Publications by authors named "Christine Chen"

227 Publications

Fixed duration prolonged duration treatment after first line therapy in patients with systemic light chain amyloidosis.

Amyloid 2021 Sep 14:1-8. Epub 2021 Sep 14.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.

Background: The main objective of treatment in systemic light chain amyloidosis (AL amyloidosis) is to achieve the best hematological response. Deeper responses are associated with better organ responses and survival. In this study, we analysed the efficacy of prolonged duration treatment after first line in patients with AL amyloidosis.

Methods: Retrospective analysis that included patients older than 18 years with AL amyloidosis. We excluded patients with more than 30% marrow plasmacytosis or concurrent multiple myeloma. Two cohorts identified accordingly if they received or not prolonged treatment after the first line. Survival analysis regarding progression free survival (PFS) and overall survival (OS) estimated with Kaplan-Meier and comparisons between groups with log-rank.

Results: Thirty-eight patients were included in the analysis with a median age of 55 years. Twenty-one patients received prolonged duration treatment and 17 did not. In the prolonged duration group, after a median duration of 12 months, the median PFS was 58.8 months. In the fixed duration treatment group, PFS was 30.6 months. The difference was significant with  = .0045 favouring prolonged duration treatment. Organ response was sustained for a longer period in the prolonged duration treatment group. For OS, the difference was not significant.

Conclusions: Prolonged duration treatment in patients with systemic light chain amyloidosis correlated with better PFS and deeper organ responses. Prospective studies are needed to analyse this further.
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http://dx.doi.org/10.1080/13506129.2021.1978423DOI Listing
September 2021

Altered cortical activation associated with mirror overflow driven by non-dominant hand movement in attention-deficit/hyperactivity disorder.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Aug 27;112:110433. Epub 2021 Aug 27.

Kennedy Krieger Institute, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Mirror overflow is involuntary movement that accompanies unilateral voluntary movement on the opposite side of the body, and is commonly seen in Attention-Deficit/Hyperactivity Disorder (ADHD). Children with ADHD show asymmetry in mirror overflow between dominant and non-dominant hand, yet there are competing mechanistic accounts of why this occurs. Using EEG during a sequential, unimanual finger-tapping task, we found that children with ADHD exhibited significantly more mirror overflow than typically developing (TD) controls, especially during the tapping of the non-dominant hand. Furthermore, source-level EEG oscillation analysis revealed that children with ADHD showed decreased alpha (8-12 Hz) event-related desynchronization (ERD) compared with controls in both hemispheres, but only during tapping of the non-dominant hand. Moreover, only the ERD ipsilateral to the mirror overflow during non-dominant hand movement correlated with both magnitude of overflow movements and higher ADHD symptom severity (Conners ADHD Hyperactivity/Impulsiveness scale) in children with ADHD. TD controls did not show these relationships. Our findings suggest that EEG differences in finger-tapping in ADHD are related primarily to voluntary movement in the non-dominant hand. Our results are also consistent with the Ipsilateral Corticospinal Tract (CST) Hypothesis, which posits that the atypical persistence of mirror overflow in ADHD may originate in the sensorimotor areas ipsilateral to mirror overflow and be transmitted via non-decussating CST fibers.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110433DOI Listing
August 2021

Light Chain Amyloidosis (AL) Associated With B Cell Lymphoma a Single Center Experience.

Clin Lymphoma Myeloma Leuk 2021 Jul 19. Epub 2021 Jul 19.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Ontario, Canada.

Introduction: Light chain (AL) amyloidosis and B-cell lymphoma represent 5% to 7% of all AL, Systemic amyloidosis, deposits in sites remote from the underlying lymphoma, and peritumoral amyloidosis deposition is within the immediate vicinity.

Materials And Methods: We conducted a retrospectively study to identify and describe AL with B cell lymphoma at Princess Margaret Cancer Center from 01 January 1997 to 31 July 2019.

Results: Thirty-five patients with AL and lymphoma, an incidence of 6, 2%, median age of diagnosis of 66 (range 47 to 86), majority male, most had underlying Waldestrom's Macroglobulinemia. 21 patients with peritumoral AL (PAL), and 15 with systemic AL. 42.8% of the patients had major organ involvement. 35% got treatment with Rituximab with alkylator, 20% received proteasome inhibitors, 17% patients were on a watch and wait approach, amyloid response showed very good partial response > 45.8%, and lymphoma ORR was 42.8%, with a median follow up of 31.5 months. A 36 month overall survival (OS) and progression-free survival (PFS) showed worse outcomes for heart involvement OS (P = .002), PFS (0.057) and IgM subtype OS (P = .02), PFS (0.01).

Conclusion: We have shown adverse outcome with IgM AL and to document a differences in OS and PFS not previously reported for PAL.
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http://dx.doi.org/10.1016/j.clml.2021.07.003DOI Listing
July 2021

Combat and Operational Stress Control Interventions and PTSD: A Systematic Review and Meta-Analysis.

Mil Med 2021 Jul 28. Epub 2021 Jul 28.

The Gehr Family Center for Health Systems Science and Innovation, Keck School of Medicine, RAND Corporation, Santa Monica, CA 90407, USA.

Introduction: Military personnel must prepare for and respond to life-threatening crises on a daily basis. This lifestyle places stress on personnel, and particularly so on deployed service members who are isolated from support systems and other resources. As part of a larger systematic review on the acceptability, efficacy, and comparative effectiveness of interventions designed to prevent, identify, and manage stress reactions, we assessed posttraumatic stress disorder (PTSD) outcomes.

