Adopt-A-Classroom Program: A Potential Platform to Address the Root of Health Disparities in the US.

The underrepresentation of Black doctors is a significant issue in the US that led to the perpetuation of health disparities in the African American community. Racial and ethnic minorities in the US have been shown to have higher rates of chronic diseases, such as hypertension, diabetes, and cardiovascular disease, as well as higher rates of obesity and premature death compared to White people. While Blacks make up more than 13% of the US population, they comprise only 4% of US doctors and less than 7% of medical students. It is believed that this problem requires more deliberate efforts by policymakers and the educational establishment, not only at the undergraduate and medical school level, but earlier in the educational "pipeline"-the K-12 school system. While the medical field is rooted in Science, Technology, Engineering, and Mathematics (STEM), we have launched a new initiative that will provide year-round STEM development activities for K-12 education in Connecticut in Hartford and Waterbury districts, especially among populations with health disparities.

Pomalidomide, Bortezomib, and Dexamethasone in Lenalidomide-Pretreated Multiple Myeloma: A Subanalysis of OPTIMISMM by Frailty and Bortezomib Dose Adjustment.

INTRODUCTION: A proportion of patients with multiple myeloma (MM) are older and/or have comorbidities, requiring dose adjustments. Data from OPTIMISMM (NCT01734928) supported the use of pomalidomide, bortezomib, and dexamethasone (PVd) for treating relapsed/refractory MM. This subanalysis of OPTIMISMM assessed outcome by frailty and/or bortezomib dose adjustment. METHODS: Patient frailty (nonfrail vs. frail) was classified using age, Charlson Comorbidity Index, and Eastern Cooperative Oncology Group performance status. Data from patients requiring a bortezomib dose reduction, interruption, and/or withdrawal during PVd treatment were assessed. RESULTS: Among 559 patients, 93 of 281 (33.1%) and 93 of 278 (33.5%) patients who received PVd and bortezomib and dexamethasone (Vd), respectively, were frail. Overall response rate (ORR) and median progression-free survival (PFS) were higher in nonfrail vs. frail with PVd treatment (ORR, 82.8% vs. 79.6%; PFS, 14.7 vs. 9.7 months); significantly higher than with Vd regardless of frailty. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were higher with PVd vs. Vd, regardless of frailty. Discontinuations of PVd were lower in nonfrail vs. frail patients (19.2% vs. 30.1%); the median duration of treatment was similar (DoT; 8.8 vs. 8.9 months, respectively). Patients who received PVd with a bortezomib dose adjustment (n = 240) had a longer median DoT (9.3 vs. 4.5 months) and PFS (12.1 vs. 8.4 months) vs. those without. CONCLUSION: Frail patients treated with PVd demonstrated a higher ORR and a longer PFS and DoT vs. Vd, despite a higher frequency of grade ≥ 3 TEAEs leading to pomalidomide, bortezomib, and/or dexamethasone discontinuation. Therefore, PVd treatment may improve patient outcomes, regardless of frailty.

Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.

Background: Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown. Methods: We conducted an immune-profiling of a longitudinal cohort of 366 peripheral blood samples from the CC4047-MM-007 (OPTIMISMM, NCT01734928) study. This study followed relapsed/refractory Multiple Myeloma (RRMM) patients who were treated with Velcade + dexamethasone (Vd), or Vd with pomalidomide (PVd). 366 blood samples from 186 patients were evaluated using multi-color flow cytometry at 3 timepoints: screening, day 8 of cycle 1, and cycle 3. Results: Among NK and NKT cell populations, adding pomalidomide showed no inhibition in the frequency of NK cells. When expression of double positivity for activation markers like, p46/NKG2D, on NK cells was higher than the median, PVd treated patients showed significantly better (p=0.05) progression-free survival (PFS) (additional 15 months) than patients with lower than the median expression of p46/NKG2D on NK cells. PVd treated patients who expressed CD158a/b below the median at cycle 1 demonstrated a significantly better PFS (more than 18months). Among B cell subtypes, PVd treatment significantly increased the abundance of B1b cells (p<0.05) and decreased Bregs (p<0.05) at day 8 of both cycle 1 and cycle 3 when compared to screening samples. Of all the B cell-markers evaluated among paired samples, a higher expression of MZB cells at day 8 of cycle 1 has resulted in enhanced PFS in PVd treated patients. Within T cells, pomalidomide treatment did not decrease the frequency of CD8 T cells when compared with screening samples. The higher the surface expression of OX-40 on CD8 T cells and the lower the expression of PD-1 and CD25 on CD4 T cells by PVd treatment resulted in improved PFS. Conclusion: The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.

