Publications by authors named "Yunfeng Dai"

71 Publications

Application of a multiplex urinalysis test for the prediction of intravesical BCG treatment response: A pilot study.

Cancer Biomark 2021 Sep 3. Epub 2021 Sep 3.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background: Intravesical Bacillus Calmette-Guerin (BCG), a live attenuated tuberculosis vaccine that acts as a non-specific immune system stimulant, is the most effective adjuvant treatment for patients with intermediate or high-risk non-muscle-invasive bladder cancer (NMIBC). However, to date, there are no reliable tests that are predictive of BCG treatment response. In this study, we evaluated the performance of OncuriaTM, a bladder cancer detection test, to predict response to intravesical BCG.

Methods: OncuriaTM data was evaluated in voided urine samples obtained from a prospectively collected cohort of 64 subjects with intermediate or high risk NMIBC prior to treatment with intravesical BCG. The OncuriaTM test, which measures 10 cancer-associated biomarkers was performed in an independent clinical laboratory. The ability of the test to identify those patients in whom BCG is ineffective against tumor recurrence was tested. Predictive models were derived using supervised learning and cross-validation analyses. Model performance was assessed using ROC curves.

Results: Pre-treatment urinary concentrations of MMP9, VEGFA, CA9, SDC1, PAI1, APOE, A1AT, ANG and MMP10 were increased in patients who developed disease recurrence. A combinatorial predictive model of treatment outcome achieved an AUROC 0.89 [95% CI: 0.80-0.99], outperforming any single biomarker, with a test sensitivity of 81.8% and a specificity of 84.9%. Hazard ratio analysis revealed that patients with higher urinary levels of ANG, CA9 and MMP10 had a significantly higher risk of disease recurrence.

Conclusions: Monitoring the urinary levels of a cancer-associated biomarker panel enabled the discrimination of patients who did not respond to intravesical BCG therapy. With further study, the multiplex OncuriaTM test may be applicable for the clinical evaluation of bladder cancer patients considering intravesical BCG treatment.
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http://dx.doi.org/10.3233/CBM-210221DOI Listing
September 2021

Diagnostic performance of Oncuria™, a urinalysis test for bladder cancer.

J Transl Med 2021 04 6;19(1):141. Epub 2021 Apr 6.

Cedars-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.

Background: Due to insufficient accuracy, urine-based assays currently have a limited role in the management of patients with bladder cancer. The identification of multiplex molecular signatures associated with disease has the potential to address this deficiency and to assist with accurate, non-invasive diagnosis and monitoring.

Methods: To evaluate the performance of Oncuria™, a multiplex immunoassay for bladder detection in voided urine samples. The test was evaluated in a multi-institutional cohort of 362 prospectively collected subjects presenting for bladder cancer evaluation. The parallel measurement of 10 biomarkers (A1AT, APOE, ANG, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) was performed in an independent clinical laboratory. The ability of the test to identify patients harboring bladder cancer was assessed. Bladder cancer status was confirmed by cystoscopy and tissue biopsy. The association of biomarkers and demographic factors was evaluated using linear discriminant analysis (LDA) and predictive models were derived using supervised learning and cross-validation analyses. Diagnostic performance was assessed using ROC curves.

Results: The combination of the 10 biomarkers provided an AUROC 0.93 [95% CI 0.87-0.98], outperforming any single biomarker. The addition of demographic data (age, sex, and race) into a hybrid signature improved the diagnostic performance AUROC 0.95 [95% CI 0.90-1.00]. The hybrid signature achieved an overall sensitivity of 0.93, specificity of 0.93, PPV of 0.65 and NPV of 0.99 for bladder cancer classification. Sensitivity values of the diagnostic panel for high-grade bladder cancer, low-grade bladder cancer, MIBC and NMIBC were 0.94, 0.89, 0.97 and 0.93, respectively.

Conclusions: Urinary levels of a biomarker panel enabled the accurate discrimination of bladder cancer patients and controls. The multiplex Oncuria™ test can achieve the efficient and accurate detection and monitoring of bladder cancer in a non-invasive patient setting.
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http://dx.doi.org/10.1186/s12967-021-02796-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025333PMC
April 2021

The T681I mutation is highly resistant to imatinib and dasatinib and detectable in clinical samples prior to treatment.

Haematologica 2021 08 1;106(8):2242-2245. Epub 2021 Aug 1.

Department of Pediatrics, Benioff Children's Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA.

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http://dx.doi.org/10.3324/haematol.2020.261354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8327742PMC
August 2021

Prognostic impact of minimal residual disease at the end of consolidation in NCI standard-risk B-lymphoblastic leukemia: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2021 04 9;68(4):e28929. Epub 2021 Feb 9.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

The 5-year disease-free survival (DFS) of National Cancer Institute (NCI) high-risk (HR) B-lymphoblastic leukemia (B-ALL) patients with end of induction (EOI) minimal residual disease (MRD) ≥0.1% and end of consolidation (EOC) MRD ≥0.01% is 39 ± 7%, warranting consideration of hematopoietic stem cell transplant (HSCT). However, the impact of EOC MRD in NCI standard-risk (SR) B-ALL patients using COG regimens is unknown. We found that SR patients with MRD ≥0.01% at both EOI and EOC have a 4-year DFS/overall survival (OS) of 72.9 ± 19.0%/91.7 ± 10.8% versus 90.7 ± 2.9%/95.5 ± 2.0% (p = .0019/.25) for those with EOI MRD ≥0.01% and EOC MRD <0.01%. These data suggest that routine use of HSCT may not be warranted in EOC MRD ≥0.01% SR patients.
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http://dx.doi.org/10.1002/pbc.28929DOI Listing
April 2021

Variations in hospitalization rates across Parkinson's Foundation Centers of Excellence.

Parkinsonism Relat Disord 2020 12 3;81:123-128. Epub 2020 Oct 3.

Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital and the University of Toronto, Toronto, Ontario, Canada.

Introduction: Patients with Parkinson's disease (PD) are at increased risk for hospitalization and often experience worsening of PD when hospitalized. It is therefore important to identify strategies to prevent hospitalization.