Materials And Methods: We searched the electronic databases PsycINFO, PubMed, PTSDPubs, the Defense Technical Information Center, and Cochrane Central, as well as bibliographies of existing systematic reviews, to identify English-language studies evaluating the efficacy or comparative effectiveness of stress control interventions published since 1990. Controlled trials and cohort comparisons of interventions with military, law enforcement, and first responders were included. Two independent reviewers screened literature using predetermined eligibility criteria. Researchers individually abstracted study-level information and outcome data and assessed the risk of bias of included studies; data were reviewed for accuracy by the project leader. Changes in PTSD symptom scores from baseline to post-intervention were converted to standardized mean differences for comparison across studies. Risk ratios were calculated for PTSD case rates post-deployment. When several studies that compared an intervention group with a similar control/comparator reported the same outcome category and measure type, we conducted meta-analysis. We conducted meta-regression by adding a categorical variable, representing setting (i.e., in theater) or population (military vs. law enforcement or first responders) to the meta-analysis model to assess whether this variable was associated with the outcome across studies. The quality of the body of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, which considers study limitations (risk of bias), directness, consistency, precision, and publication bias.

Results: Sixteen controlled trials and 13 cohort comparisons reporting PTSD outcomes met inclusion criteria. Eight controlled trials and two cohort studies had high risk of bias, primarily due to poor, differential, or unknown response rate at follow-up. Twenty-four of the 29 studies included military personnel. Interventions included Acceptance-based Skills training, Attention Bias Modification training, stress inoculation with biofeedback, Critical Incident Stress Debriefing, group psychological debriefing, Eye Movement Desensitization and Reprocessing for sub-clinical stress, embedding mental health providers in theater, Third Location Decompression, reintegration programs, and a 3-week post-deployment residential program for psychological resource strengthening.Meta-analyses of studies comparing a group that received a stress control intervention to a group that did not receive an intervention found no significant difference in reduction in PTSD symptom scores (moderate QoE) or PTSD case rate post-deployment (low QoE). A meta-analysis of studies comparing a specific stress control intervention to an active comparator (usually standard stress management education) found no significant effect on PTSD symptom scores (moderate QoE).

Conclusion: Although combat and operational stress control (COSC) interventions may play a valuable role in decreasing stress, decreasing absenteeism, and enabling return to duty, a systematic review of 29 studies that included a control/comparison group found little evidence that COSC is effective in preventing PTSD or decreasing PTSD symptom scores in military personnel.
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http://dx.doi.org/10.1093/milmed/usab310DOI Listing
July 2021

Evaluation of the LI-RADS treatment response algorithm in hepatocellular carcinoma after trans-arterial chemoembolization.

Clin Imaging 2021 Jun 24;80:117-122. Epub 2021 Jun 24.

Weill Cornell Medical College, Division of Liver Transplantation and Hepatobiliary Surgery, United States of America.

Purpose: To evaluate the diagnostic performance of LI-RADS treatment response algorithm (LR-TRA) and modified RECIST (mRECIST) for the detection of viable hepatocellular carcinoma (HCC) on MRI after trans-arterial chemoembolization (TACE).

Materials And Methods: This retrospective study includes cirrhotic patients that underwent trans-arterial chemoembolization prior to liver transplantation from 2013 to 2017 with a pre- and post-treatment MRI available. Three blinded readers assigned a LR-TRA and mRECIST category to each lesion. Lesions on MRI and explant pathology were matched and characterized as complete (100% necrosis) or incomplete necrosis (≤99% necrosis). Diagnostic performance of LR-TRA and mRECIST were calculated with a generalized estimating equation.

Results: A total of 52 patients with 71 lesions were included, 47 with incomplete and 24 with complete necrosis. In consensus, 45 lesions were categorized as LR-TR Nonviable, of which 62.2% (28/45) had incomplete and 37.8% (17/45) had complete necrosis. Six lesions were categorized as LR-TR Equivocal, of which 33.3% (2/6) had incomplete and 66.7% (4/6) had complete necrosis. Twenty lesions were categorized as LR-TR Viable of which 85.0% (17/20) had incomplete and 15.0% (3/20) had complete necrosis. The sensitivity of LR-TR Viable for detecting incompletely necrotic tumor when LR-TR Equivocal was considered as viable, in consensus was 40.4%; specificity 70.8%; accuracy 50.7%. The sensitivity of mRECIST for detecting incompletely necrotic tumor was 37.0%; specificity 79.2%; accuracy 51.4%. There was no significant difference in diagnostic performance between mRECIST and LR-TRA (p = 0.14-0.33). Agreement for LR-TRA category was moderate (k = 0.53 [95% CI: 0.45, 0.67]).

Conclusion: LI-RADS treatment response algorithm demonstrates high specificity and low to moderate sensitivity for the detection of viable HCC after TACE in a North American cirrhotic cohort, without significant difference in diagnostic performance between LR-TRA and mRECIST.
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http://dx.doi.org/10.1016/j.clinimag.2021.06.009DOI Listing
June 2021

Prostate heterogeneity correlates with clinical features on multiparametric MRI.

Abdom Radiol (NY) 2021 Jul 22. Epub 2021 Jul 22.

Department of Radiology, Weill Cornell Medicine, 525 East 68th Street, New York, NY, 10065, USA.

Background: Prostate heterogeneity on multi-parametric MRI (mpMRI) may confound image interpretation by obscuring lesions; systematic biopsy may have a role in this context.

Purpose: To determine if prostate heterogeneity (1) correlates with clinical risk factors for prostate cancer and (2) associates with higher-grade tumor in systematic biopsy (SB), compared with MRI-directed target biopsy (MDTB), i.e., SB > MDTB, thus providing a rationale for combined biopsy.

Methods: IRB-approved retrospective study included men who underwent mpMRI, SB, and MDTB between 2015 and 2017. Regions of interest were applied to the entire transition zone (TZ) and peripheral zone (PZ) on T2-weighted imaging (T2WI), apparent diffusion coefficient maps (ADC), and early dynamic contrast-enhanced (DCE) images on the midgland slice. Mean signal intensities and standard deviation (SD) of each zone were calculated. SD served as a measure of heterogeneity. Spearman's rank correlation analysis of clinical and imaging variables was performed. Univariate logistic regression was used to determine if any imaging variable associated with SB > MDTB.

