Publications by authors named "Sarah Kim"

197 Publications

The impact of sentinel lymph node sampling versus traditional lymphadenectomy on the survival of patients with stage IIIC endometrial cancer.

Int J Gynecol Cancer 2021 Apr 14. Epub 2021 Apr 14.

Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: To investigate the survival of patients with lymph node positive endometrial carcinoma by type of surgical lymph node assessment.

Methods: Patients diagnosed between January 2012 and December 2015 with endometrial carcinoma and uterine confined disease and nodal metastases on final pathology who underwent minimally invasive hysterectomy were identified in the National Cancer Database. Patients who had sentinel lymph node biopsy alone or underwent systematic lymphadenectomy were selected. Overall survival was evaluated following generation of Kaplan-Meier curves and compared with the log rank test. A Cox model was constructed to evaluate survival after controlling for confounders.

Results: A total of 1432 patients were identified: 1323 (92.4%) and 109 (7.6%) underwent systematic lymphadenectomy and sentinel lymph node biopsy only, respectively. The rate of adjuvant treatment was comparable between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (83.5% vs 86.6%, p=0.39). However, patients who had sentinel lymph node biopsy were less likely to receive chemotherapy alone (13.6% vs 36.6%, p<0.001) and more likely to receive radiation therapy alone (19.8% vs 5.4%, p<0.001) compared with patients who had systematic lymphadenectomy. There was no difference in overall survival between patients who had sentinel lymph node biopsy alone and systematic lymphadenectomy (p=0.27 from log rank test), and 3 year overall survival rates were 82.2% and 79.4%, respectively (p>0.05). After controlling for confounders, there was no difference in survival between the systematic lymphadenectomy and sentinel lymph node biopsy alone groups (hazard ratio 0.82, 95% confidence interval 0.46 to 1.45).

Conclusions: Performance of sentinel lymph node biopsy alone was not associated with an adverse impact on survival in patients with lymph node positive endometrial cancer.
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http://dx.doi.org/10.1136/ijgc-2021-002450DOI Listing
April 2021

In Vitro Synergistic Interactions of Isavuconazole and Echinocandins against .

Antibiotics (Basel) 2021 Mar 28;10(4). Epub 2021 Mar 28.

Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

is an emergent fungal pathogen that causes severe infectious outbreaks globally. The public health concern when dealing with this pathogen is mainly due to reduced susceptibility to current antifungal drugs. A valuable alternative to overcome this problem is to investigate the efficacy of combination therapy. The aim of this study was to determine the in vitro interactions of isavuconazole with echinocandins against . Interactions were determined using a checkerboard method, and absorbance data were analyzed with different approaches: the fractional inhibitory concentration index (FICI), Greco universal response surface approach, and Bliss interaction model. All models were in accordance and showed that combinations of isavuconazole with echinocandins resulted in an overall synergistic interaction. A wide range of concentrations within the therapeutic range were selected to perform time-kill curves. These confirmed that isavuconazole-echinocandin combinations were more effective than monotherapy regimens. Synergism and fungistatic activity were achieved with combinations that included isavuconazole in low concentrations (≥0.125 mg/L) and ≥1 mg/L of echinocandin. Time-kill curves revealed that once synergy was achieved, combinations of higher drug concentrations did not improve the antifungal activity. This work launches promising results regarding the combination of isavuconazole with echinocandins for the treatment of infections.
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http://dx.doi.org/10.3390/antibiotics10040355DOI Listing
March 2021

Mesonephric and mesonephric-like carcinomas of the female genital tract: molecular characterization including cases with mixed histology and matched metastases.

Mod Pathol 2021 Mar 26. Epub 2021 Mar 26.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Mesonephric carcinoma of the cervix is a rare tumor derived from Wolffian remnants. Mesonephric-like carcinomas of the ovary and endometrium, while morphologically similar, do not have obvious Wolffian derivation. Here, we sought to characterize the repertoire of genetic alterations in primary mesonephric and mesonephric-like carcinomas, in the distinct histologic components of mixed cases, as well as in matched primary tumors and metastases. DNA from microdissected tumor and normal tissue from mesonephric carcinomas (cervix, n = 8) and mesonephric-like carcinomas (ovarian n = 15, endometrial n = 13) were subjected to sequencing targeting 468 cancer-related genes. The histologically distinct components of four cases with mixed histology and four primary tumors and their matched metastases were microdissected and analyzed separately. Mesonephric-like carcinomas were underpinned by somatic KRAS mutations (25/28, 89%) akin to mesonephric carcinomas (8/8, 100%), but also harbored genetic alterations more frequently reported in Müllerian tumors. Mesonephric-like carcinomas that lacked KRAS mutations harbored NRAS (n = 2, ovary) or BRAF (n = 1, endometrium) hotspot mutations. PIK3CA mutations were identified in both mesonephric-like (8/28, 28%) and mesonephric carcinomas (2/8, 25%). Only mesonephric-like tumors harbored CTNNB1 hotspot (4/28, 14%) and PTEN (3/13, 23%) mutations. Copy number analysis revealed frequent gains of chromosomes 1q and 10 in both mesonephric (87% 1q; 50% chromosome 10) and mesonephric-like tumors (89% 1q; 43% chromosome 10). Chromosome 12 gains were more frequent in ovarian mesonephric-like carcinomas, and losses of chromosome 9 were more frequent in mesonephric than in mesonephric-like carcinomas (both p = 0.01, Fisher's exact test). The histologically distinct components of four mixed cases were molecularly related and shared similar patterns of genetic alterations. The progression from primary to metastatic lesions involved the acquisition of additional mutations, and/or shifts from subclonal to clonal mutations. Our findings suggest that mesonephric-like carcinomas are derived from a Müllerian substrate with differentiation along Wolffian/mesonephric lines.
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http://dx.doi.org/10.1038/s41379-021-00799-6DOI Listing
March 2021

Outcomes of sentinel lymph node mapping for patients with FIGO stage I endometrioid endometrial carcinoma.