Methods: Hospital encounter rates in different Parkinson's Foundation Centers of Excellence in United States, Canada, Israel and the Netherlands were analyzed as part of the Parkinson Foundation Parkinson's Outcomes Project (PF-POP). Multivariate logistic regression was used to estimate the odds ratio for hospitalization, adjusted for risk factors.

Results: Baseline age, disease duration, other relative than spouse/partner as care giver, cancer, arthritis, other comorbidities, falls, use of levodopa, use of dopamine agonist, use of COMT inhibitor, occupational therapy before the baseline visit, PDQ-39, MSCI total score and time between visits were significantly associated with the risk of hospital encounters. After adjustment for these factors, two centers had significantly lower odds for hospitalization admission and ER visit (minimum OR 0.3) and four centers had significantly higher odds (maximum OR 1.5) than the average center. Four centers had significantly lower hazard ratios for time to re-hospitalization compared to the average center. Reducing hospital admission rates in those centers with higher than average rates would reduce overall hospitalizations by 11%. Applied to PD patients over 65 nationwide this represents a potential for cost savings of greater than $1 billion over 48 months.

Conclusion: Encounter rates vary even across expert centers and suggest that practices carried out in some centers may reduce the risk of hospitalization. Further research will be necessary to identify these practices and implement them more widely to improve care for people with PD.
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http://dx.doi.org/10.1016/j.parkreldis.2020.09.006DOI Listing
December 2020

Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia.

J Natl Cancer Inst 2021 04;113(4):408-417

Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA.

Background: Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on interpatient variability in MRD.

Methods: A genome-wide association study was performed on 2597 children on the Children's Oncology Group AALL0232 trial for high-risk B-cell ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863 370 single nucleotide polymorphisms (SNPs), adjusting for genetic ancestry and treatment strata. Top variants were further evaluated in a validation cohort of 491 patients from the Children's Oncology Group P9905 and 6 ALL trials. The independent prognostic value of single nucleotide polymorphisms was determined in multivariable analyses. All statistical tests were 2-sided.

Results: In the discovery genome-wide association study, we identified a genome-wide significant association at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84; P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count, and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively).

Conclusion: Inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of germline variants in upfront risk stratification in ALL.
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http://dx.doi.org/10.1093/jnci/djaa138DOI Listing
April 2021

DEC1 directly interacts with estrogen receptor (ER) α to suppress proliferation of ER-positive breast cancer cells.

Biochem Biophys Res Commun 2020 08 7;528(4):740-745. Epub 2020 Jun 7.

School of Medical Technolog, Qiqihar Medical University, Qiqihar, Heilongjiang, China. Electronic address:

Aberrant ERα signaling and altered circadian rhythms are both features of ER-positive breast cancer, however, the molecular interaction between them is still not fully understood. Herein, we analyzed the interplay between the circadian rhythm molecule DEC1 and ERα and its effect on the proliferation of ER-positive breast cancer cells, providing a new clue for clarifying the pathogenesis of breast cancer. In this study, we revealed that DEC1 negatively regulates the proliferation of ER-positive breast cancer MCF-7 cells through interaction with ERα protein. DEC1 co-localized with ERα in the nucleus of MCF7 cells, stabilized ERα protein independently of its transcriptional activity and without affecting by estrogen stimulation and inhibited the degradation of ERα mediated by CHX in a time-dependent manner. Moreover, results from luciferase reporter assay showed that overexpression of DEC1 significantly inhibits ERα-mediated transcriptional activity in a dose-dependent manner. These results together suggested that DEC1 may serve as a co-repressor of ERα in ER-positive breast cancer. Although DEC1 improved the stability of ERα and alleviated protein degradation, DEC1 inhibited the proliferation of MCF7 cells by decreasing ERα-mediated signal transduction.
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http://dx.doi.org/10.1016/j.bbrc.2020.05.123DOI Listing
August 2020

Impact of Intrathecal Triple Therapy Versus Intrathecal Methotrexate on Disease-Free Survival for High-Risk B-Lymphoblastic Leukemia: Children's Oncology Group Study AALL1131.

J Clin Oncol 2020 08 4;38(23):2628-2638. Epub 2020 Jun 4.

Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: The high-risk stratum of Children's Oncology Group Study AALL1131 was designed to test the hypothesis that postinduction CNS prophylaxis with intrathecal triple therapy (ITT) including methotrexate, hydrocortisone, and cytarabine would improve the postinduction 5-year disease-free survival (DFS) compared with intrathecal methotrexate (IT MTX), when given on a modified augmented Berlin-Frankfurt-Münster backbone.

Patients And Methods: Children with newly diagnosed National Cancer Institute (NCI) high-risk B-cell acute lymphoblastic leukemia (HR B-ALL) or NCI standard-risk B-ALL with defined minimal residual disease thresholds during induction were randomly assigned to receive postinduction IT MTX or ITT. Patients with CNS3-status disease were not eligible. Postinduction IT therapy was given for a total of 21 to 26 doses. Neurocognitive assessments were performed during therapy and during 1 year off therapy.

Results: Random assignment was closed to accrual in March 2018 after a futility boundary had been crossed, concluding that ITT could not be shown to be superior to IT MTX. The 5-year postinduction DFS and overall survival rates (± SE) of children randomly assigned to IT MTX versus ITT were 93.2% ± 2.1% 90.6% ± 2.3% ( = .85), and 96.3% ± 1.5% 96.7% ± 1.4% ( = .77), respectively. There were no differences in the cumulative incidence of isolated bone marrow relapse, isolated CNS relapse, or combined bone marrow and CNS relapse rates, or in toxicities observed for patients receiving IT MTX compared with ITT. There were no significant differences in neurocognitive outcomes for patients receiving IT MTX compared with ITT.

Conclusion: Postinduction CNS prophylaxis with ITT did not improve 5-year DFS for children with HR B-ALL. The standard of care for CNS prophylaxis for children with B-ALL and no overt CNS involvement remains IT MTX.
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http://dx.doi.org/10.1200/JCO.19.02892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402996PMC
August 2020

Prognostic Significance of Lymphocyte Infiltration and a Stromal Immunostaining of a Bladder Cancer Associated Diagnostic Panel in Urothelial Carcinoma.