Results: 93 patients were included. Significant correlations included age and TZ ADC heterogeneity (rho = 0.34, p = 0.013), PSA density, and mean TZ ADC (rho = - 0.29, p = 0.049). PZ T2WI heterogeneity correlated with PZ ADC heterogeneity (rho = 0.48, p < 0.001). PZ DCE heterogeneity correlated with TZ DCE heterogeneity (rho = 0.46, p < 0.001). TZ ADC heterogeneity was associated with SB > MDTB prior to multiple comparison correction (p = 0.032). p value after correction was 0.24.

Conclusion: TZ ADC heterogeneity correlated with age and may reflect prostatic hyperplasia and/or prostate cancer. PZ heterogeneity, possibly a measure of prostatitis, correlated with TZ hyperplasia and/or inflammation. TZ ADC heterogeneity was associated with SB > MDTB with p value of < 0.05 prior to multiple correction; future investigation is needed to further elucidate significance of ADC heterogeneity in prostate imaging.
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http://dx.doi.org/10.1007/s00261-021-03221-6DOI Listing
July 2021

Radiation Therapy for Brain Metastases: A Systematic Review.

Pract Radiat Oncol 2021 Sep-Oct;11(5):354-365. Epub 2021 Jun 9.

Southern California Evidence-Based Practice Center, RAND Corporation, Santa Monica, California; Southern California Evidence Review Center, Keck School of Medicine, University of Southern California, Los Angeles, California.

Purpose: This evidence report synthesizes the available evidence on radiation therapy for brain metastases.

Methods And Materials: The literature search included PubMed, EMBASE, Web of Science, Scopus, CINAHL, clinicaltrials.gov, and published guidelines in July 2020; independently submitted data, expert consultation, and contacting authors. Included studies were randomized controlled trials (RCTs) and large observational studies (for safety assessments), evaluating whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) alone or in combination, as initial or postoperative treatment, with or without systemic therapy for adults with brain metastases due to lung cancer, breast cancer, or melanoma.

Results: Ninety-seven studies reported in 189 publications were identified, but the number of analyses was limited owing to different intervention and comparator combinations as well as insufficient reporting of outcome data. Risk of bias varied, and 25 trials were terminated early, predominantly owing to poor accrual. The combination of SRS plus WBRT compared with SRS alone or WBRT alone showed no statistically significant difference in overall survival (hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.69%-1.73%; 4 RCTs) or death owing to brain metastases (relative risk [RR], 0.93; 95% CI, 0.48%-1.81%; 3 RCTs). Radiation therapy after surgery did not improve overall survival compared with surgery alone (HR, 0.98; 95% CI, 0.76%-1.26%; 5 RCTs). Data for quality of life, functional status, and cognitive effects were insufficient to determine effects of WBRT, SRS, or postsurgery interventions. We did not find systematic differences across interventions in serious adverse events, number of adverse events, radiation necrosis, fatigue, or seizures. WBRT plus systemic therapy (RR 1.44; 95% CI, 1.03%-2.00%; 14 studies) was associated with increased risks for vomiting compared with WBRT alone.

Conclusions: Despite the substantial research literature on radiation therapy, comparative effectiveness information is limited. There is a need for more data on patient-relevant outcomes such as quality of life, functional status, and cognitive effects.
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http://dx.doi.org/10.1016/j.prro.2021.04.002DOI Listing
June 2021

Athlete Enjoyment of Prior Education Moderates change in Concussion-Reporting Intention after Interactive Education.

Inquiry 2021 Jan-Dec;58:469580211022641

Stanford School of Medicine, Palo Alto, CA, USA.

Undiagnosed concussions increase risk of additional injuries and can prolong recovery. Because of the difficulties recognizing concussive symptoms, concussion education must specifically target improving athlete concussion reporting. Many concussion education programs are designed without significant input from athletes, resulting in a less enjoyable athlete experience, with potential implications on program efficacy. Athlete enjoyment of previous concussion education programs moderates the improvement in concussion-reporting intention after experiencing the research version of CrashCourse (CC) concussion education. Prospective cohort study. Level of evidence: Level IV. Quantitative assessment utilizing ANOVA with moderation analysis of 173 male high school football players, aged 13 to 17, who completed baseline assessments of concussion knowledge, concussion reporting, and attitudes about prior educational interventions. Athletes were subsequently shown CC, before a follow-up assessment was administered assessing the same domains. At baseline, only 58.5% of athletes reported that they enjoyed their previous concussion education. After CC, athletes were significantly more likely to endorse that they would report a suspected concussion (from 69.3% of athletes to 85.6%;  < .01). Enjoyment of previous concussion education moderated concussion-reporting intention after CC ( = .02), with CC having a greater effect on concussion-reporting intention in athletes with low enjoyment of previous concussion education ( = 0.21,  = .02), than on individuals with high enjoyment of previous concussion education ( = .99). Enjoyment of CC did not have a moderating effect on concussion-reporting intention. Athletes who previously did not enjoy concussion education exhibited greater gains in concussion-reporting intention than athletes who enjoyed previous education. Given the potential risks associated with undiagnosed concussions, concussion education has sought to improve concussion reporting. Because most athletes participate in concussion education programs due to league or state mandates, improving concussion-reporting intention in these low-enjoyment athletes is of particular relevance to improving concussion-reporting intention broadly.
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http://dx.doi.org/10.1177/00469580211022641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170270PMC
May 2021

A retrospective review of specialist referrals for refugees into Greece's health system: A humanitarian organization's perspective.

Avicenna J Med 2021 Apr-Jun;11(2):84-92. Epub 2021 Apr 19.

Syrian American Medical Society, Washington, DC, USA.