Patients' Beliefs About Their Cardiovascular Medications After Acute Coronary Syndrome: A Prospective Observational Study.

Background: Adherence to secondary preventive pharmacotherapy after an acute coronary syndrome (ACS) is generally poor and is associated with recurrent cardiovascular events. Patients' beliefs about their medications are a strong predictor of intentional nonadherence. Methods: This prospective, observational study assessed adult patients' beliefs about their post-ACS medications, using the Beliefs About Medicines Questionnaire (BMQ), and adherence, using the Medication Adherence Report Scale (MARS-5) at St. Paul's Hospital in Vancouver, Canada during May-December, 2022. The BMQ and MARS-5 were administered in-hospital and at 4 weeks after discharge. Outcomes included difference in BMQ necessity-concerns differential (BMQ-NCD) from hospitalization to 4-week follow-up and factors associated with the BMQ-NCD. Results: Forty-seven participants completed the 4-week follow-up. The mean age was 64 years, and 83% were male. Most presented with a non-ST-segment-elevation ACS. No difference occurred in BMQ-NCD (7.3 vs 6.6, P = 0.29) or MARS-5 scores from discharge to 4 weeks (22.8 vs 23.7, P = 0.06); however, the BMQ specific-necessity subscale score decreased significantly (20.3 vs 18.8, P = 0.002). South Asian and Middle Eastern ethnic origins, compared to European, were associated with a higher BMQ-NCD. Part-time employment and male sex were associated with a lower BMQ-NCD. Conclusions: Participants held favourable beliefs about their post-ACS medications, which were largely unchanged from hospitalization to 4 weeks postdischarge, except for beliefs about the necessity of taking their medications. Those of European descent, those with part-time employment, and males had the lowest BMQ-NCD. Self-reported adherence was high. Ongoing reassessment of patients' beliefs about the necessity of taking their post-ACS medications may be warranted to mitigate further decline in BMQ-NCD.

Contexte: L'adhésion à une pharmacothérapie préventive secondaire après la survenue d'un syndrome coronarien aigu (SCA) est généralement faible et associée à des manifestations cardiovasculaires récurrentes. Les croyances du patient au sujet de ses médicaments représentent un facteur prédictif majeur de la non-adhésion intentionnelle. Méthodologie: Cette étude observationnelle prospective avait pour objectif d'évaluer les croyances des patients au sujet des médicaments à prendre après la survenue d'un SCA, au moyen du questionnaire BMQ (Beliefs About Medicines), ainsi que l'adhésion thérapeutique, à l'aide de l'échelle de rapport sur l'adhésion aux médicaments MARS-5 (Medication Adherence Report Scale), à l'hôpital St. Paul de Vancouver, au Canada, de mai à décembre 2022. Les questionnaires BMQ et MARS-5 ont été administrés pendant l'hospitalisation, puis 4 semaines après le congé de l'hôpital. Les résultats comprenaient la différence du score BMQ-NCD (necessity-concerns differential ­ écart nécessité-inquiétudes), entre l'hospitalisation et le suivi à 4 semaines, et les facteurs associés au score BMQ-NCD. Résultats: Au total, 47 participants ont terminé l'étude, jusqu'au suivi à 4 semaines. L'âge moyen était de 64 ans, et 83 % des sujets étaient de sexe masculin. La plupart des sujets présentaient un SCA sans élévation du segment ST. Aucune variation du score BMQ-NCD (7,3 vs 6,6; p = 0,29) ou MARS-5 (22,8 vs 23,7; p = 0,06) n'a été observée entre le congé de l'hôpital et le suivi à 4 semaines; cependant, le score BMQ spécifique à la nécessité avait significativement diminué (20,3 vs 18.8; p = 0,002). Les origines ethniques sud-asiatiques et moyen-orientales étaient associées à des scores BMQ-NCD plus élevés que les origines européennes. L'occupation d'un emploi à temps partiel et le sexe masculin étaient associés à des scores BMQ-NCD inférieurs. Conclusions: Les participants entretenaient des croyances favorables envers leurs médicaments à prendre après la survenue d'un SCA, qui sont demeurées largement les mêmes entre l'hospitalisation et le suivi, 4 semaines après le congé de l'hôpital, à l'exception des croyances au sujet de la nécessité de prendre les médicaments. Les sujets d'origine européenne, ceux occupant un emploi à temps partiel et les sujets masculins ont eu les scores BMQ-NCD les plus faibles. L'adhésion thérapeutique autosignalée était élevée. Des réévaluations constantes des croyances des patients au sujet de la nécessité de prendre leurs médicaments après la survenue d'un SCA pourraient être justifiées afin d'éviter que les scores BMQ-NCD diminuent davantage.