Diagnostics (Basel) 2019 Dec 28;10(1). Epub 2019 Dec 28.

Clinical and Translational Research Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder cancer-associated diagnostic signature were chemokines, cytokines, or secreted proteins, we set out to report the stromal staining pattern of the diagnostic signature as well as CD3 (T-cell) cell and CD68 (macrophage) cell staining in human bladder tumors as a snapshot of the tumor immune landscape. Immunohistochemical staining was performed on 213 tumor specimens and 74 benign controls. Images were digitally captured and quantitated using Aperio (Vista, CA). The expression patterns were correlated with tumor grade, tumor stage, and outcome measures. We noted a positive correlation of seven of the 10 proteins (excluding A1AT and IL8 which had a negative association and VEGFA had no association) in bladder cancer. The overexpression of MMP10 was associated with higher grade disease, while overexpression of MMP10, PAI1, SDC1 and ANG were associated with high stage bladder cancer and CA9 was associated with low stage bladder cancer. Increased tumor infiltration of CD68 cells were associated with higher stage disease. Overall survival was significantly reduced in bladder cancer patients' whose tumors expressed eight or more of the 10 proteins that comprise the bladder cancer diagnostic panel. These findings confirm that the chemokines, cytokines, and secreted proteins in a urine-based diagnostic panel are atypically expressed, not only in the epithelial component of bladder tumors, but also in the stromal component of bladder tumors and portends a worse overall survival. Thus, when assessing immunohistochemical staining, it is important to report staining patterns within the stroma as well as the entire stroma itself.
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http://dx.doi.org/10.3390/diagnostics10010014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168167PMC
December 2019

Biopsychosocial Influences on Shoulder Pain: Analyzing the Temporal Ordering of Postoperative Recovery.

J Pain 2020 Jul - Aug;21(7-8):808-819. Epub 2019 Dec 28.

Department of Orthopedic Surgery, Duke University, Durham, North Carolina; Duke Clinical Research Institute, Duke University, Durham, North Carolina.

Shoulder surgery is a primary intervention for shoulder pain, yet many individuals experience persistent postoperative pain. Previously, we found individuals categorized as having a high-risk phenotype (comprised of COMT variation and pain catastrophizing) had approximately double the chance of not reaching a 12-month pain recovery criterion. As a means to better understand the development of persistent postoperative shoulder pain, this study advanced our previous work by examining temporal ordering of postoperative shoulder recovery based on potential mediating factors, and expansion of outcomes to include movement-evoked pain and shoulder active range of motion. Before surgery, individuals were categorized as either high-risk (high pain catastrophizing, COMT-genotype linked to low enzyme activity [n = 41]) or low-risk (low pain catastrophizing, COMT-genotype linked to normal enzyme activity [n = 107]). We then compared potential mediating variables at 3, 6, and 12 months postoperatively 1) endogenous pain modulation defined by a conditioned pain modulation paradigm; and 2) and emotion factors such as anxiety, fear of movement, and depressive symptoms. At 3 months, the high-risk subgroup had higher fear and movement-evoked pain, and causal mediation analysis confirmed the direct effect of risk subgroup on 12-month movement evoked pain. However, baseline to 12-month change in depressive symptoms were found to mediate 53% of the total effect of risk subgroup on 12-month movement-evoked pain. This study introduces potential temporal components and relationships to the development of persistent postoperative shoulder pain, which future studies will confirm and assess for potential therapeutic targets. PERSPECTIVE: This study expands upon postoperative shoulder recovery measures to include movement-evoked pain and depressive symptoms, and provides preliminary indication of temporal ordering to postoperative shoulder recovery for a preidentified high-risk subgroup. Future studies will distinguish temporal components of shoulder surgery that may optimize treatment targets of postoperative recovery.
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http://dx.doi.org/10.1016/j.jpain.2019.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321871PMC
December 2019

Mixed-phenotype acute leukemia: A cohort and consensus research strategy from the Children's Oncology Group Acute Leukemia of Ambiguous Lineage Task Force.

Cancer 2020 02 29;126(3):593-601. Epub 2019 Oct 29.

Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta/Emory University, Atlanta, Georgia.

Background: Optimal chemotherapy for treating mixed-phenotype acute leukemia (MPAL) and the role of hematopoietic stem cell transplantation (HSCT) remain uncertain. Major limitations in interpreting available data are MPAL's rarity and the use of definitions other than the currently widely accepted criteria: the World Health Organization 2016 (WHO2016) classification.

Methods: To assess the relative efficacy of chemotherapy types for treating pediatric MPAL, the Children's Oncology Group (COG) Acute Leukemia of Ambiguous Lineage Task Force assembled a retrospective cohort of centrally reviewed WHO2016 MPAL cases selected from banking studies for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Patients were not treated in COG trials; treatment and outcome data were captured separately. The findings were then integrated with the available, mixed literature to develop a prospective trial in pediatric MPAL.

Results: The central review confirmed that 54 of 70 cases fulfilled WHO2016 criteria for MPAL. ALL induction regimens achieved remission in 72% of the cases (28 of 39), whereas AML regimens achieved remission in 69% (9 of 13). The 5-year event-free survival (EFS) and overall survival (OS) rates for the entire cohort were 72% ± 8% and 77% ± 7%, respectively. EFS and OS were 75% ± 13% and 84% ± 11%, respectively, for those receiving ALL chemotherapy alone without HSCT (n = 21).

Conclusions: The results of the COG MPAL cohort and a literature review suggest that ALL chemotherapy without HSCT may be the preferred initial therapy. A prospective trial within the COG is proposed to investigate this approach; AML chemotherapy and/or HSCT will be reserved for those with treatment failure as assessed by minimal residual disease. Embedded biology studies will provide further insight into MPAL genomics.
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http://dx.doi.org/10.1002/cncr.32552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489437PMC
February 2020

Contaminant transport in a largely-deformed aquitard affected by delayed drainage.

J Contam Hydrol 2019 Feb 11;221:118-126. Epub 2019 Feb 11.

School of Engineering, Sun Yat-sen University, Guangzhou 510275, China.