Aim: Refugee arrivals to Europe have numbered more than one million since 2015 with the majority arriving through Greece. The healthcare needs of refugees have placed strains on Greece's healthcare system which has already been affected by its ongoing economic crisis. At the peak of arrivals during 2016, primary healthcare was primarily provided by humanitarian organizations with specialist referrals into the Greek healthcare system. There is little published literature on the type and impacts of specialist referrals for refugees in Greece. The aim of this retrospective review is to identify the type and impacts of specialist referrals for refugees into Greece's health system.

Methods: This retrospective study reviewed the number and type of specialty referrals from one humanitarian organization providing primary healthcare for refugees in Greece. All consultations during an 8-month period (December 1, 2016-July 31, 2017) were reviewed.

Results: Of 4168 consultations, 42% were patients aged 17 years or younger, 52% were male, and 90% were Syrian. Two hundred and thirty-three patients (11%) required a specialist referral; 25% were for dental (provided by another humanitarian organization), 10% each for obstetrics and gynecology and pediatrics, and 8% for ophthalmology. Respiratory complaints were most frequently seen, and these were more predominant in the winter months. Pediatric consultations varied according to month, likely due to population movements.

Conclusion: Dentistry was noted to be a gap in humanitarian response programming and accounted for the greatest need for specialist input with referrals for women and children accounting for a large proportion of referrals.
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http://dx.doi.org/10.4103/ajm.ajm_136_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101647PMC
April 2021

Magnetic Resonance Imaging Radiomics-Based Machine Learning Prediction of Clinically Significant Prostate Cancer in Equivocal PI-RADS 3 Lesions.

J Magn Reson Imaging 2021 May 10. Epub 2021 May 10.

Department of Urology, Weill Cornell Medicine, New York, New York, USA.

Background: While Prostate Imaging Reporting and Data System (PI-RADS) 4 and 5 lesions typically warrant prostate biopsy and PI-RADS 1 and 2 lesions may be safely observed, PI-RADS 3 lesions are equivocal.

Purpose: To construct and cross-validate a machine learning model based on radiomics features from T -weighted imaging (T WI) of PI-RADS 3 lesions to identify clinically significant prostate cancer (csPCa), that is, pathological Grade Group ≥ 2.

Study Type: Single-center retrospective study.

Population: A total of 240 patients were included (training cohort, n = 188, age range 43-82 years; test cohort, n = 52, age range 41-79 years). Eligibility criteria were 1) magnetic resonance imaging (MRI)-targeted biopsy between 2015 and 2020; 2) PI-RADS 3 index lesion identified on multiparametric MRI; (3) biopsy performed within 1 year of MRI. The percentages of csPCa lesions were 10.6% and 15.4% in the training and test cohorts, respectively.

Field Strength/sequence: A 3 T; T WI turbo-spin echo, diffusion-weighted spin-echo echo planar imaging, dynamic contrast-enhanced MRI with time-resolved T1-weighted imaging.

Assessment: Multislice volumes-of-interest (VOIs) were drawn in the PI-RADS 3 index lesions on T WI. A total of 107 radiomics features (first-order histogram and second-order texture) were extracted from the segmented lesions.

Statistical Tests: A random forest classifier using the radiomics features as input was trained and validated for prediction of csPCa. The performance of the machine learning classifier, prostate specific antigen (PSA) density, and prostate volume for csPCa prediction was evaluated using receiver operating characteristic (ROC) analysis.

Results: The trained random forest classifier constructed from the T WI radiomics features good and statistically significant area-under-the-curves (AUCs) of 0.76 (P = 0.022) for prediction of csPCa in the test set. Prostate volume and PSA density showed moderate and nonsignificant performance (AUC 0.62, P = 0.275 and 0.61, P = 0.348, respectively) for csPCa prediction in the test set.

Conclusion: The machine learning classifier based on T WI radiomic features demonstrated good performance for prediction of csPCa in PI-RADS 3 lesions.

Evidence Level: 4 TECHNICAL EFFICACY: 2.
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http://dx.doi.org/10.1002/jmri.27692DOI Listing
May 2021

Altering the intra-liver distribution of phospholipid-free small unilamellar vesicles using temperature-dependent size-tunability.

J Control Release 2021 05 23;333:151-161. Epub 2021 Mar 23.

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, BC, Canada. Electronic address:

We demonstrated that phospholipid-free small unilamellar vesicles (PFSUVs) composed of TWEEN 80 and cholesterol (25/75, mol%) could be fabricated using a staggered herringbone micromixer with precise controlling of their mean size between 54 nm and 147 nm. Increasing the temperature or decreasing the flow rate led to an increase in the resulting particle diameter. In zebrafish embryos, 120-nm PFSUVs showed 3-fold higher macrophage clearance compared to the 60-nm particles, which exhibited prolonged blood circulation. In mice, the 60-nm particles showed dominant accumulation in the liver hepatocytes (66% hepatocytes positive), while the 120-nm particles were delivered equally to the liver and spleen macrophages. Accordingly, in a murine model of acetaminophen-induced hepatotoxicity the 60-nm particles loaded with chlorpromazine reduced the serum alanine aminotransferase level and liver necrosis 2- to 4-fold more efficiently than their 120-nm counterparts and the free drug, respectively. This work showed that the intra-liver distribution of PFSUVs was largely determined by the size. Most other nanoparticles published to date are predominantly cleared by the liver Kupffer cells. The 60-nm PFSUVs, on the other hand, focused the delivery to the hepatocytes with significant advantages for the therapy of liver diseases.
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http://dx.doi.org/10.1016/j.jconrel.2021.03.025DOI Listing
May 2021

Evaluation of 3--methyldopa as a biomarker for aromatic L-amino acid decarboxylase deficiency in 7 Brazilian cases.

Mol Genet Metab Rep 2021 Jun 13;27:100744. Epub 2021 Mar 13.

PPGBM, UFRGS, Porto Alegre, Brazil.