Gynecol Oncol 2021 Mar 23. Epub 2021 Mar 23.

Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA.

Objective: Investigate the overall survival of patients with FIGO stage I endometrioid endometrial carcinoma who underwent sentinel lymph node biopsy (SLNBx).

Methods: Patients diagnosed between 2012 and 2015 with pathological stage I endometrioid endometrial carcinoma who underwent minimally invasive hysterectomy and had at least one month of follow-up were identified in the National Cancer Database (NCDB). Patients who underwent SLNBx or systematic lymphadenectomy (LND) (defined as at least 20 lymph nodes removed) were selected. Overall survival (OS) was evaluated following generation of Kaplan-Meier curves and compared with the log-rank test. A Cox model was constructed to evaluate survival after controlling for confounders.

Results: A total of 13,010 patients with endometrioid endometrial carcinoma who met the inclusion criteria were identified; 9861 (75.8%) and 3149 (24.2%) patients had systematic LND and SLNBx, respectively. Patients who had LND were more likely to receive radiation therapy (27.4% vs 19.3%, p < 0.001) and chemotherapy (13% vs 8.7%, p < 0.001) compared to those who had SLNBx. After controlling for patient age, race, insurance status, depth of myometrial invasion, tumor grade, tumor size, presence of lymph-vascular invasion and receipt of radiation therapy, the performance of SLNBx was not associated with worse survival (HR: 0.99, 95% CI: 0.80, 1.21). For high-intermediate risk patients (based on GOG-99 criteria) after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.07, 95% CI: 0.80, 1.44). For intermediate risk patients who did not receive external beam radiation therapy or chemotherapy after controlling for confounders, performance of SLNBx was not associated with worse survival (HR: 1.58, 95% CI: 0.94, 2.65).

Conclusions: SLNBx had no negative impact on the survival of patients with FIGO stage I endometrioid endometrial carcinoma who undergo hysterectomy.
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http://dx.doi.org/10.1016/j.ygyno.2021.03.018DOI Listing
March 2021

Deep Learning for Integrated Analysis of Insulin Resistance with Multi-Omics Data.

J Pers Med 2021 Feb 15;11(2). Epub 2021 Feb 15.

Department of Life Science, Handong Global University, Pohang-si, Gyeonbuk 37554, Korea.

Technological advances in next-generation sequencing (NGS) have made it possible to uncover extensive and dynamic alterations in diverse molecular components and biological pathways across healthy and diseased conditions. Large amounts of multi-omics data originating from emerging NGS experiments require feature engineering, which is a crucial step in the process of predictive modeling. The underlying relationship among multi-omics features in terms of insulin resistance is not well understood. In this study, using the multi-omics data of type II diabetes from the Integrative Human Microbiome Project, from 10,783 features, we conducted a data analytic approach to elucidate the relationship between insulin resistance and multi-omics features, including microbiome data. To better explain the impact of microbiome features on insulin classification, we used a developed deep neural network interpretation algorithm for each microbiome feature's contribution to the discriminative model output in the samples.
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http://dx.doi.org/10.3390/jpm11020128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918166PMC
February 2021

Is there a benefit of performing an omentectomy for clinical stage I high-grade endometrial carcinoma?

Surg Oncol 2021 Feb 13;37:101534. Epub 2021 Feb 13.

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Objectives: Routine omentectomy is generally not performed in patients with endometrial cancer unless there is evidence of gross omental metastases. The aim of the current study was to evaluate the role of omentectomy in the staging of clinical stage I high-grade endometrial carcinoma and its impact on overall survival.

Methods: Patients in the National Cancer Database who presented between 2010 and 2015 with clinical stage I serous, clear cell, carcinosarcoma, or grade 3 endometrioid carcinoma and underwent hysterectomy with lymphadenectomy were selected. Patients who did and did not receive an omentectomy were identified and clinico-pathological characteristics were compared. Overall survival was evaluated for patients diagnosed between 2010 and 2014 who had at least one month of follow-up following generation of Kaplan-Meier curves and comparison with the log-rank test. A Cox model was constructed to control for confounders.

Results: A total of 9097 patients were identified, and 36.3% underwent an omentectomy. Patients who underwent omentectomy were more likely to be managed in academic institutions (50% vs. 44%, p < 0.001). They were also more likely to have an open surgery (48.2% vs. 27.2%, p < 0.001) and receive adjuvant chemotherapy (54.7% vs. 38.2%, p < 0.001). There was no difference in overall survival between patients who did and did not undergo omentectomy, p = 0.61; the 3-year OS rates were 82.3% and 82.2%, respectively. After controlling for confounders, the performance of an omentectomy was not associated with better survival (hazard ratio [HR]: 0.94, 95% confidence intervals [CI]: 0.84, 1.05).

Conclusions: Routine omentectomy may not be associated with a survival benefit for patients with clinical stage I high-grade endometrial carcinoma.
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http://dx.doi.org/10.1016/j.suronc.2021.101534DOI Listing
February 2021

Pain Catastrophizing and Quality of Life in Adults With Chronic Rhinosinusitis.