Approach to Cardiac Masses Using Multimodal Cardiac Imaging.

Incidental cardiac masses can pose diagnostic challenges given the numerous differentials, and difficulty in obtaining tissue confirmation without invasive procedures. With recent advancements in cardiac imaging technology, noninvasive efforts to diagnose the intracardiac lesions have become more surmountable. In this paper, we report a case of a patient incidentally found to have an intracardiac mass during routine evaluation. Transthoracic echocardiography demonstrated a small mass attached to the tricuspid valve, which was not visualized on follow up cardiac magnetic resonance imaging. Here, we review the currently available cardiac imaging modalities and discuss their values and limitations. From this, we also propose a workflow in the approach to utilizing different imaging modalities to reach a conclusive diagnosis of undifferentiated cardiac masses.

The Effects of Nonconventional Exercise on Functional Capacity and Quality of Life in Patients With Heart Failure: A Systematic Review.

BACKGROUND: Patients with heart failure (HF) experience decreased functional capacity (FC) and poor quality of life (QOL). Exercise and cardiac rehabilitation programs are an integral part of managing HF because they have been shown to provide a multitude of benefits including improved FC and QOL. In recent years, nonconventional exercise interventions have offered a promising approach for promoting physical activity in patients with HF, thus leading to improved FC and QOL. PURPOSE: This review aimed to assess the effects of either supervised or unsupervised, nonconventional exercise interventions on FC and QOL in patients with HF. METHODS: A literature search using PubMed, Web of Science, Cochrane Library, and Science Direct for relevant studies was conducted. Experimental studies that examined nonconventional exercise interventions in adults with HF were eligible for inclusion. Two reviewers independently selected the studies, assessed the quality of the studies, and then narratively synthesized each study. RESULTS: The authors identified 14 studies that included 879 patients with HF. Most studies were ranked moderate to high quality where 13 studies found significantly improved FC and 10 found significantly improved QOL after nonconventional exercises. CONCLUSIONS: This review provides preliminary evidence that patients with HF may benefit from alternative forms of exercise to improve FC and QOL. Walking was the most frequent exercise, but other nonconventional exercises such as aquatic exercise, dance, resistance training, stretching, Tai Chi, and yoga are also promising interventions that may improve FC and QOL in patients with HF. CLINICAL IMPLICATIONS: Nonconventional exercise can be a convenient and alternative method of exercise versus traditional cardiac rehabilitation, thereby providing new opportunities that can lead to improved FC and QOL.

Aiding early clinical drug development by elucidation of the relationship between tumor growth inhibition and survival in relapsed/refractory multiple myeloma patients.