This paper employed a one-dimensional large-deformation model in consideration of the coupling of mechanical consolidation and solute transport, to study the transport of contaminants in a largely-deformed aquitard. An analytical solution has been derived to describe the drawdown variation in a largely-deformed aquitard which is subjected to abrupt hydraulic head decline in adjacent confined aquifers. The pore water flux and void ratio variation were obtained on the basis of the analytical solution. The equation for transient contaminant flux was solved by the finite difference method. A hypothetical case study was done to explore the effect of consolidation on the contaminant transport in a largely-deformed aquitard. The transit time of contaminant transport in the aquitard is mainly determined by the hydraulic conductivity, thickness, partitioning coefficient, void ratio and effective diffusion coefficients of aquitard, as well as the drawdown in the adjacent confined aquifer. The impact of delayed drainage on the contaminant transport in the largely-deformed aquitard is mainly controlled by two factors: the transient water flow and the decrease of aquitard thickness, in the process of aquitard consolidation. The former increases the breakthrough time of contaminant transport in the aquitard, and the latter gives rise to an opposite case with its effect decreasing with increasing contaminant partitioning coefficient for soil particles sorption. A larger deformation, which may be induced by a larger thickness, higher specific storativity of aquitard or a larger drawdown of the adjacent confined aquifer, and a lower hydraulic conductivity of aquitard cause a more significant impact of delayed drainage on the contaminant transport in an aquitard.
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http://dx.doi.org/10.1016/j.jconhyd.2019.02.002DOI Listing
February 2019

Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group.

J Clin Oncol 2019 04 11;37(10):780-789. Epub 2019 Feb 11.

14 New York University Langone Medical Center, New York, NY.

Purpose: Children and young adults with hypodiploid B-lymphoblastic leukemia (B-ALL) fare poorly and hematopoietic stem-cell transplantation (HSCT) is often pursued in first complete remission (CR1). We retrospectively reviewed the outcomes of children and young adults with hypodiploid B-ALL who were enrolled in recent Children's Oncology Group (COG) trials to evaluate the impact of HSCT on outcome.

Patients And Methods: Cytogenetic analyses and DNA index were performed at COG-approved laboratories, and hypodiploidy was defined as modal chromosome number less than 44 and/or DNA index less than 0.81. Minimal residual disease (MRD) was determined centrally using flow cytometry at two reference laboratories. Patients with hypodiploid ALL came off protocol therapy postinduction and we retrospectively collected details on their subsequent therapy and outcomes. Event-free survival (EFS) and overall survival (OS) were estimated for the cohort.

Results: Between 2003 and 2011, 8,522 patients with National Cancer Institute standard-risk and high-risk B-ALL were enrolled in COG AALL03B1 ( ClinicalTrials.gov identifier: NCT00482352). Hypodiploidy occurred in 1.5% of patients (n = 131), 98.3% of whom achieved CR after induction therapy. Five-year EFS and OS were 52.2% ± 4.9% and 58.9% ± 4.8%, respectively. Outcomes for patients undergoing CR1 HSCT were not significantly improved: 5-year EFS and OS were 57.4% ± 7.0% and 66.2% ± 6.6% compared with 47.8% ± 7.5% and 53.8% ± 7.6%, respectively ( P = .49 and .34, respectively) for those who did not undergo transplantation. Patients with MRD of 0.01% or greater at the end of induction had 5-year EFS and OS of 26.7% ± 9.3% and 29.3% ± 10.1%, respectively, and HSCT had no significant impact on outcomes.

Conclusion: Children and young adults with hypodiploid B-ALL continue to fare poorly and do not seem to benefit from CR1 HSCT. This is especially true for patients with MRD of 0.01% or greater at the end of induction. New treatment strategies are urgently needed for these patients.
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http://dx.doi.org/10.1200/JCO.18.00884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440386PMC
April 2019

PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.

Nat Genet 2019 02 14;51(2):296-307. Epub 2019 Jan 14.

HARP Pharma Consulting, Mystic, CT, USA.

Recent genomic studies have identified chromosomal rearrangements defining new subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL), however many cases lack a known initiating genetic alteration. Using integrated genomic analysis of 1,988 childhood and adult cases, we describe a revised taxonomy of B-ALL incorporating 23 subtypes defined by chromosomal rearrangements, sequence mutations or heterogeneous genomic alterations, many of which show marked variation in prevalence according to age. Two subtypes have frequent alterations of the B lymphoid transcription-factor gene PAX5. One, PAX5alt (7.4%), has diverse PAX5 alterations (rearrangements, intragenic amplifications or mutations); a second subtype is defined by PAX5 p.Pro80Arg and biallelic PAX5 alterations. We show that p.Pro80Arg impairs B lymphoid development and promotes the development of B-ALL with biallelic Pax5 alteration in vivo. These results demonstrate the utility of transcriptome sequencing to classify B-ALL and reinforce the central role of PAX5 as a checkpoint in B lymphoid maturation and leukemogenesis.
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http://dx.doi.org/10.1038/s41588-018-0315-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525306PMC
February 2019

Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG.

Haematologica 2019 05 13;104(5):986-992. Epub 2018 Dec 13.

Department of Pediatrics, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

With modern chemotherapy, approximately 90% of patients with pediatric acute lymphoblastic leukemia are now cured. However, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic strategies designed to improve survival. The AALL1131 trial was designed to determine, in a randomized fashion, whether substitution with cyclophosphamide/etoposide (experimental arm 1) would improve the 4-year disease-free survival of children, adolescents, and young adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1-30 years of age with newly diagnosed very high-risk B-cell acute lymphoblastic leukemia were randomized after induction in a 1:2 fashion to the control arm or experimental arm 1 in which they were given cyclophosphamide (440 mg/m days 1-5)/etoposide (100 mg/m days 1-5) during part 2 of consolidation and delayed intensification. Prospective interim monitoring rules for efficacy and futility were included where futility would be determined for a one-sided P-value ≥0.7664. The study was stopped for futility as the interim monitoring boundary was crossed [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very high-risk arm of AALL1131 was closed in February 2017. Using data current as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children's Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival.
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http://dx.doi.org/10.3324/haematol.2018.204545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909PMC
May 2019

Genetic and psychological factors interact to predict physical impairment phenotypes following exercise-induced shoulder injury.