Laryngoscope 2021 Jan 29. Epub 2021 Jan 29.

Department of Otolaryngology/Head and Neck Surgery, Virginia Commonwealth University, Richmond, Virginia, U.S.A.

Objectives/hypothesis: Psychological comorbidity is common in patients with chronic rhinosinusitis (CRS) and is correlated with decreased overall and disease-specific quality of life (QoL). Prior research reported that anxiety and depression, as measured by the hospital anxiety and depression scale (HADS), are associated with worse CRS-specific QoL, as assessed via the Rhinosinusitis Disability Index (RSDI). Furthermore, patients prone to anxiety/depression may display an exaggerated response to real or anticipated discomfort; the pain catastrophizing scale (PCS) is a validated instrument designed to measure this phenomenon. This study is intended to explore the role of pain catastrophizing in relation to anxiety, depression, and disease-specific QoL in patients with facial pain attributed to CRS.

Study Design: Prospective cohort study.

Methods: Diagnosis of presumed CRS was based upon current American Academy of Otolaryngology - Head & Neck Surgery (AAO-HNS) guidelines; all participants reported facial pain as a component of their CRS symptomatology. RSDI, HADS, and PCS questionnaires were administered upon presentation prior to intervention, and objective measurements of sinonasal inflammation were obtained via nasal endoscopy and computed tomography (CT).

Results: Seventy-five patients were enrolled in the study. Significant positive correlations were found between PCS and HADS, total RSDI, and RSDI emotional sub-scores (P < .05). The incidence of objective evidence of disease, as measured via nasal endoscopy and CT, was not significantly different in catastrophizing patients.

Conclusions: Pain catastrophizing correlates with anxiety/depression and worse disease-specific QoL in patients meeting symptomatic criteria for CRS. Otolaryngologists should be aware that catastrophic thinking can intensify a patient's perception of sinonasal symptoms, and clinicians may consider management of psychological comorbidity to optimize rhinologic outcomes.

Level Of Evidence: 4 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29405DOI Listing
January 2021

HyperEmesis Level Prediction (HELP Score) Identifies Patients with Indicators of Severe Disease: a Validation Study.

Geburtshilfe Frauenheilkd 2021 Jan 19;81(1):90-98. Epub 2021 Jan 19.

Keck School of Medicine, University of Southern California, Department of Maternal-Fetal Medicine, Los Angeles, CA, USA.

Hyperemesis gravidarum (HG) severity can be underestimated resulting in undertreatment and adverse outcomes. This study was conducted to validate a tool (HELP Score) designed to score HG severity. A survey link which included PUQE and HELP Score (HELP) tool questions was posted on websites related to HG. HELP scores were compared to PUQE scores for indicators of severe disease. HELP classified 92% of women reporting "nothing goes or stays down" as severe, compared to 58% using PUQE. Women self-categorizing symptoms as severe were more likely categorized as severe using HELP. Women hospitalized for HG were more likely classified as severe using HELP. HELP performs better than PUQE in identifying patients with severe symptoms requiring intervention. This study provides a novel tool that should be implemented to determine the need for intervention for NVP that may be overlooked using PUQE or empirical assessment.
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http://dx.doi.org/10.1055/a-1309-1997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815331PMC
January 2021

Dose Fractionation of Moxifloxacin for Treatment of Tuberculosis: Impact of Dosing Interval and Elimination Half-Life on Microbial Kill and Resistance Suppression.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

The repurposed agent moxifloxacin has become an important addition to the physician's armamentarium for the therapy of When a drug is administered, we need to have metrics for success. As for most antimicrobial chemotherapy, we contend that for therapy, these metrics should be a decline in the susceptible bacterial burden and the suppression of amplification of less-susceptible populations. To achieve optimal outcomes relative to these metrics, a dose and schedule of administration need to be chosen. For large populations of patients, there are true between-patient differences in important pharmacokinetic parameters. These distributions of parameter values may have an impact on these metrics, depending on what measure of drug exposure drives the metrics. To optimize dose and schedule choice of moxifloxacin, we performed a dose fractionation experiment in the hollow fiber infection model. We examined 12-, 24-, and 48-h dosing intervals with doses of 200, 400, and 800 mg for each interval, respectively. Within each interval, we had an arm where half-lives of 12, 8, and 4 h were simulated. We attempted to keep the average concentration () or area under the concentration-time curve (AUC) constant across arms. We found that susceptible bacterial load decline was linked to , as we had indicated previously. Resistance suppression, a nonmonotonic function, had minimum concentration () as the linked index. The 48-h interval with the 4-h half-life had the largest less-susceptible population. Balancing bacterial kill, resistance suppression, toxicity (linked to peak concentration []), and adherence, we conclude that the dose of 400 mg daily is optimal for moxifloxacin.
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http://dx.doi.org/10.1128/AAC.02533-20DOI Listing
March 2021

pH-triggered pore-forming peptides with strong composition-dependent membrane selectivity.

Biophys J 2021 Feb 16;120(4):618-630. Epub 2021 Jan 16.

Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore, Maryland. Electronic address:

Peptides that self-assemble into nanometer-sized pores in lipid bilayers could have utility in a variety of biotechnological and clinical applications if we can understand their physical chemical properties and learn to control their membrane selectivity. To empower such control, we have used synthetic molecular evolution to identify the pH-dependent delivery peptides, a family of peptides that assemble into macromolecule-sized pores in membranes at low peptide concentration but only at pH < ∼6. Further advancements will also require better selectivity for specific membranes. Here, we determine the effect of anionic headgroups and bilayer thickness on the mechanism of action of the pH-dependent delivery peptides by measuring binding, secondary structure, and macromolecular poration. The peptide pHD15 partitions and folds equally well into zwitterionic and anionic membranes but is less potent at pore formation in phosphatidylserine-containing membranes. The peptide also binds and folds similarly in membranes of various thicknesses, but its ability to release macromolecules changes dramatically. It causes potent macromolecular poration in vesicles made from phosphatidylcholine with 14 carbon acyl chains, but macromolecular poration decreases sharply with increasing bilayer thickness and does not occur at any peptide concentration in fluid bilayers made from phosphatidylcholine lipids with 20-carbon acyl chains. The effects of headgroup and bilayer thickness on macromolecular poration cannot be accounted for by the amount of peptide bound but instead reflect an inherent selectivity of the peptide for inserting into the membrane-spanning pore state. Molecular dynamics simulations suggest that the effect of thickness is due to hydrophobic match/mismatch between the membrane-spanning peptide and the bilayer hydrocarbon. This remarkable degree of selectivity based on headgroup and especially bilayer thickness is unusual and suggests ways that pore-forming peptides with exquisite selectivity for specific membranes can be designed or evolved.
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http://dx.doi.org/10.1016/j.bpj.2021.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896028PMC
February 2021

Physiologically-based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate.

CPT Pharmacometrics Syst Pharmacol 2021 Mar 10;10(3):199-210. Epub 2021 Feb 10.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.
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http://dx.doi.org/10.1002/psp4.12589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965836PMC
March 2021

Anti-oxidant copper layer by remote mode N plasma for low temperature copper-copper bonding.

Sci Rep 2020 12 10;10(1):21720. Epub 2020 Dec 10.

Graduate School of Nano-IT Design, Seoul National University of Science and Technology, 232 Gongneung-ro, Nowon-gu, Seoul, 01811, Korea.

An anti-oxidant Cu layer was achieved by remote mode N plasma. Remote mode plasma treatment offers the advantages of having no defect formation, such as pinholes, by energetic ions. In this study, an activated Cu surface by Ar plasma chemically reacted with N free radicals to evenly form Cu nitride passivation over the entire Cu surface. According to chemical state analysis using XPS, Cu oxidation was effectively prevented in air, and the thickness of the Cu nitride passivation was within 3 nm. Based on statistical analysis using the DOE technique with N plasma variables, namely, RF power, working pressure, and plasma treatment time, we experimentally demonstrated that a lower RF power is the most effective for forming uniform Cu nitride passivation because of a lower plasma density. When the N plasma density reached approximately 10 cm in which the remote mode was generated, high energy electrons in the plasma were significantly reduced and the amount of oxygen detected on the Cu surface was minimized. Finally, low temperature (300 °C) Cu-Cu bonding was performed with a pair of the anti-oxidant Cu layers formed by the remote mode N plasma. Cu atomic diffusion with new grains was observed across the bonded interface indicating significantly improved bonding quality over bare Cu-Cu bonding.
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http://dx.doi.org/10.1038/s41598-020-78396-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730425PMC
December 2020

Utilization and outcomes of sentinel lymph node biopsy in patients with early stage vulvar cancer.

Int J Gynecol Cancer 2021 Jan 26;31(1):40-44. Epub 2020 Nov 26.

Division of Gynecologic Oncology, Penn Medicine, Philadelphia, Pennsylvania, USA.

Objective: A retrospective cohort study comparing survival and perioperative outcomes of patients with early vulvar cancer who underwent sentinel lymph node biopsy versus standard lymphadenectomy METHODS: Patients diagnosed between January 2012 and December 2015 with vulvar squamous cell carcinoma of less than 4 cm in size, with invasion of at least 1 mm, who underwent sentinel lymph node biopsy, lymphadenectomy, or both were identified from the National Cancer Database. Overall survival was evaluated following generation of Kaplan-Meier curves and compared with the log-rank test for patients who had at least 1 month of follow-up. A Cox model was constructed to control for confounders.

Results: A total of 1583 patients were identified; 304 patients (19.2%) underwent sentinel lymph node biopsy alone. Sentinel lymph node biopsy utilization increased 13.9% between 2012 and 2015. Patients who underwent sentinel node biopsy alone were less likely to have comorbidities compared with those undergoing lymphadenectomy only or sentinel node biopsy with lymphadenectomy (25.3% vs 32.9% vs 31.9%, p=0.042), had smaller tumors (median 1.6 vs 2.0 vs 2.0 cm, p<0.001), and were less likely to have positive lymph nodes (11% vs 19.6% vs 28.1%, p<0.001). There was no difference in 3 year overall survival between the three groups (86.3% vs 82.1% vs 77.9%, p=0.26). After controlling for age, race, insurance, comorbidities, lymph node metastases, and tumor size, sentinel lymph node biopsy alone was not associated with worse overall survival compared with lymphadenectomy (HR 0.86, 95% CI 0.57 to 1.32). The sentinel node only group had shorter inpatient stays compared with lymphadenectomy only (median 1 vs 2 days, p<0.001) and a lower rate of unplanned readmission (1.7% vs 5.0%, p=0.010).

Conclusions: The utilization of sentinel lymph node biopsy is increasing in the management of vulvar cancer and is associated with superior perioperative outcomes without impacting overall survival.
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http://dx.doi.org/10.1136/ijgc-2020-001934DOI Listing
January 2021

The juvenile gangliosidoses: A timeline of clinical change.