Early prognosis of clinical efficacy is an urgent need for oncology drug development. Herein, we systemically examined the quantitative approach of tumor growth inhibition (TGI) and survival modeling in the space of relapsed and refractory multiple myeloma (MM), aiming to provide insights into clinical drug development. Longitudinal serum M-protein and progression-free survival (PFS) data from three phase III studies (N = 1367) across six treatment regimens and different patient populations were leveraged. The TGI model successfully described the longitudinal M-protein data in patients with MM. The tumor inhibition and growth parameters were found to vary as per each study, likely due to the patient population and treatment regimen difference. Based on a parametric time-to-event model for PFS, M-protein reduction at week 4 was identified as a significant prognostic factor for PFS across the three studies. Other factors, including Eastern Cooperative Oncology Group performance status, prior anti-myeloma therapeutics, and baseline serum ß2-microglobulin level, were correlated with PFS as well. In conclusion, patient disease characteristics (i.e., baseline tumor burden and treatment lines) were important determinants of tumor inhibition and PFS in MM patients. M-protein change at week 4 was an early prognostic biomarker for PFS.

Patterns of Pediatric Facial Fractures.

OBJECTIVE: The aim of this study was to assess patterns of maxillofacial trauma in the pediatric population in Atlanta. This information is important to help guide management and allocate resources for treatment of maxillofacial injuries at Children's Healthcare of Atlanta (CHOA). METHODS: This study was a retrospective chart review of children who presented from 2006 to 2015. Inclusion criteria were: (1) age 18 years old or younger, (2) presentation to emergency department, (3) diagnosis of maxillofacial fractures, and (4) evaluation by Oral and Maxillofacial Surgery, Otolaryngology, or Plastic Surgery services. Medical records were reviewed to record demographic, mechanism of injury, fracture location, and yearly incidence of injury. Descriptive statistics were computed to summarize findings and overall trends. RESULTS: During the study period, 39,833 patients were identified. Of them, 1995 met the inclusion criteria. The majority were male (n = 1359, 68%) with an average age of 9.4 years old (range of 1 month to 18 years old). Mechanisms of injury were motor vehicle collisions (MVC) (n = 597, 29.9%), fall (n = 565, 28.3%), sports injury (n = 317, 15.9%), pedestrian struck (n = 215, 10.8%), assault/abuse (n = 204, 10.2%), other (n = 81, 4.1%), or gunshot wound (n = 16, 0.8%). Fracture sites were mandible (n = 519, 26%), complex (n = 479, 24%), nasal (n = 419, 21%), dentoalveolar (n = 279, 14%), orbital (n = 259, 13%), and maxilla (n = 40, 2%). Males had a higher incidence of assault than females (n = 185, 91% of assaults). The incidence of maxillofacial trauma increased with age with a peak incidence in 13 to 16-year-olds (n = 566, 28.3%). During the years examined, there was an upward trend in MVCs as the etiology with a peak incidence of facial fractures due to MVCs occurring in 2015. All other mechanisms remained constant during this time period. CONCLUSIONS: There was an increase in pediatric facial fractures secondary to motor vehicle collisions from 2007 to 2015 despite improvements in regulations, traffic safety, and technology.

Health Café Series: a Potential Platform to Reduce Health Disparities.

To help bridge the increasing gap between health scientists/physicians and the community, we have developed a new seminar program-Health Café series. Health Café takes place in causal settings, is open to everyone, and features a keynote speaker regarding prevalent healthcare-related topics. Health Café topics are usually generated via community feedback and are coordinated in partnership with local nonprofit community organizations. The Health Café series is completely free, and no prior knowledge is required to attend seminars. We have been collaborating with a web of community organizations in the Hartford areas of Connecticut, especially among populations with health disparities. We believe our new Health Café series program would serve as a forum to reduce health disparities in the region.

Changes in Psychotropic Prescribing for Patients With Dementia, 2014-2016: Potential implications for Pharmacists.