J Pain Res 2018 23;11:2497-2508. Epub 2018 Oct 23.

Duke Clinical Research Institute and Department of Orthopaedic Surgery, Duke University, Durham, NC, USA.

Background: We investigated interactions between genetic and psychological factors in predicting shoulder impairment phenotypes. We hypothesized that pro-inflammatory genes would display stronger relationships compared with pain-related genes when combined with psychological factors for predicting phenotypic changes.

Subjects And Methods: Altogether, 190 participants completed a 5-day experimental protocol. An experimental shoulder injury model was used to induce physical impairment, and a priori selected genetic (pain-related, pro-inflammatory) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, kinesiophobia) factors were included as predictors of interest. Impairment phenotypes were injury-induced deficits in range of motion (ROM) and strength. After controlling for age, sex, and race, genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each phenotype.

Results: Strong statistical evidence was provided for interactions between: 1) IL-1β (rs1143634) and fear of pain for predicting loss of shoulder flexion and abduction, 2) IL-1β (rs1143634) and anxiety for predicting loss of flexion, and 3) IL-1β (rs1143634) and depressive symptoms for predicting loss of internal rotation. In addition, the interaction between OPRM1 (rs1799971) and fear of pain as well as COMT (rs4818) and pain catastrophizing provided strong statistical evidence for predicting strength loss.

Conclusion: Pro-inflammatory gene variants contributed more to physical impairment with two single nucleotide polymorphisms (SNPs; IL-1β [rs1143634] and TNF/LTA [rs2229094]) interacting with psychological factors to predict six shoulder impairment phenotypes. In comparison, two pain-related gene SNPs (OPRM1 [rs1799971] and COMT [rs4818]) interacted with psychological factors to predict four shoulder impairment phenotypes (abduction: 5-day average loss; strength loss: 5-day average, peak, and relative loss).
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http://dx.doi.org/10.2147/JPR.S171498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205136PMC
October 2018

Genomic and outcome analyses of Ph-like ALL in NCI standard-risk patients: a report from the Children's Oncology Group.

Blood 2018 08 11;132(8):815-824. Epub 2018 Jul 11.

Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; --like ALL) in children with National Cancer Institute (NCI) intermediate- or high-risk (HR) ALL is associated with poor outcome. Ph-like ALL is characterized by genetic alterations that activate cytokine receptor and kinase signaling and may be amenable to treatment with tyrosine kinase inhibitors. The prevalence, outcome, and potential for targeted therapy of Ph-like ALL in standard-risk (SR) ALL is less clear. We retrospectively analyzed a cohort of 1023 SR childhood B-ALL consecutively enrolled in the Children's Oncology Group AALL0331 clinical trial. The Ph-like ALL gene expression profile was identified in 206 patients, and 67 patients with either - (n = 6) or - (n = 61) were excluded from downstream analysis, leaving 139 of 1023 (13.6%) as Ph-like. Targeted reverse transcription polymerase chain reaction assays and RNA-sequencing identified kinase-activating alterations in 38.8% of SR Ph-like cases, including rearrangements (29.5% of Ph-like), -class fusions (1.4%), fusions (1.4%), an fusion (0.7%), and other sequence mutations (, , ; 5.6%). Patients with Ph-like ALL had inferior 7-year event-free survival compared with non-Ph-like ALL (82.4 ± 3.6% vs 90.7 ± 1.0%, = .0022), with no difference in overall survival (93.2 ± 2.4% vs 95.8 ± 0.7%, = .14). These findings illustrate the significant differences in the spectrum of kinase alterations and clinical outcome of Ph-like ALL based on presenting clinical features and establish that genomic alterations potentially targetable with approved kinase inhibitors are less frequent in SR than in HR ALL.
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http://dx.doi.org/10.1182/blood-2018-04-841676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107876PMC
August 2018

[ study of a novel micro-arc oxidation coated magnesium-zinc-calcium alloy scaffold/autologous bone particles repairing critical size bone defect in rabbit].

Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2018 03;32(3):298-305

Department of Orthopedics, Second Affiliated Hospital of Harbin Medical University, Harbin Heilongjiang, 150086, P.R.China.

Objective: To evaluate the effect of a novel micro-arc oxidation (MAO) coated magnesium-zinc-calcium (Mg-Zn-Ca) alloy scaffold/autologous bone particles to repair critical size bone defect (CSD) in rabbit and explore the novel scaffold corrosion resistance and biocompatibility.

Methods: Seventy-two New Zealand white rabbits were randomly divided into 3 groups ( =24), group A was uncoated Mg-Zn-Ca alloy scaffold group, group B was 10 μm MAO coated Mg-Zn-Ca alloy scaffold group, and group C was control group with only autologous bone graft. The animals were operated to obtain bilateral ulnar CSD (15 mm in length) models. The bone fragment was removed and minced into small particles and were filled into the scaffolds of groups A and B. Then, the scaffolds or autologous bone particles were replanted into the defects. The animals were sacrificed at 2, 4, 8, and 12 weeks after surgery (6 rabbits each group). The local subcutaneous pneumatosis was observed and recorded. The ulna defect healing was evaluated by X-ray image and Van Gieson staining. The X-ray images were assessed and scored by Lane-Sandhu criteria. The percentage of the lost volume of the scaffold (ΔV) and corrosion rate (CR) were calculated by the Micro-CT. The Mg and Ca concentrations were monitored during experiment and the rabbit liver, brain, kidney, and spleen were obtained to process HE staining at 12 weeks after surgery.

