tolerability, and efficacy profiles. In this mini-review, we summarize our results from three studies demonstrating that SALT is a robust and versatile platform to improve active loading of poorly water-soluble compounds. We have validated SALT as a tool for improving drug solubility, liposomal loading efficiency and retention, stability, palatability, and pharmacokinetics (PK), while retaining the ability of the compounds to exert pharmacological effects.

Recent advances in applying nanotechnologies for cancer immunotherapy.

Cancer immunotherapy aimed at boosting cancer-specific immunoresponses to eradicate tumor cells has evolved as a new treatment modality. Nanoparticles incorporating antigens and immunomodulatory agents can activate immune cells and modulate the tumor microenvironment to enhance anti-tumor immunity. The nanotechnology approach has been demonstrated to be superior to standard formulations in in-vivo settings. In this article, we focus on recent advances made within the last 5 years in nanoparticle-based cancer immunotherapy, including peptide- and nucleic acid-based nanovaccines, nanomedicines containing an immunoadjuvant to activate anti-tumor immunity, nanoparticle delivery of immune checkpoint inhibitors and the combination of the above approaches. Encouraging results and new emerging nanotechnologies in drug delivery promise the continuous growth of this field and ultimately clinical translation of enhanced immunotherapy of cancer.