OBJECTIVE: To assess changes in psychotropic pharmacotherapy for patients with dementia over a three-year period.
SETTING: National Ambulatory Medical Care Survey, physician office visits from 2014 to 2016.
PRACTICE DESCRIPTION: Retrospective analysis of publicly available, nationally representative data on patient characteristics; diagnoses, including comorbidities; and treatments, including medications. Included were patients with a diagnosis of Alzheimer's disease or dementia who were 18 years of age or older. No sample exclusions were applied.
INTERVENTION: Time period, comparing calendar year (CY) 2014 versus the calendar years 2015 and 2016 using Pearson chi-square tests.
MAIN OUTCOME MEASURE(S): Prescribing rates of psychotropic medications, grouped by therapy class.
RESULTS: The sample included 647 patients (337 in 2014 and 310 in 2015-2016). A majority (69.5%) of the patients were 75 years of age or older; 62.4% were female. Prescribing rates remained relatively stable for antipsychotics (15.1% in 2014 to 12.9% in 2015-16; P = 0.607); antidepressants (35.0% to 27.7%; P = 0.263); acetylcholinesterase inhibitors (38.6% to 33.9%; P = 0.446); and memantine (19.4% to 16.8%; P = 0.551). Significant increases were noted for sedatives (11.9% to 21.7%; P = 0.037) and anticonvulsants (10.0% to 27.6%, P = 0.001).
CONCLUSION: Clinically significant increases in the prescribing of anticonvulsants and sedatives suggest the possibility that these agents are used to combat behavioral and psychological symptoms of dementia in patients with dementia. Further research is required to assess the rationale, efficacy, and safety of these uses.

A single nucleotide polymorphism assay sheds light on the extent and distribution of genetic diversity, population structure and functional basis of key traits in cultivated north American cannabis.

BACKGROUND: The taxonomic classification of Cannabis genus has been delineated through three main types: sativa (tall and less branched plant with long and narrow leaves), indica (short and highly branched plant with broader leaves) and ruderalis (heirloom type with short stature, less branching and small thick leaves). While still under discussion, particularly whether the genus is polytypic or monotypic, this broad classification reflects putative geographical origins of each group and putative chemotype and pharmacologic effect. METHODS: Here we describe a thorough investigation of cannabis accessions using a set of 23 highly informative and polymorphic SNP (Single Nucleotide Polymorphism) markers associated with important traits such as cannabinoid and terpenoid expression as well as fibre and resin production. The assay offers insight into cannabis population structure, phylogenetic relationship, population genetics and correlation to secondary metabolite concentrations. We demonstrate the utility of the assay for rapid, repeatable and cost-efficient genotyping of commercial and industrial cannabis accessions for use in product traceability, breeding programs, regulatory compliance and consumer education. RESULTS: We identified 5 clusters in the sample set, including industrial hemp (K5) and resin hemp, which likely underwent a bottleneck to stabilize cannabidiolic acid (CBDA) accumulation (K2, Type II & III). Tetrahydrocannabinolic acid (THCA) resin (Type I) makes up the other three clusters with terpinolene (K4 - colloquial "sativa" or "Narrow Leaflet Drug" (NLD), myrcene/pinene (K1) and myrcene/limonene/linalool (K3 - colloquial "indica", "Broad Leaflet Drug" (BLD), which also putatively harbour an active version of the cannabichrometic acid Synthase gene (CBCAS). CONCLUSION: The final chemical compositions of cannabis products have key traits related to their genetic identities. Our analyses in the context of the NCBI Cannabis sativa Annotation Release 100 allows for hypothesis testing with regards to secondary metabolite production. Genetic markers related to secondary metabolite production will be important in many sectors of the cannabis marketplace. For example, markers related to THC production will be important for adaptable and compliant large-scale seed production under the new US Domestic Hemp Production Program.

Pharmacotherapy in body dysmorphic disorder: relapse prevention and novel treatments.

Introduction: Body dysmorphic disorder is a debilitating disorder that often presents with significant delusionality, low insight, and both medical and psychiatric comorbidities, presenting a challenge for treatment and long-term management. Its typically chronic course requires that therapy be continued indefinitely, but only a few studies of long-term pharmacotherapeutic management exist. Areas covered: The authors discuss the current understanding of body dysmorphic disorder, focusing specifically on: epidemiology, clinical presentation, challenges in treatment, treatment options, and the importance of the further study of the long-term management of the disorder. Expert opinion: Serotonin reuptake inhibitors are the established drug of choice in patients with body dysmorphic disorder. Initial studies suggest that other agents such as augmentation antipsychotic medication may also be of use in combination with serotonin reuptake inhibitors, but there is a lack of studies comparing new treatments to serotonin reuptake inhibitors. Due to the chronic nature of body dysmorphic disorder, further research is needed to clarify the role of pharmacotherapy in long-term management and relapse prevention. Future studies should explore the long-term use of therapies and combinations of different therapeutics with the goal of effectively managing this debilitating, chronic condition.