Aromatic L-amino acid decarboxylase (AADCD) deficiency is an autosomal recessive neurometabolic disorder, caused by biallelic mutations in the gene, that impairs the synthesis or metabolism of neurotransmitters leading to severe motor dysfunction. The main clinical signs are oculogyric crisis, hypotonia, hypokinesia, and dystonia. The biochemical diagnosis can be performed in cerebrospinal fluid by neurotransmitter analysis, which requires an invasive lumbar puncture, and the sample needs to be shipped frozen to a reference laboratory, usually across a country border. Measurement of AADC activity in plasma is also possible, but available in a few labs globally. 3--methyldopa (3-OMD) is a catabolic product of L-dopa and it is elevated in patients with AADC deficiency. The quantification of 3-OMD can be performed in dried blood spots (DBS), a sample that could be shipped at room temperature. 3-OMD levels of AADCD patients and controls were quantified in DBS by liquid chromatography tandem mass spectrometry. DBS samples from 7 Brazilian patients previously diagnosed with AADCD were used to validate the 3-OMD quantification as a screening procedure for this condition. All AADCD patients had at least a four-fold increase of 3-OMD. Thus, 3-OMD seems to be a reliable marker for AADCD, with potential use also in the newborn screening of this disease.
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http://dx.doi.org/10.1016/j.ymgmr.2021.100744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973244PMC
June 2021

How to Build an Antiracist Cardiovascular Culture, Community, and Profession.

J Am Coll Cardiol 2021 Mar;77(9):1257-1261

Department of Internal Medicine, Reno School of Medicine, University of Nevada, Reno, Nevada, USA. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2020.11.073DOI Listing
March 2021

Weekly carfilzomib plus cyclophosphamide and dexamethasone in the treatment of relapsed/refractory multiple myeloma: Final results from the MCRN-003/MYX.1 single arm phase II trial.

Am J Hematol 2021 05;96(5):552-560

Queen's University, Canadian Cancer Trials Group, Kingston, Ontario, Canada.

The MCRN-003/CCTGMYX.1 is a single arm phase II trial of weekly carfilzomib, cyclophosphamide and dexamethasone (wKCd), exploring a convenient immunomodulator (IMiD)-free regimen in relapsed myeloma. Weekly carfilzomib (20/70 mg/m ), dexamethasone 40 mg and cyclophosphamide 300 mg/m was delivered over 28-day cycles. The primary endpoint was overall response after four cycles. Secondary endpoints included toxicity, response depth, PFS and OS. Exploratory endpoints included the impact of cytogenetics, prior therapy exposure and serum free light chain (sFLC) escape; 76 patients were accrued. The ORR was 85% (68% ≥very good partial response [VGPR] and 29% ≥complete response [CR]). The median OS and PFS were 27 and 17 months respectively. High-risk cytogenetics conferred a worse ORR (75% vs. 97%, p = .013) and median OS (18 months vs. NR, p = .002) with a trend toward a worse median PFS (14 vs. 22 months, p = .06). Prior proteasome inhibitor (PI) or lenalidomide did not influence OS or PFS. The sFLC was noted in 15% of patients with a median PFS of 17 months when included as a progression event. The most common ≥ grade 3 non-hematologic adverse events were infectious (40%), vascular (17%) and cardiac (15%). The wKCD is a safe and effective regimen in relapse, especially for patients ineligible for lenalidomide-based therapies.
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http://dx.doi.org/10.1002/ajh.26147DOI Listing
May 2021

Symptomatic BK Virus Disease in Patients With Heavily Pretreated Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Jun 14;21(6):e506-e509. Epub 2021 Jan 14.

Princess Margaret Cancer Centre, Toronto, Canada.

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http://dx.doi.org/10.1016/j.clml.2021.01.009DOI Listing
June 2021

Paraneoplastic limbic encephalitis as initial presentation of testicular neoplasm: A case report.

Clin Imaging 2021 Aug 3;76:61-64. Epub 2021 Feb 3.

Weill Cornell Medicine, Department of Radiology, 525 East 68(th) Street, New York, NY 10065, United States of America.

Paraneoplastic limbic encephalitis (PLE) is an immunopathologic syndrome associated with malignancy and represents a rare remote outcome of tumor on the nervous system. We report a case of PLE caused by a regressed testicular germ cell tumor in an otherwise healthy young man, who presented with acute-onset confusion, memory impairment and anterograde amnesia. Prompt recognition of PLE is critical as it allows early treatment of both the primary tumor and PLE-related neurologic impairments, which can be severe and irreversible if treatment is delayed. Complete tumor treatment response offers the best chance for neurologic recovery in patients with PLE. To our knowledge, this is the second reported case of PLE with radiologic-pathologic correlation in the setting of a regressed testicular germ cell tumor.
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http://dx.doi.org/10.1016/j.clinimag.2021.01.032DOI Listing
August 2021

Temporomandibular disorders in prospective orthodontic patients.

Angle Orthod 2021 05;91(3):377-383

Objectives: To determine the prevalence and severity of temporomandibular disorders (TMDs) in prospective orthodontic patients. The association between TMDs and malocclusion severity as well as the impact of TMDs on oral health-related quality of life (OHRQoL) were also examined.

Materials And Methods: A total of 350 consecutive patients seeking orthodontic treatment were invited to participate in the study. The presence of TMDs was established with the Fonseca Anamnestic Index (FAI), while malocclusion severity and OHRQoL were evaluated using the Peer Assessment Rating (PAR) index and Oral Health Impact Profile-14 (OHIP-14), respectively. Data were analyzed using chi-square, Kruskal-Wallis, and Mann-Whitney U tests and Spearman's correlation (P < .05).

Results: Of the 350 patients, 164 consented to participation. Data from 26 participants were excluded because of incomplete entries, and that from 138 subjects (mean age 21.02 ± 5.45 years) were examined. TMD-related symptoms were present in two-thirds of the subjects, with 20.3% experiencing moderate/severe TMDs. While no significant difference in PAR scores were observed between the group with no TMDs and those with TMDs, subjects with TMDs had significantly higher OHIP-14 summary/domain scores than those without TMDs. Although a moderately strong correlation was observed between the FAI and summary OHIP-14 scores (rs = 0.57), no association was observed between FAI and PAR index scores.