Mol Genet Metab Rep 2020 Dec 14;25:100676. Epub 2020 Nov 14.

Department of Pediatrics, University of Minnesota, 2450 Riverside Avenue, Minneapolis, MN 55454-1450, USA.

Background: The gangliosidoses are rare inherited diseases that result in pathologic accumulation of gangliosides in the central nervous system and other tissues, leading to severe and progressive neurological impairment and early death in the childhood forms. No treatments are currently approved for the gangliosidoses, and development of treatments is impaired by limited understanding of the natural history of these diseases.

Objective: The objective of this study is to improve understanding of the juvenile gangliosidoses phenotypes and the late-infantile phenotypic subtype.

Methods: Through a prospective natural history study of subjects with juvenile GM1- and GM2-gangliosidosis, a timeline of clinical changes was developed for the classic juvenile phenotypes and the late-infantile phenotypes and results of serial neurodevelopmental testing was analyzed.

Results: Several candidate 'outcome measures' were identified: changes in ambulation and verbalization skills, the communication domain from neurodevelopmental testing and the caregiver-reported socialization domain.

Conclusions: The most common symptoms leading caregivers to seek a genetic diagnosis were changes in ambulation and verbalization.
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http://dx.doi.org/10.1016/j.ymgmr.2020.100676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674119PMC
December 2020

User Characteristics of a Low-Acuity Emergency Department Alternative for Low-Income Patients.

West J Emerg Med 2020 Oct 27;21(6):162-171. Epub 2020 Oct 27.

University of Illinois at Chicago, College of Medicine, Chicago, Illinois.

Introduction: Emergency department (ED) use for healthcare that can be treated elsewhere is costly to the healthcare system. However, convenience settings such as urgent care centers (UCC) are generally inaccessible to low-income patients. Housing an UCC within a federally qualified health center (FQHC UCC) provides an accessible convenience setting for low-income patients. In 2014 a FQHC UCC opened two blocks from an ED in the same health system. Our goal was to compare characteristics, access to care, and utilization preferences for FQHC UCC and low-acuity ED patients through retrospective chart review and prospective surveying.

Methods: We completed a retrospective chart review of all patients from March 1, 2018-March 1, 2019, and compared characteristics of low-acuity ED patients (N = 3,911) and FQHC UCC patients (N = 12,571). We also surveyed FQHC UCC patients (N = 201) and low-acuity ED patients (N = 198) from January-July 2019.

Results: Half of FQHC UCC patients had private insurance. Of ED patients, 29% were aware of the FQHC UCC. Both groups had similar rates of primary care providers. The most common reason for choosing the ED was perceived severity, and for choosing a FQHC UCC was speed.

Conclusion: These findings show similarities and differences between these two patient populations. Future research is needed to determine utilization patterns and in-depth reasons behind them. Interventions that help patients decide where to go for low-acuity care may create more utilization efficiency.
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http://dx.doi.org/10.5811/westjem.2020.8.47970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673865PMC
October 2020

The Funnel: a Screening Technique for Identifying Optimal Two-Drug Combination Chemotherapy Regimens.

Antimicrob Agents Chemother 2021 01 20;65(2). Epub 2021 Jan 20.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

The drug discovery effort has generated a substantial number of new/repurposed drugs for therapy for this pathogen. The arrival of these drugs is welcome, but another layer of difficulty has emerged. Single agent therapy is insufficient for patients with late-stage tuberculosis because of resistance emergence. To achieve our therapeutic ends, it is requisite to identify optimal combination regimens. These regimens go through a lengthy and expensive evaluative process. If we have a modest group of 6 to 8 new or repurposed agents, this translates into 15 to 28 possible 2-drug combinations. There is neither time nor resources to give an extensive evaluation for all combinations. We sought a screening procedure that would identify combinations that had a high likelihood of achieving good bacterial burden decline. We examined pretomanid, moxifloxacin, linezolid, and bedaquiline in log-phase growth, acid-phase growth, and nonreplicative persister (NRP) phase in the Greco interaction model. We employed the interaction term α and the calculated bacterial burden decline as metrics to rank different regimens in different metabolic states. No relationship was found between α and bacterial kill. We chose bacterial kill as the prime metric. The combination of pretomanid plus moxifloxacin emerged as the clear frontrunner, as the largest bacterial declines were seen in log phase and acid phase with this regimen and it was second best in NRP phase. Bedaquiline also produced good kill. This screening process may identify optimal combinations that can be further evaluated in both the hollow-fiber infection model and in animal models of infection.
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http://dx.doi.org/10.1128/AAC.02172-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848982PMC
January 2021

Survival following minimally invasive radical hysterectomy for patients with cervical carcinoma and tumor size ≤2 cm.

Am J Obstet Gynecol 2021 03 28;224(3):317-318.e2. Epub 2020 Oct 28.

Division of Gynecologic Oncology, Hospital of the University of Pennsylvania, 3400 Spruce St., 1 West Gates, Philadelphia, PA 19104.

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http://dx.doi.org/10.1016/j.ajog.2020.10.044DOI Listing
March 2021

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Clin Pharmacol Ther 2021 Jan 10;109(1):193-200. Epub 2020 Dec 10.

Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.
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http://dx.doi.org/10.1002/cpt.2087DOI Listing
January 2021

Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype-Derived Activity Scores.

CPT Pharmacometrics Syst Pharmacol 2020 Dec 3;9(12):678-685. Epub 2020 Nov 3.