Pharmacological Treatment of Body Dysmorphic Disorder.

Body dysmorphic disorder is a challenging disorder that manifests as erroneously perceived flaws in one's physical appearance and repetitive behaviors in response to appearance concerns. This disorder is also frequently comorbid with other psychiatric disorders, including major depressive disorder and autism spectrum disorder. It is currently understood to arise from a combination of biological, psychological, and environmental factors. Treatment of body dysmorphic disorder typically consists of a combination of pharmacotherapy and cognitive behavioral therapy. However, not all patients respond to treatment, and BDD symptoms remain even in those who do respond. This review outlines current pharmacological and neuromodulation treatments for body dysmorphic disorder and suggests directions for future studies of novel treatments such as augmentation with atypical antipsychotics and the use of intranasal oxytocin in cases of body dysmorphic disorder that show residual symptomatology even with tailored monotherapy. There is emerging evidence suggesting that non-invasive neurostimulatory techniques, such as repetitive transcranial magnetic stimulation, may be of value in treatment-resistant cases.

Polyvalent Hybrid Virus-Like Nanoparticles with Displayed Heparin Antagonist Peptides.

The potential applications for nanomaterials continue to grow as new materials are developed and environmental and safety concerns are more adequately addressed. In particular, virus-like particles (VLPs) have myriad applications in medicine and biology, exploiting both the reliable, symmetric self-assembly mechanism and the ability to take advantage of surface functionalities that may be appropriately modified through mutation or bioconjugation. Herein we describe the design and application of hybrid VLPs for use as potent heparin antagonists, providing an alternative to the toxic heparin antidote protamine. A two-plasmid system was utilized to generate VLPs that contain both the wild-type coat protein and a second coat protein with either a C- or N-terminal cationic peptide extension (4-28 amino acids). Incorporation of the modified coat proteins varied from 8 to 31%, while activated partial thromboplastin time (APTT) assays revealed a range of the heparin antagonist activity. Notably, when examined on the basis of the quantity of peptide delivered due to the varied incorporation rates, it appeared that the VLPs largely followed a similar trend, with the quantity of peptide delivered more closely correlating with heparin antagonist activity. The particle with the highest incorporation rate and best antiheparin activity displayed the C-terminal peptide ARK2A2KA, which corresponds to the Cardin-Weintraub consensus sequence for binding to glycosaminoglycans. Analysis of this particle using heparin affinity chromatography with fraction collection revealed that particles eluting at higher salt concentration had a greater proportion of peptide incorporation. Preliminary dual polarization interferometry experiments further support a strong interaction between this particle and heparin.

New perspectives in the treatment of body dysmorphic disorder.

Body dysmorphic disorder (BDD) is a disabling illness with a high worldwide prevalence. Patients demonstrate a debilitating preoccupation with one or more perceived defects, often marked by poor insight or delusional convictions. Multiple studies have suggested that selective serotonin reuptake inhibitors and various cognitive behavioral therapy modalities are effective first-line treatments in decreasing BDD severity, relieving depressive symptoms, restoring insight, and increasing quality of life. Selective serotonin reuptake inhibitors have also recently been shown to be effective for relapse prevention. This review provides a comprehensive summary of the current understanding of BDD, including its clinical features, epidemiology, genetics, and current treatment modalities. Additional research is needed to fully elucidate the relationship between BDD and comorbid illnesses such as obsessive-compulsive-related disorders and depression and to develop therapies for refractory patients and those who have contraindications for pharmacological intervention.

Heparin Binding to an Engineered Virus-like Nanoparticle Antagonist.