Results: The local subcutaneous pneumatosis in group B was less than that in group A at 2, 4, and 8 weeks after surgery, showing significant differences between 2 groups at 2 and 4 weeks after surgery ( <0.05); and the local subcutaneous pneumatosis was significantly higher in group B than that in group A at 12 weeks after surgery ( <0.05). The X-ray result showed that the score of group C was significantly higher than those of groups A and B at 4 and 8 weeks after surgery ( <0.05), and the score of group B was significantly higher than that of group A at 8 weeks ( <0.05). At 12 weeks after surgery, the scores of groups B and C were significantly higher than that of group A ( <0.05). Meanwhile, the renew bone moulding of group B was better than that in group A at 12 weeks after surgery. Micro-CT showed that ΔV and CR in group B were significantly lower than those in group A ( <0.05). Van Gieson staining showed that group B had better biocompatibility and osteanagenesis than group A. The Mg and Ca concentrations in serum showed no significant difference between groups during experiments ( >0.05). And there was no obvious pathological changes in the liver, brain, kidney, and spleen of the 3 groups with HE staining at 12 weeks.

Conclusion: The MAO coated Mg-Zn-Ca alloy scaffold/autologous bone particles could be used to repair CSD effectively. At the same time, 10 μm MAO coating can effectively improve the osteanagenesis, corrosion resistance, and biocompatibility of Mg-Zn-Ca alloy scaffold.
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http://dx.doi.org/10.7507/1002-1892.201710003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414268PMC
March 2018

Optimal Screening for Prediction of Referral and Outcome (OSPRO) for Musculoskeletal Pain Conditions: Results From the Validation Cohort.

J Orthop Sports Phys Ther 2018 06 7;48(6):460-475. Epub 2018 Apr 7.

Study Design Observational, prospective cohort. Background Musculoskeletal pain is a common reason to seek health care, and earlier nonpharmacological treatment and enhancement of personalized care options are 2 high-priority areas. Validating concise assessment tools is an important step toward establishing better care pathways. Objectives To determine the predictive validity of Optimal Screening for Prediction of Referral and Outcome (OSPRO) tools for individuals with neck, low back, shoulder, or knee pain. Methods A convenience sample (n = 440) was gathered by Orthopaedic Physical Therapy-Investigator Network clinics (n = 9). Participants completed demographic, clinical, and comorbidity questionnaires and the OSPRO tools, and were followed for 12-month outcomes in pain intensity, region-specific disability, quality of life, and comorbidity change. Analyses predicted these 12-month outcomes with models that included the OSPRO review-of-systems (OSPRO-ROS) and yellow flag (OSPRO-YF) tools and planned covariates (accounting for comorbidities and established demographic and clinical factors). Results The 10-item OSPRO-YF tool (baseline and 4-week change score) consistently added to predictive models for 12-month pain intensity, region-specific disability, and quality of life. The 10-item OSPRO-ROS tool added to a predictive model for quality of life (mental summary score), and 13 additional items of the OSPRO-ROS+ tool added to prediction of 12-month comorbidity change. Other consistent predictors included age, race, income, previous episode of pain in same region, comorbidity number, and baseline measure for the outcome of interest. Conclusion The OSPRO-ROS and OSPRO-YF tools statistically improved prediction of multiple 12-month outcomes. The additional variance explained was small, and future research is necessary to determine whether these tools can be used as measurement adjuncts to improve management of musculoskeletal pain. J Orthop Sports Phys Ther 2018;48(6):460-475. Epub 7 Apr 2018. doi:10.2519/jospt.2018.7811.
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http://dx.doi.org/10.2519/jospt.2018.7811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6053060PMC
June 2018

Meta-analysis of a 10-plex urine-based biomarker assay for the detection of bladder cancer.

Oncotarget 2018 Jan 3;9(6):7101-7111. Epub 2018 Jan 3.

Department of Urology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

A 10-plex urine-based bladder cancer (BCa) diagnostic signature has the potential to non-invasively predict the presence of BCa in at-risk patients, as reported in various case-control studies. The present meta-analysis was performed to re-evaluate and demonstrate the robustness and consistency of the diagnostic utility of the 10-plex urine-based diagnostic assay. We re-analyzed primary data collected in five previously published case-control studies on the 10-plex diagnostic assay. Studies reported the sensitivity and specificity of ten urinary protein biomarkers for the detection of BCa, including interleukin 8, matrix metalloproteinases 9 and 10, angiogenin, apolipoprotein E, syndecan 1, alpha-1 antitrypsin, plasminogen activator inhibitor-1, carbonic anhydrase 9, and vascular endothelial growth factor A. Data were extracted and reviewed independently by two investigators. Log odds ratios (ORs) were calculated to determine how strongly the 10-plex biomarker panel and individual biomarkers are associated with the presence of BCa. Data pooled from 1,173 patients were analyzed. The log OR for each biomarker was improved by 1.5 or greater with smaller 95% CI in our meta-analysis of the overall cohort compared with each analysis of an individual cohort. The combination of the ten biomarkers showed a higher log OR (log OR: 3.46, 95% CI: 2.60-4.31) than did any single biomarker irrespective of histological grade or disease stage of tumors. We concluded that the 10-plex BCa-associated diagnostic signature demonstrated a higher potential to identify BCa when compared to any single biomarker. Our results justify further advancement of the 10-plex protein-based diagnostic signature toward clinical application.
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http://dx.doi.org/10.18632/oncotarget.23872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805539PMC
January 2018

Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia.

Blood 2018 03 5;131(9):995-999. Epub 2018 Jan 5.

Division of Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

As a consequence of acquired or intrinsic disease resistance, the prognosis for patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) is dismal. Novel, less toxic drugs are clearly needed. One of the most promising emerging therapeutic strategies for cancer treatment is targeted immunotherapy. Immune therapies have improved outcomes for patients with other hematologic malignancies including B-cell ALL; however no immune therapy has been successfully developed for T-ALL. We hypothesize targeting CD38 will be effective against T-ALL. We demonstrate that blasts from patients with T-ALL have robust surface CD38 surface expression and that this expression remains stable after exposure to multiagent chemotherapy. CD38 is expressed at very low levels on normal lymphoid and myeloid cells and on a few tissues of nonhematopoietic origin, suggesting that CD38 may be an ideal target. Daratumumab is a human immunoglobulin G1κ monoclonal antibody that binds CD38, and has been demonstrated to be safe and effective in patients with refractory multiple myeloma. We tested daratumumab in a large panel of T-ALL patient-derived xenografts (PDX) and found striking efficacy in 14 of 15 different PDX. These data suggest that daratumumab is a promising novel therapy for pediatric T-ALL patients.
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http://dx.doi.org/10.1182/blood-2017-07-794214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833263PMC
March 2018

TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children.