Department of Pharmacotherapy and Translation Research, Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, Florida, USA.

Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S-metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P < 0.001). The natural log of CLo was lower with an AS of 1 (7.6 ± 0.4 mL/minute) vs. 2-2.25 (8.3 ± 0.6 mL/minute; P = 0.012), similar between an AS of 1 and 1.25-1.5 (7.8 ± 0.5 mL/minute; P = 0.702), and lower with an AS of 1.25-1.5 vs. 2-2.25 (P = 0.03). There was also a greater reduction in heart rate with metoprolol among study participants with AS of 1 (-10.8 ± 5.5) vs. 2-2.25 (-7.1 ± 5.6; P < 0.001) and no significant difference between those with an AS of 1 and 1.25-1.5 (-9.2 ± 4.7; P = 0.095). These data highlight linear trends among CYP2D6 AS and metoprolol PK and PD, but inconsistencies with the phenotypes assigned by AS based on the current standards. Overall, this case study with metoprolol suggests that utilizing CYP2D6 AS, instead of collapsing AS into phenotype categories, may be the most precise approach for utilizing CYP2D6 pharmacogenomics in clinical practice.
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http://dx.doi.org/10.1002/psp4.12563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762806PMC
December 2020

Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice.

Mol Metab 2020 12 10;42:101098. Epub 2020 Oct 10.

Bone Research Program, ANZAC Research Institute, The University of Sydney, Australia; Concord Clinical School, The University of Sydney, Australia. Electronic address:

Objective: Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging.

Methods: Mice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured.

Results: As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2-tg mice remained leptin-sensitive throughout the study. Compared to HSD2-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2-tg mice, compared to wild-type mice.

Conclusions: Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.
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http://dx.doi.org/10.1016/j.molmet.2020.101098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596342PMC
December 2020

Patterns of use and outcomes of sentinel lymph node mapping for patients with high-grade endometrial cancer.

Gynecol Oncol 2020 12 29;159(3):732-736. Epub 2020 Sep 29.

Division of Gynecologic Oncology, University of Pennsylvania Health System, Philadelphia, PA, USA.

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http://dx.doi.org/10.1016/j.ygyno.2020.09.023DOI Listing
December 2020

A Qualitative Exploration of Barriers and Facilitators to Physical Activity Among Low-Income Latino Adolescents.

Hisp Health Care Int 2020 Sep 10:1540415320956933. Epub 2020 Sep 10.

8785University of California, San Francisco, CA, USA.

Introduction: Latino adolescents experience high rates of obesity and physical activity can protect against obesity and obesity comorbidities. Health interventions to promote physical activity are more likely to be successful if they take into account the experiences and perspectives of their target population. Our study objective was to explore barriers and facilitators to physical activity among Latino adolescents with the goal of informing future interventions for this population.

Method: Semistructured interviews were conducted with ( = 30) low-income, Latino adolescents. The interviews were analyzed using inductive methods and the Capability-Opportunity-Motivation model of behavior.

Results: Adolescents described capability gaps including lacking skills for preferred activities. School physical education and parks provided opportunities for adolescents to be physically active. Adolescents also described opportunity challenges, including age limits, not being able to afford preferred classes, and safety concerns. Families provided role modeling but rarely engaged in activities with adolescents. Adolescents were motivated to engage in physical activity but often lacked the necessary resources.

Conclusions: Interventions to increase physical activity among urban Latino adolescents should offer tailored programming, incorporate families, enhance physical education, and improve the safety and appeal of recreational facilities.
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http://dx.doi.org/10.1177/1540415320956933DOI Listing
September 2020

LFA-1 signals to promote actin polymerization and upstream migration in T cells.

J Cell Sci 2020 09 9;133(17). Epub 2020 Sep 9.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA

T cell entry into inflamed tissue requires firm adhesion, cell spreading, and migration along and through the endothelial wall. These events require the T cell integrins LFA-1 and VLA-4 and their endothelial ligands ICAM-1 and VCAM-1, respectively. T cells migrate against the direction of shear flow on ICAM-1 and with the direction of shear flow on VCAM-1, suggesting that these two ligands trigger distinct cellular responses. However, the contribution of specific signaling events downstream of LFA-1 and VLA-4 has not been explored. Using primary mouse T cells, we found that engagement of LFA-1, but not VLA-4, induces cell shape changes associated with rapid 2D migration. Moreover, LFA-1 ligation results in activation of the phosphoinositide 3-kinase (PI3K) and ERK pathways, and phosphorylation of multiple kinases and adaptor proteins, whereas VLA-4 ligation triggers only a subset of these signaling events. Importantly, T cells lacking Crk adaptor proteins, key LFA-1 signaling intermediates, or the ubiquitin ligase cCbl (also known as CBL), failed to migrate against the direction of shear flow on ICAM-1. These studies identify novel signaling differences downstream of LFA-1 and VLA-4 that drive T cell migratory behavior.This article has an associated First Person interview with the first author of the paper.
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http://dx.doi.org/10.1242/jcs.248328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502589PMC
September 2020

Intervention Enhancement Strategies Among Adults With Type 2 Diabetes in a Very Low-Carbohydrate Web-Based Program: Evaluating the Impact With a Randomized Trial.

JMIR Diabetes 2020 Sep 9;5(3):e15835. Epub 2020 Sep 9.

Osher Center for Integrative Medicine, University of California San Francisco, San Francisco, CA, United States.