The anticoagulant activity of heparin administered during medical interventions must be reversed to restore normal clotting, typically by titrating with protamine. Given the acute toxicity associated with protamine, we endeavored to generate safer heparin antagonists by engineering bacteriophage Qß virus-like particles (VLPs) to display motifs that bind heparin. A particle bearing a single amino acid change from wild-type (T18R) was identified as a promising candidate for heparin antagonism. Surface potential maps generated through molecular modeling reveal that the T18R mutation adds synergistically to adjacent positive charges on the particle surface, resulting in a large solvent-accessible cationic region that is replicated 180 times over the capsid. Chromatography using a heparin-sepharose column confirmed a strong interaction between heparin and the T18R particle. Binding studies using fluorescein-labeled heparin (HepFL) resulted in a concentration-dependent change in fluorescence intensity, which could be perturbed by the addition of unlabeled heparin. Analysis of the fluorescence data yielded a dissociation constant of approximately 1 nM and a 1:1 binding stoichiometry for HepFL:VLP. Dynamic light scattering (DLS) experiments suggested that T18R forms discrete complexes with heparin when the VLP:heparin molar ratios are equivalent, and in vitro clotting assays confirmed the 1:1 binding stoichiometry as full antagonism of heparin is achieved. Biolayer interferometry and backscattering interferometry corroborated the strong interaction of T18R with heparin, yielding Kd ∼ 1-10 nM. These biophysical measurements further validated T18R, and VLPs in general, for potential clinical use as effective, nontoxic heparin antagonists.

Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone: A pooled analysis.

OBJECTIVES: Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. METHODS: This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. RESULTS: The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. CONCLUSIONS: Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines.

Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials.

Renal impairment (RI) is a major comorbidity in patients with multiple myeloma (MM). Here we present the pooled safety and efficacy analysis of three clinical trials (MM-002, MM-003, and MM-010) of pomalidomide + low-dose dexamethasone (POM + LoDEX) in patients with moderate RI (creatinine clearance [CrCl] ≥ 30 to <60 mL/min) and without RI (≥ 60 mL/min). Trial protocols were approved by the institutional review board of each site involved. Patients with RI were older than patients without RI, although other baseline characteristics were similar. The dosing and safety profile of POM + LoDEX was similar across RI subgroups. Median overall response rate, progression-free survival, time to progression, and duration of response were not significantly different between RI subgroups. However, patients with vs. without RI had significantly shorter median overall survival (10.5 vs. 14.0 months, respectively; p = .004). This analysis demonstrates that POM + LoDEX is a safe and effective treatment for patients with moderate RI. The trials were registered at ClinicalTrials.gov as NCT00833833 (MM-002), NCT01311687 (MM-003), and NCT01712789 (MM-010) and at EudraCT as 2010-019820-30 (MM-003) and 2012-001888-78 (MM-010).

Relationship of response and survival in patients with relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone in the MM-003 trial randomized phase III trial (NIMBUS).

Relapsed/refractory multiple myeloma (RRMM) patients have poor overall survival (OS). Pomalidomide plus low-dose dexamethasone (POM + LoDEX) significantly extends OS in RRMM vs. high-dose dexamethasone. Survival of patients with stable disease (SD) was compared to patients with progressive disease (PD) or ≥ partial response (≥PR) at cycles (C) 3, 5, and 7. Among 302 patients randomized to POM + LoDEX, at C3 19.2% achieved ≥ PR, 38.4% SD, and 14.6% PD. Patients with SD at C3 (17.4%) and C5 (13.6%) showed improved responses at C7. Median OS from randomization by response at C3 was 22.4 months for ≥ PR (n = 58, HR 0.66; 95% CI 0.40-1.08, p = 0.0976 vs. SD), 16.2 months for SD (n = 116), and 6.3 months for PD (n = 44, HR 3.43; 95% CI 2.23-5.27, p < 0.0001 vs. SD). Similar patterns were observed for C5 and C7. Results show that POM + LoDEX should be a standard treatment after lenalidomide and bortezomib, including in SD patients.