Conclusions: The prevalence of TMD-related symptoms in prospective orthodontic patients was high, emphasizing the importance of screening the masticatory system before initiating orthodontic therapy. Although the presence of TMDs was not associated with malocclusion severity, it had a significant negative impact on OHRQoL.
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http://dx.doi.org/10.2319/010720-863.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084469PMC
May 2021

Computerized cognitive training in post-treatment hematological cancer survivors: a feasibility study.

Pilot Feasibility Stud 2021 Jan 30;7(1):36. Epub 2021 Jan 30.

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.

Background: Computerized cognitive training (CCT) programs have shown some effectiveness in alleviating cognitive symptoms in long-term cancer survivors. For patients presenting with cognitive symptoms in the early post-treatment phase, the benefit of CCT is unclear. To assess the possibility of testing the effectiveness of CCT in the early post-treatment period, our aim was to investigate the feasibility of an 8-week home-based, online CCT intervention among patients who have recently completed treatment for hematological malignancy.

Methods: This study was a single-arm, non-blinded, feasibility study. All participants were provided with the CCT intervention for an 8-week period. Feasibility was evaluated based on participant adherence and patient perceptions of the intervention, assessed through responses to an acceptability questionnaire and semi-structured interviews at the end of the intervention period.

Results: The feasibility study included 19 patients who had completed treatment for hematological malignancy at a Canadian tertiary cancer center. Adherence to the CCT intervention was limited, with only one participant meeting the criteria for intervention adherence. At the end of the intervention period, participants characterized the program as easy to follow (92%) and felt well-prepared for how to complete the exercises (100%). In semi-structured interviews, participants highlighted post-treatment barriers to intervention adherence that included symptom burden and competing time demands. Participants also suggested improvements to the intervention that could help maintain adherence despite these barriers, such as fostering a sense of accountability, providing personalized feedback and coaching, and enabling opportunities for peer support.

Conclusions: Participation in CCT can be challenging in the post-treatment period for hematological cancers. Further research on the effectiveness of CCT in this setting may require the implementation of strategies that support participants' engagement with the intervention in the context of symptoms and competing demands, such as establishing a minimum dose requirement and integrating approaches to help promote and sustain motivation.
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http://dx.doi.org/10.1186/s40814-021-00778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847007PMC
January 2021

Evaluating the Effect of Concussion Education Programs on Intent to Report Concussion in High School Football.

J Athl Train 2021 Jan 6. Epub 2021 Jan 6.

Lecturer and Adjunct Affiliate, Stanford University, School of Education. email:

Context: Concussion underreporting leads to delays in diagnosis and treatment, prolonging recovery time. Athletes' self-report of concussion symptoms therefore reduces risk.

Objective: Evaluate the efficacy of three concussion education programs in improving concussion-reporting intention.

Design: Randomized controlled clinical trial with assessment immediately and one-month after education.

Setting: Three high schools in California.

Patients Or Other Participants: 118 male football players were randomly assigned to receive concussion education via: CrashCourse (CC), Centers for Disease Control (CDC) video educational materials (Vi), or CDC written educational materials (Wr).

Main Outcome Measures: Concussion-reporting intention was assessed at baseline, immediately after education, and at one-month follow-up. Secondary outcomes included concussion knowledge, attitudes, perceived reporting norms, and perceived behavioral control.

Results: Athletes across all educational formats had significant improvement in concussion-reporting intention immediately following education and at one-month follow-up (mean improvement 6.8% and 11.4%, respectively; p<0.001). Similar findings were observed across all education formats in secondary analyses examining knowledge, attitudes, and perceived behavioral control. However, there were significant differences by education and time (p=0.03). On post-hoc analysis, athletes who received CC had increased concussion-reporting intention immediately and at one-month (baseline=4.7, immediate=6.1, one-month=6.0; p=0.007 compared to significant increases only at one-month for CDC-Vi (baseline=4.3, immediate=5.2, one-month=5.8; p=0.001), and no significant improvement for CDC-Wr (p=0.10). Secondary analyses indicated significant differences between CC and both CDC interventions, in concussion knowledge and attitudes, immediately after education and at one-month. There were no significant differences in perceived behavioral control between-interventions or in perceived concussion-reporting norms across or between interventions.

Conclusion: All athletes exhibited improved intent to report concussions, increased concussion knowledge, better concussion attitudes, and more perceived behavioral control, both immediately after education and at one-month follow-up. However, athletes randomized to CC reported greater intent to report concussion, more knowledge, and improved concussion-reporting attitudes, when compared to CDC-Vi and CDC-Wr.

Trial Registry: ClinicalTrials.gov trial ID number is XXX.
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http://dx.doi.org/10.4085/509-20DOI Listing
January 2021

Nature and Predictors of Response Changes in Modified-Delphi Panels.

Value Health 2020 12 5;23(12):1630-1638. Epub 2020 Oct 5.

RAND Corporation, Santa Monica, CA, USA.

Objectives: To describe the extent and nature of changes in participants' responses after exposure to group feedback and discussion in modified-Delphi panels and to identify factors affecting those changes.

Methods: We analyzed data from 2 online modified-Delphi panels, each consisting of 2 rating rounds and an online discussion round. We included responses from 55 participants who answered 38 questions in both rating rounds. Because not all participants answered each question twice, our sample consisted of 1846 cases (response changes). We used mixed-effect logistic and multinomial logistic regression to identify factors predicting response changes and their direction relative to group median-our consensus measure.

Results: Participants changed, on average, 49% of their responses. A response was changed in 47% of the 1846 cases: 28% of responses were changed toward consensus and 19% away from it. Although some measures of subjective participation experiences had a marginally significant impact on the propensity and direction of response changes, several objective measures of discussion engagement were statistically significant predictors of both the presence and direction of response changes.