Background: Adults with type 2 diabetes may experience health benefits, including glycemic control and weight loss, from following a very low-carbohydrate, ketogenic (VLC) diet. However, it is unclear which ancillary strategies may enhance these effects.

Objective: This pilot study aims to estimate the effect sizes of 3 intervention enhancement strategies (text messages, gifts, and breath vs urine ketone self-monitoring) that may improve outcomes of a 12-month web-based ad libitum VLC diet and lifestyle intervention for adults with type 2 diabetes. The primary intervention also included other components to improve adherence and well-being, including positive affect and mindfulness as well as coaching.

Methods: Overweight or obese adults (n=44; BMI 25-45 kg/m) with type 2 diabetes (glycated hemoglobin [HbA] ≥6.5%), who had been prescribed either no glucose-lowering medications or metformin alone, participated in a 12-month web-based intervention. Using a 2×2×2 randomized factorial design, we compared 3 enhancement strategies: (1) near-daily text messages about the intervention's recommended behaviors (texts n=22 vs no texts n=22), (2) mailed gifts of diet-relevant foods and cookbooks (6 rounds of mailed gifts n=21 vs no gifts n=23), and (3) urine- or breath-based ketone self-monitoring (urine n=21 vs breath n=23). We assessed HbA and weight at baseline and at 4, 8, and 12 months. We evaluated whether each strategy exerted a differential impact on HbA and weight at 12 months against an a priori threshold of Cohen d of 0.5 or greater.

Results: We retained 73% (32/44) of the participants at 12 months. The intervention, across all conditions, led to improvements in glucose control and reductions in body weight at the 12-month follow-up. In intent-to-treat (ITT) analyses, the mean HbA reduction was 1.0% (SD 1.6) and the mean weight reduction was 5.3% (SD 6.0), whereas among study completers, these reductions were 1.2% (SD 1.7) and 6.3% (SD 6.4), respectively, all with a P value of less than .001. In ITT analyses, no enhancement strategy met the effect size threshold. Considering only study completers, 2 strategies showed a differential effect size of at least a d value of 0.5 or greater.

Conclusions: Text messages, gifts of food and cookbooks, and urine-based ketone self-monitoring may potentially enhance the glycemic or weight loss benefits of a web-based VLC diet and lifestyle intervention for individuals with type 2 diabetes. Future research could investigate other enhancement strategies to help create even more effective solutions for the treatment of type 2 diabetes.

Trial Registration: ClinicalTrials.gov NCT02676648; http://clinicaltrials.gov/ct2/show/NCT02676648.
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http://dx.doi.org/10.2196/15835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511867PMC
September 2020

Building Optimal Three-Drug Combination Chemotherapy Regimens.

Antimicrob Agents Chemother 2020 10 20;64(11). Epub 2020 Oct 20.

Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA.

Multidrug therapy is often required. Examples include antiviral therapy, nosocomial infections, and, most commonly, anti- therapy. Our laboratory previously identified a mathematical approach to identify 2-drug regimens with a synergistic or additive interaction using a full factorial study design. Our objective here was to generate a method to identify an optimal 3-drug therapy. We studied isolate H37Rv in log-phase growth in flasks. Pretomanid and moxifloxacin were chosen as the base 2-drug regimen. Bedaquiline (plus M2 metabolite) was chosen as the third drug for evaluation. Total bacterial burden and bacterial burden less-susceptible to study drugs were enumerated. A large mathematical model was fit to all the data. This allowed extension to evaluation of the 3-drug regimen by employing a Monte Carlo simulation. Pretomanid plus moxifloxacin demonstrated excellent bacterial kill and suppressed amplification of less-susceptible pathogens. Total bacterial burden was driven to extinction in 3 weeks in 6 of 9 combination therapy evaluations. Only the lowest pretomanid/moxifloxacin exposures in combination did not extinguish the bacterial burden. No combination regimen allowed resistance amplification. Generation of 95% credible intervals about estimates of the interaction parameters α (α, α, and α) by bootstrapping showed the interaction was near synergistic. The addition of bedaquiline/M2 metabolite was evaluated by forming a 95% confidence interval regarding the decline in bacterial burden. The addition of bedaquiline/M2 metabolite shortened the time to eradication by 1 week and was significantly different. A model-based system approach to evaluating combinations of 3 agents shows promise to rapidly identify the most promising combinations that can then be trialed.
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http://dx.doi.org/10.1128/AAC.01610-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577121PMC
October 2020

Dihydrotestosterone (DHT) Enhances Wound Healing of Major Burn Injury by Accelerating Resolution of Inflammation in Mice.

Int J Mol Sci 2020 Aug 28;21(17). Epub 2020 Aug 28.

Burns Research and Reconstructive Surgery, ANZAC Research Institute, University of Sydney, Sydney 2139, Australia.

Androgens have been known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. The aim of this study is to investigate the role of dihydrotestosterone (DHT) as a new therapeutic approach in treating major burn injury. In the present study, mice received systemic androgen treatment post major burn injury. Wound healing rate and body weight were monitored over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry. Healing phases of inflammation, re-epithelialization, cell proliferation and collagen deposition were also examined. In results, DHT treated mice lost less weight and displayed accelerated wound healing but has no impact on hypermetabolism. Mice, after burn injury, displayed acute systemic inflammatory responses over 21 days. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocyte numbers on day 14 and 21. DHT treatment also reduced wound infiltrating macrophage numbers. In conclusion, DHT treatment facilitates local wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response.
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http://dx.doi.org/10.3390/ijms21176231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504698PMC
August 2020

Signal amplification by reversible exchange for COVID-19 antiviral drug candidates.