J Clin Oncol 2018 02 4;36(6):591-599. Epub 2018 Jan 4.

Maoxiang Qian, Xueyuan Cao, Wenjian Yang, Cheng Cheng, Hui Zhang, Takaya Moriyama, Gerard Zambetti, Kim E. Nichols, Ching-Hon Pui, Charles G. Mullighan, William E. Evans, Mary V. Relling, and Jun J. Yang, St Jude Children's Research Hospital, Memphis, TN; Meenakshi Devidas and Yunfeng Dai, University of Florida, Gainesville, FL; Andrew Carroll, University of Alabama at Birmingham, Birmingham, AL; Nyla A. Heerema and Julie M. Gastier-Foster, The Ohio State University and Wexner Medical Center; Julie M. Gastier-Foster and Elaine R. Mardis, Nationwide Children's Hospital, Columbus, OH; Hui Zhang, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong; Heng Xu, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China; Elizabeth Raetz, University of Utah, Salt Lake City, UT; Eric Larsen, Maine Children's Cancer Program, Scarborough, ME; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; W. Paul Bowman, Cook Children's Medical Center, Fort Worth, TX; Paul L. Martin, Duke University, Durham, NC; Robert Fulton, Washington University School of Medicine, St Louis, MO; Michael Borowitz, Johns Hopkins Medical Institute, Baltimore, MD; Brent Wood, University of Washington, Seattle, WA; William L. Carroll, New York University, New York, NY; Stephen P. Hunger, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA; and Mignon L. Loh, Benioff Children's Hospital and University of California, San Francisco, San Francisco, CA.

Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children's Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% ( P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.
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http://dx.doi.org/10.1200/JCO.2017.75.5215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815403PMC
February 2018

Measurable residual disease detection by high-throughput sequencing improves risk stratification for pediatric B-ALL.

Blood 2018 03 28;131(12):1350-1359. Epub 2017 Dec 28.

Adaptive Biotechnologies, Seattle, WA.

Early response to induction chemotherapy is an important prognostic factor in B-lymphoblastic leukemia (B-ALL). Here, we compare high-throughput sequencing (HTS) of and genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.
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http://dx.doi.org/10.1182/blood-2017-09-806521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865233PMC
March 2018

Transmitted cardiovascular pulsations on high resolution esophageal impedance manometry, and their significance in dysphagia.

World J Gastroenterol 2017 Nov;23(44):7840-7848

Department of Medicine, Division of Gastroenterology, University of Florida, Gainesville, FL 32610, United States.

Aim: To investigate the behavior of pulsatile pressure zones (PPZ's) as noted on high resolution esophageal impedance manometry (HREIM), and determine their association with dysphagia.

Methods: Retrospective, single center case control design screening HREIM studies for cases (dysphagia) and controls (no dysphagia). Thoracic radiology studies were reviewed further in cases for (thoracic cardiovascular) thoracic cardiovascular (TCV) structures in esophageal proximity to compare with HREIM findings. Manometric data was collected for number, location, axial length, PPZ pressure and esophageal clearance function (impedance).

Results: Among 317 screened patients, 56% cases and 64% controls had PPZ's. Fifty cases had an available thoracic radiology comparison. The distribution of PPZ's in these 50 cases and 59 controls was similar (average 1.4 PPZ/patient). Controls (mean 31.2 ± SD 12 years) were a significantly younger population than cases (mean 67.3 ± SD 14.9 years) with < 0.0001. The upright posture PPZ pressure was higher in controls (15.7 ± 10.0 mmHg) than cases (10.8 ± 9.7 mmHg). Although statistically significant ( = 0.005), it was a weak predictor using logistic regression and ROC model (AUC = 0.65). Three dysphagia patients had partial compression from external TCV on radiology (1 aberrant subclavian artery, 2 dilated left atrium). The posture (supine upright) with more prominent PPZ's impaired bolus clearance in 9 additional cases by > 20%.

Conclusion: Transmitted TCV pulsations observed in HREIM bear no significant impact on swallowing. However, in older adults with dysphagia, evidence of impaired bolus clearance on impedance should be evaluated for external TCV compression. These associations have never been explored previously in literature, and are novel.
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http://dx.doi.org/10.3748/wjg.v23.i44.7840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703913PMC
November 2017

Targeting Behavioral Symptoms and Functional Decline in Dementia: A Randomized Clinical Trial.

J Am Geriatr Soc 2018 02 28;66(2):339-345. Epub 2017 Nov 28.

Center of Innovation on Disability and Rehabilitation Research, North Florida/South Georgia Veterans Health System, Department of Veterans Affairs, Gainesville, Florida.

Background/objectives: Dementia-related behavioral symptoms and functional dependence result in poor quality of life for persons with dementia and their caregivers. The goal was to determine whether a home-based activity program (Tailored Activity Program; TAP-VA) would reduce behavioral symptoms and functional dependence of veterans with dementia and caregiver burden.

Design: Single-blind (interviewer), parallel, randomized, controlled trial (Clinicaltrials.gov: NCT01357564).

Setting: Veteran's homes.

Participants: Veterans with dementia and their family caregivers (N = 160 dyads).

Intervention: Dyads in TAP-VA underwent 8 sessions with occupational therapists to customize activities to the interests and abilities of the veterans and educate their caregivers about dementia and use of customized activity. Caregivers assigned to attention control received up to 8 telephone-based dementia education sessions with a research team member.

Measurements: Primary outcomes included number of behaviors and frequency of their occurrence multiplied by severity of occurrence; secondary outcomes were functional dependence, pain, emotional well-being, caregiver burden (time spent caregiving, upset with behaviors) and affect at 4 (primary endpoint) and 8 months.