Conclusion: Our results illustrate the nature of response changes and highlight the importance of exposing participants to alternative perspectives and encouraging them to explain their perspectives.
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http://dx.doi.org/10.1016/j.jval.2020.08.2093DOI Listing
December 2020

Continuous lenalidomide and low-dose dexamethasone in patients with transplant-ineligible newly diagnosed MM: FIRST trial subanalysis of Canadian/US patients.

Cancer Med 2020 12 13;9(23):8923-8930. Epub 2020 Oct 13.

Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France.

The phase 3 FIRST trial demonstrated significant improvement in progression-free survival (PFS) and overall survival (OS) with an immune-stimulatory agent, lenalidomide, in combination with low-dose dexamethasone until disease progression (Rd continuous) vs melphalan +prednisone + thalidomide (MPT) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Rd continuous similarly extended PFS vs fixed-duration Rd for 18 cycles (Rd18). Outcomes in the Canadian/US subgroup (104 patients per arm) are reported in this analysis. Rd continuous demonstrated a significant improvement in PFS vs MPT (median, 29.3 vs 20.2 months; HR, 0.69 [95% CI, 0.49-0.97]; p = 0.03326) and an improvement vs Rd18 (median, 21.9 months). Median OS was 56.9 vs 46.8 months with Rd continuous vs MPT (p = 0.15346) and 59.5 months with Rd18. The overall response rate was higher with Rd continuous and Rd18 (78.8% and 79.8%) vs MPT (65.4%). In the 49.0%, 52.9%, and 29.8% of patients with at least very good partial response in the Rd continuous, Rd18, and MPT arms, respectively, the median PFS was 56.0, 30.9, and 40.2 months, respectively. The most common grade 3/4 treatment-emergent adverse events were neutropenia (28.4%, 30.1%, and 52.0%), anemia (23.5%, 21.4%, and 23.5%), and infections (37.3%, 30.1%, and 24.5%) with Rd continuous, Rd18, and MPT, respectively. These results were consistent with those in the intent-to-treat population, confirming the benefit of Rd continuous vs MPT in the Canadian/US subgroup and supporting the role of Rd continuous as a standard of care for transplant-ineligible patients with NDMM.
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http://dx.doi.org/10.1002/cam4.3511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724300PMC
December 2020

Andean drought and glacial retreat tied to Greenland warming during the last glacial period.

Nat Commun 2020 10 12;11(1):5135. Epub 2020 Oct 12.

College of Earth, Ocean, and Atmospheric Science, Oregon State University, Corvallis, OR, USA.

Abrupt warming events recorded in Greenland ice cores known as Dansgaard-Oeschger (DO) interstadials are linked to changes in tropical circulation during the last glacial cycle. Corresponding variations in South American summer monsoon (SASM) strength are documented, most commonly, in isotopic records from speleothems, but less is known about how these changes affected precipitation and Andean glacier mass balance. Here we present a sediment record spanning the last ~50 ka from Lake Junín (Peru) in the tropical Andes that has sufficient chronologic precision to document abrupt climatic events on a centennial-millennial time scale. DO events involved the near-complete disappearance of glaciers below 4700 masl in the eastern Andean cordillera and major reductions in the level of Peru's second largest lake. Our results reveal the magnitude of the hydroclimatic disruptions in the highest reaches of the Amazon Basin that were caused by a weakening of the SASM during abrupt arctic warming. Accentuated warming in the Arctic could lead to significant reductions in the precipitation-evaporation balance of the southern tropical Andes with deleterious effects on this densely populated region of South America.
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http://dx.doi.org/10.1038/s41467-020-19000-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552390PMC
October 2020

Comparing covariation among vaccine hesitancy and broader beliefs within Twitter and survey data.

PLoS One 2020 8;15(10):e0239826. Epub 2020 Oct 8.

RAND Corporation, Boston, Massachusetts, United States of America.

Over the past decade, the percentage of adults in the United States who use some form of social media has roughly doubled, increasing from 36 percent in early 2009 to 72 percent in 2019. There has been a corresponding increase in research aimed at understanding opinions and beliefs that are expressed online. However, the generalizability of findings from social media research is a subject of ongoing debate. Social media platforms are conduits of both information and misinformation about vaccines and vaccine hesitancy. Our research objective was to examine whether we can draw similar conclusions from Twitter and national survey data about the relationship between vaccine hesitancy and a broader set of beliefs. In 2018 we conducted a nationally representative survey of parents in the United States informed by a literature review to ask their views on a range of topics, including vaccine side effects, conspiracy theories, and understanding of science. We developed a set of keyword-based queries corresponding to each of the belief items from the survey and pulled matching tweets from 2017. We performed the data pull of the most recent full year of data in 2018. Our primary measures of belief covariation were the loadings and scores of the first principal components obtained using principal component analysis (PCA) from the two sources. We found that, after using manually coded weblinks in tweets to infer stance, there was good qualitative agreement between the first principal component loadings and scores using survey and Twitter data. This held true after we took the additional processing step of resampling the Twitter data based on the number of topics that an individual tweeted about, as a means of correcting for differential representation for elicited (survey) vs. volunteered (Twitter) beliefs. Overall, the results show that analyses using Twitter data may be generalizable in certain contexts, such as assessing belief covariation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239826PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544030PMC
November 2020

Data, Decisions, White Coats.

AMA J Ethics 2020 09 1;22(9):E818-820. Epub 2020 Sep 1.

Second-year medical student at UT Southwestern Medical School in Dallas, Texas.