Sci Rep 2020 08 31;10(1):14290. Epub 2020 Aug 31.

Department of Chemistry, Korea Military Academy, Seoul, 01805, South Korea.

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.
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http://dx.doi.org/10.1038/s41598-020-71282-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459298PMC
August 2020

Modified Hyper-CVAD With Proteasome Inhibition for Multiple Myeloma: A Single-Center Retrospective Analysis.

Clin Lymphoma Myeloma Leuk 2020 Dec 29;20(12):e961-e985. Epub 2020 Jul 29.

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA. Electronic address:

Background: Although novel agents have changed the treatment landscape of multiple myeloma (MM), cytotoxic chemotherapy regimens continue to have a role in aggressive or rapidly progressive disease. In such cases, our institution has utilized a hyperfractionated cyclophosphamide regimen (termed mCAD), similar to hyper-CVAD, in which vincristine is omitted or replaced with a proteasome inhibitor (PI), either bortezomib or carfilzomib. On occasion, doxorubicin is also omitted because of patient history and provider preference.

Patients And Methods: We retrospectively reviewed the charts of adult patients with MM receiving mCAD regimens at our institution between 2012 and 2016 and analyzed utilization patterns, toxicity profiles, and clinical outcomes.

Results: A total of 131 patients received mCAD, including 9% for newly diagnosed MM (NDMM), 18% attempting to optimize response to frontline therapy (OPT-MM), and 73% for treatment of relapsed/refractory MM (RRMM). Renal dysfunction was common; 31% had estimated glomerular filtration rate < 50 mL/min and 14% were dialysis dependent. The overall response rate was 83%, 63%, and 67% with a median progression-free survival of 17.4, 23.7, and 4.2 months, respectively, for NDMM, OPT-MM, and RRMM. Median overall survival was not reached for NDMM or OPT-MM, and was 15.2 months for RRMM. Most patients (90%) bridged to subsequent therapy, including 32% who proceeded to autologous transplantation. Hematologic, infectious, and cardiac toxicities were common and were similar to those expected for cytotoxic chemotherapy.

Conclusion: mCAD regimens were safe and active across patient groups, including patients with renal dysfunction. Most patients were able to bridge to subsequent therapy.
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http://dx.doi.org/10.1016/j.clml.2020.07.015DOI Listing
December 2020

Using Physiologically Based Pharmacokinetic Modeling to Assess the Risks of Failing Bioequivalence Criteria: a Tale of Two Ibuprofen Products.

AAPS J 2020 08 23;22(5):113. Epub 2020 Aug 23.

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy,, University of Florida, 6550 Sanger Road, Office 146, Orlando, Florida, 32827, USA.

The aims of the proposed study were to develop and verify a quantitative model-based framework to anticipate the in vivo bioequivalence of ibuprofen immediate release formulations. This stepwise approach integrated virtual bioequivalence trials to simulate the test to reference (T/R) ratio for positive (i.e., bioequivalent) and negative (i.e., non-bioequivalent) control formulations containing ibuprofen, approximated distribution of interoccasion variability (IOV) on ibuprofen peak (C) and extent of exposure (AUC) by bootstrapping resampling methods, post hoc incorporation of IOV to simulated T/R ratios, and power curve analysis. After post hoc incorporation of the bootstrapped IOV to the simulated C T/R geometric mean ratios, the resulting 90% confidence intervals overlapped with the in vivo observations for both pairwise comparisons. On the other hand, simulated and observed AUC TNBE/R geometric mean ratios differed, likely due to the lack of propagating clearance-related IOV to the simulations. This approach is in line with modern regulatory initiatives that advocate leveraging quantitative methods and modeling to modernize generic drug development and review. Graphical abstract.
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http://dx.doi.org/10.1208/s12248-020-00495-4DOI Listing
August 2020

Discriminating between sleep and exercise-induced fatigue using computer vision and behavioral genetics.

J Neurogenet 2020 Sep-Dec;34(3-4):453-465. Epub 2020 Aug 19.

Carney Institute for Brain Science, Brown University, Providence, RI, USA.

Following prolonged swimming, cycle between active swimming bouts and inactive quiescent bouts. Swimming is exercise for and here we suggest that inactive bouts are a recovery state akin to fatigue. It is known that cGMP-dependent kinase (PKG) activity plays a conserved role in sleep, rest, and arousal. Using EGL-4 PKG, we first validate a novel learning-based computer vision approach to automatically analyze locomotory behavior and an edge detection program that is able to distinguish between activity and inactivity during swimming for long periods of time. We find that EGL-4 PKG function impacts timing of exercise-induced quiescent (EIQ) bout onset, fractional quiescence, bout number, and bout duration, suggesting that previously described pathways are engaged during EIQ bouts. However, EIQ bouts are likely not sleep as animals are feeding during the majority of EIQ bouts. We find that genetic perturbation of neurons required for other sleep states also does not alter EIQ dynamics. Additionally, we find that EIQ onset is sensitive to age and DAF-16 FOXO function. In summary, we have validated behavioral analysis software that enables a quantitative and detailed assessment of swimming behavior, including EIQ. We found novel EIQ defects in aged animals and animals with mutations in a gene involved in stress tolerance. We anticipate that further use of this software will facilitate the analysis of genes and pathways critical for fatigue and other behaviors.
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http://dx.doi.org/10.1080/01677063.2020.1804565DOI Listing
August 2020