Results: Of 160 dyads (n = 76 TAP-VA; n = 84 control), 111 completed 4-month interviews (n = 51 TAP-VA; n = 60 control), and 103 completed 8-month interviews (n = 50 TAP-VA; n = 53 control). At 4 months, compared to controls, the TAP-VA group showed reductions in number (difference in mean change from baseline = -0.68, 95% CI = -1.23 to -0.13) and frequency by severity (-24.3, 95% CI = -45.6 to -3.1) of behavioral symptoms, number of activities needing assistance with (-0.80, 95% CI = -1.41 to -0.20), functional dependence level (4.09, 95% CI = 1.06, 7.13), and pain (-1.18, 95% CI = -2.10 to -0.26). Caregivers of veterans in TAP-VA reported less behavior-related distress. Benefits did not extend to 8 months.

Conclusion: TAP-VA had positive immediate effects and no adverse events. Because TAP-VA reduces behavioral symptoms, slows functional dependence, and alleviates pain and caregiver distress, it is a viable treatment option for families.
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http://dx.doi.org/10.1111/jgs.15194DOI Listing
February 2018

Minimal residual disease by either flow cytometry or cytogenetics prior to an allogeneic hematopoietic stem cell transplant is associated with poor outcome in acute myeloid leukemia.

Blood Cancer J 2017 11 27;7(12):634. Epub 2017 Nov 27.

Division of Hematology and Oncology, Department of Internal Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.

Relapsed acute myeloid leukemia (AML) is a significant challenge after allogeneic hematopoietic cell transplant (HCT). Multiparameter flow cytometry (MFC), conventional cytogenetics (CG), and fluorescence in situ hybridization (FISH) are routinely performed on bone marrow specimens prior to HCT to assess disease status. We questioned the extent by which pre-HCT evidence of minimal residual disease (MRD) detected by these standard assays, corresponded with post-HCT relapse. We conducted a single center, retrospective study of 166 AML patients who underwent HCT. Thirty-eight of one hundred sixty-six (23%) patients in complete remission (CR) or CR with incomplete count recovery (CRi) had MRD detectable by MFC, CG, or FISH. MRD was more frequently seen in patients with poor risk karyotype at diagnosis (P = 0.011). MRD-negative patients (MRD) had significantly longer overall survival (OS) and relapse-free survival than patients who were MRD positive (MRD) (P = 0.002 and 0.013, respectively). In patients with MRD prior to HCT, the presence of acute graft vs. host disease (GVHD) (grade ≥ 2) or chronic GVHD significantly improved progression free survival (PFS) (hazard ratio (HR) = 0.053 (95% confidence interval (CI): 0.01-0.279), P = 0.0005) and OS (HR = 0.211 (95% CI: 0.081-0.547), P = 0.0014).
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http://dx.doi.org/10.1038/s41408-017-0007-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5802525PMC
November 2017

Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.

Blood 2017 06 13;129(25):3352-3361. Epub 2017 Apr 13.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by genomic alterations that activate cytokine receptor and kinase signaling. We examined the frequency and spectrum of targetable genetic lesions in a retrospective cohort of 1389 consecutively diagnosed patients with childhood B-lineage ALL with high-risk clinical features and/or elevated minimal residual disease at the end of remission induction therapy. The Ph-like gene expression profile was identified in 341 of 1389 patients, 57 of whom were excluded from additional analyses because of the presence of - (n = 46) or - (n = 11). Among the remaining 284 patients (20.4%), overexpression and rearrangement of (- or -) were identified in 124 (43.7%), with concomitant genomic alterations activating the JAK-STAT pathway (, , ) identified in 63 patients (50.8% of those with rearrangement). Among the remaining patients, using reverse transcriptase polymerase chain reaction or transcriptome sequencing, we identified targetable ABL-class fusions (, , , and ) in 14.1%, rearrangements or fusions in 8.8%, alterations activating other JAK-STAT signaling genes (, , ) in 6.3% or other kinases (, , ) in 4.6%, and mutations involving the Ras pathway (, , , ) in 6% of those with Ph-like ALL. We identified 8 new rearrangement partners for 4 kinase genes previously reported to be rearranged in Ph-like ALL. The current findings provide support for the precision-medicine testing and treatment approach for Ph-like ALL implemented in Children's Oncology Group ALL trials.
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http://dx.doi.org/10.1182/blood-2016-12-758979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482101PMC
June 2017

Perspectives on death and dying: a study of resident comfort with End-of-life care.

BMC Med Educ 2016 Nov 21;16(1):297. Epub 2016 Nov 21.

Department of Medicine, Division of Hematology and Oncology, University of Florida, 1600 SW Archer Rd, 32610, Gainesville, FL, USA.

Background: Despite the benefits to early palliative care in the treatment of terminal illness, barriers to timely hospice referrals exist. Physicians who are more comfortable having end-of-life (EOL) conversations are more likely to refer to hospice. However, very little is known about what factors influence comfort with EOL care.

Methods: An anonymous survey was sent to all the residents and fellows at a single institution. Self-reported education, experience and comfort with EOL care was assessed. Using multivariate logistic regression analysis, variables that influenced comfort with EOL conversations were analyzed.

Results: Most residents (88.1%) reported little to no classroom training on EOL care during residency. EOL conversations during residency were frequent (50.6% reported > 10) and mostly unsupervised (61.9%). In contrast, EOL conversations during medical school were infrequent (3.7% reported >10) and mostly supervised (78.6%). Most (54.3%) reported little to no classroom training on EOL care during medical school. Physicians that reported receiving education on EOL conversations during residency and those who had frequent EOL conversations during residency had significantly higher comfort levels having EOL conversations (p = 0.017 and p = 0.003, respectively). Likewise, residents that felt adequately prepared to have EOL conversations when graduating from medical school were more likely to feel comfortable (p = 0.030).

Conclusions: Most residents had inadequate education in EOL conversation skills during medical school and residency. Despite the lack of training, EOL conversations during residency are common and often unsupervised. Those who reported more classroom training during residency on EOL skills had greater comfort with EOL conversations. Training programs should provide palliative care education to all physicians during residency and fellowship, especially for those specialties that are most likely to encounter patients with advanced terminal disease.
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http://dx.doi.org/10.1186/s12909-016-0819-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117582PMC
November 2016

Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.

Nat Commun 2016 11 8;7:13331. Epub 2016 Nov 8.

US Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, USA.

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.
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http://dx.doi.org/10.1038/ncomms13331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105166PMC
November 2016
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