White coats are symbols of power that express historically entrenched ideals of clinical purity, sterility, and control. These ideals tend to oversimplify ethical and clinical complexities inherent in evolutions constantly taking place in health care practice. This pen and ink drawing interrogates these ideals visually and reimagines the white coat in the context of more realistic dynamism.
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http://dx.doi.org/10.1001/amajethics.2020.818DOI Listing
September 2020

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

J Med Chem 2020 11 24;63(22):13578-13594. Epub 2020 Sep 24.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent antitumor activity. These studies culminated in the discovery of TNO155, (3,4)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01170DOI Listing
November 2020

Shoulder muscle activation pattern recognition based on sEMG and machine learning algorithms.

Comput Methods Programs Biomed 2020 Dec 25;197:105721. Epub 2020 Aug 25.

Department of Orthopaedic Surgery and Sports Medicine, Detroit Medical Center, Detroit, MI, USA.

Background And Objective: Surface electromyography (sEMG) has been used for robotic rehabilitation engineering for volitional control of hand prostheses or elbow exoskeleton, however, using sEMG for volitional control of an upper limb exoskeleton has not been perfectly developed. The long-term goal of our study is to process shoulder muscle bio-electrical signals for rehabilitative robotic assistive device motion control. The purposes of this study included: 1) to test the feasibility of machine learning algorithms in shoulder motion pattern recognition using sEMG signals from shoulder and upper limb muscles, 2) to investigate the influence of motion speed, individual variability, EMG recording device, and the amount of EMG datasets on the shoulder motion pattern recognition accuracy.

Methods: A novel convolutional neural network (CNN) structure was constructed to process EMG signals from 12 muscles for the pattern recognition of upper arm motions including resting, drinking, backward-forward motion, and abduction motion. The accuracy of the CNN models for pattern recognition under different motion speeds, among individuals, and by EMG recording devices was statistically analyzed using ANOVA, GLM Univariate analysis, and Chi-square tests. The influence of EMG dataset number used for CNN model training on recognition accuracy was studied by gradually increasing dataset number until the highest accuracy was obtained.

Results: Results showed that the accuracy of the normal speed CNN model in motion pattern recognition was 97.57% for normal speed motions and 97.07% for fast speed motions. The accuracy of the cross-subjects CNN model in motion pattern recognition was 79.64%. The accuracy of the cross-device CNN model in motion pattern recognition was 88.93% for normal speed motion and 80.87% for mixed speed. There was a statistical difference in pattern recognition accuracy between different CNN models.

Conclusion: The EMG signals of shoulder and upper arm muscles from the upper limb motions can be processed using CNN algorithms to recognize the identical motions of the upper limb including drinking, forward/backward, abduction, and resting. A simple CNN model trained by EMG datasets of a designated motion speed accurately detected the motion patterns of the same motion speed, yielding the highest accuracy compared with other mixed CNN models for various speeds of motion pattern recognition. Increase of the number of EMG datasets for CNN model training improved the pattern recognition accuracy.
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http://dx.doi.org/10.1016/j.cmpb.2020.105721DOI Listing
December 2020

Effects of Medication-Assisted Treatment (MAT) for Opioid Use Disorder on Functional Outcomes: A Systematic Review.

Rand Health Q 2020 Jun 15;8(4). Epub 2020 Jun 15.

This systematic review addresses the question: What are the effects of medication-assisted treatment (MAT) that use buprenorphine, buprenorphine combined with naloxone, methadone, or naltrexone for opioid use disorder (OUD) on functional outcomes compared with wait-list, placebo, treatment without medication, any other comparator, or each other (e.g., buprenorphine versus naltrexone)? Functional outcomes investigated included cognitive (e.g., memory), physical (e.g., fatigue), occupational (e.g., employment status), social/behavioral (e.g., criminal activity), and neurological (e.g., balance) function. The authors searched five scientific research databases from inception to 2017 and reference mined existing reviews. Two independent literature reviewers screened 6,292 citations; 1,327 full-text publications were reviewed in detail and 37 studies met inclusion criteria. Critical appraisals assessed studies in detail, and quality of evidence was rated using established criteria. Results were synthesized in meta-analyses and presented in comprehensive evidence tables. Although MAT patients performed significantly better on some functional outcomes than persons with OUD who did not receive MAT, MAT patients performed worse on several cognitive measures than did matched "healthy" controls with no history of substance use disorder (SUD) or OUD. Because of the moderate-to-high risk of bias of most studies, quality of evidence is low or very low for all findings. The small number of studies reporting on outcomes of interest and the weaknesses in the body of evidence prevent making strong conclusions about MAT effects on functional outcomes. The literature shows that more research is needed that targets functional outcomes specifically, and there is, in particular, a lack of research evaluating potential differences in functional effects among medication types, the route of administration, treatment modality, and length of treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302321PMC
June 2020

An open-label, pharmacokinetic study of lenalidomide and dexamethasone therapy in previously untreated multiple myeloma (MM) patients with various degrees of renal impairment - validation of official dosing guidelines.

Leuk Lymphoma 2020 08 31;61(8):1860-1868. Epub 2020 May 31.

Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, Canada.

Lenalidomide is a backbone agent in the treatment of multiple myeloma, but dose adjustment is required for those with renal impairment (RI). We evaluated the pharmacokinetics (PK) and safety of lenalidomide and dexamethasone as frontline pre-transplant induction, with doses adjusted at start of each cycle based on creatinine clearance, as per the official dosing guidelines. After 4 cycles, PK studies showed that patients with moderate RI (30 ≤ CrCl < 60 mL/min) receiving 10 mg dosing may be under-dosed and those with severe RI (CrCl <30ml/min) appeared appropriately dosed initially, but sustained significant decreases in maximum serum concentration (Cmax) after repeated dosing, due to rapid clinical improvement and enhanced drug clearance. PK drug monitoring during cycle 1 may facilitate appropriate and timely dose adjustments. Adverse events rates did not vary based on severity of RI. No patient discontinued lenalidomide for toxicity. This supports the feasibility and safety of frontline lenalidomide in transplant-eligible patients with RI.
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http://dx.doi.org/10.1080/10428194.2020.1747064DOI Listing
August 2020
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