12 Dec Novel Subtypes in B Progenitor Acute Lymphoblastic Leukemia
MedicalResearch.comInterview with:
Zhaohui Gu, PhD
Postdoctoral Research Associate
St. Jude Children's Research Hospital, TN
MedicalResearch.com: What is the background for this study? What are the main findings?
Response:B-progenitor acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and the leading cause of childhood cancer death. B-ALL includes multiple subtypes that are defined by distinct genetic alterations and that play an important role in diagnosis, prognosis and therapy of patients. Advances in transcriptome sequencing (RNA-seq)have helped researchers discover additional subtypes and driver mutations inB-ALL and identify possible new therapeutic targets. Still, up to 30% of B-ALL cases do not fit into established subtypes. These patients lack targeted therapeutic approaches and commonly relapse.
Fort his study, we used integrated genomic analysis of 1,988 childhood and adult cases to revise the classification system of B-ALL. The system includes eight new subtypes and a total of 23 B-ALL subtypes. The subtypes are defined by chromosomal rearrangements, sequence mutations, or heterogeneous genomic alterations. Many show a marked variation in prevalence according to age.
The newly identified subtypes included
one (n=18) defined by rearrangements of gene BCL2, MYC and/or BCL6 anda distinctive gene expression profile (GEP). Patients in this
subtype were mostly adults (n=16) with very poor outcomes.
Another
novel subtype was defined by IKZF1
N159Y missense mutation. N159Y is in the DNA-binding domain of IKZF1, and is
known to disrupt IKZF1 function, with distinct nuclear mis-localization and
induction of aberrant intercellular adhesion. There were eight cases in this
subtype that shared highly similar GEPs.
We also
identified two subtypes with distinct GEP and characterized by PAX5 alterations. One, PAX5 altered
(PAX5alt), included 148 cases. PAX5alt was characterized by diverse PAX5 alterations including
rearrangements (n=57), sequence mutations (n=46) and/or focal intragenic
amplifications (n=8). These PAX5
alterations were found in 73.6% of PAX5alt cases. The second distinct subtype
comprised 44 cases, all with PAX5
P80R missense mutations. Bi-allelic PAX5
alterations were commonly seen in this subtype in the form of PAX5 P80R coupled with a second sequence
mutation or deletion of the wild-type PAX5
allele.
Adult PAX5 P80R cases showed better 5-year OS (61.9±13.4%) than those in PAX5alt subtype (42.1±10.2%). In addition, Pax5 P80R heterozygous and homozygous mice developed B lineage leukemia with a median latency of 166 and 87 days, respectively. The heterozygous mice acquired alterations on the second allele, which faithfully recapitulated the condition of the patient leukemia.
MedicalResearch.com: What should readers take away from your report?
Response: Identification of subtypes accurately is very
important for diagnosis, intensity-tailored therapy, and to identify targetable
lesions. In this large scale genomic study, we demonstrated the power of using RNA-seq
to classifying B-ALL and established a revised B-ALL taxonomy with 23 distinct
subtypes. We identified 8 novel subtypes, including two defined by PAX5 alterations. Through in vitro and in vivo experiments, we demonstrated that PAX5 P80R could impair B
cell differentiation and initiate leukemia.
Together with the subtype defined by IKZF1
N159Y mutation, we showed for the first time that transcription factor missense
mutations could be a subtype defining genetic lesions.
Dr. Gardner[/caption]
Rebekah L Gardner MD
Associate Professor of Medicine
Warren Alpert Medical School
Brown University
Providence, Rhode Island
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Burnout profoundly affects physicians, their patients, and the health care system.The role of technology in physician burnout, specifically health information technology (HIT), is not as well characterized as some of the other factors. We sought to understand how stress related to HIT use predicts burnout among physicians.
Our main findings are that 70% of electronic health record (EHR) users reported HIT-related stress, with the highest prevalence in primary care-oriented specialties. We found that experiencing HIT-related stress independently predicted burnout in these physicians, even accounting for other characteristics like age, gender, and practice type. In particular, those with time pressures for documentation or those doing excessive “work after work” on their EHR at home had approximately twice the odds of burnout compared to physicians without these challenges. We found that physicians in different specialties had different rates of stress and burnout.
Dr. Steen[/caption]
Dr. Lowell H. Steen, Jr., M.D.
Interventional Cardiologist
Loyola University Medical Center
Dr. Steen discusses how holiday treats & stress can increase the risk of heart attack.
MedicalResearch.com: What are the main factors that are linked to an increase in heart related adverse events during the Christmas holiday season? Who is most at risk?
Response: The increase in holiday season heart-related hospitalizations and deaths are due to a variety of behaviors such as putting off seeking medical help until after the holidays, overeating rich foods, strenuous travel, excessive alcohol consumption and stressful family interactions. These factors can all trigger heart issues.
Factors such as age, diabetes, high cholesterol and smoking all increase heart risk. Additionally, those with high blood pressure, which is a leading risk factor for heart disease and stroke, are exceptionally at risk and should celebrate the hectic holiday season with caution. 
Dr. Wadhera[/caption]
Dr. Rishi Wadhera, MD
Cardiology Fellow
Brigham and Women's Hospital
Harvard Medical School.
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: In the United States, an estimated half a million people are homeless on any given night. In recent years, policy efforts to improve the health of homeless individuals have intensified, but there is little large-scale, contemporary data on how these efforts have impacted patterns of acute illness in this vulnerable population.
In this study, we examined trends, causes, and outcomes of hospitalizations among homeless individuals in three states – Massachusetts, Florida, and California – from 2007 to 2013. We found that hospitalization rates among homeless adults increased over this period of time.
Strikingly, over one-half of these hospitalizations were for mental illness and substance use disorder. More broadly, homeless adults were hospitalized for a very different set of reasons compared with demographically similar non-homeless adults. In addition, homeless individuals had longer lengths of hospitalization but lower total costs per hospitalization.
Prof. VanderWeele[/caption]
Professor Tyler VanderWeele Ph.D
John L. Loeb and Frances Lehman Loeb Professor of Epidemiology
Harvard University
MedicalResearch.com: What is the background for this study? What are the key points of the paper?
Response: Several prior studies have suggested that religious service attendance is associated with lower rates of divorce. However, many of these studies have been with small samples and have not had rigorous study designs. In addition, most studies have focused on women earlier in life and there has been little research on the effects of religious service attendance on divorce later in life. While divorce rates in the United States in general has been falling, it has in fact been increasing for middle-aged groups, doubling between 1990 and 2010.
In our study we found that among women in mid- to late- life, regular religious service attendance was subsequently associated with 50% lower divorce rates over the following 14 years of the study.
We also found that among those who were widowed, religious service attendance was associated with a 49% increase in the likelihood of remarrying over the 14 years of the study.
Dr. Barrett[/caption]
Charles Barrett. Ph.D.
School Psychologist
Loudon County Virginia
Public Schools
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Numerous studies have shown that Black children are more likely to receive ratings that are more indicative of displaying externalizing behavior difficulties, including Attention Deficit Hyperactivity Disorder (ADHD). However, many of these studies included teachers as the informants. Consistent with most teachers in the United States, raters have typically been White females. For this reason, it is unclear if these outcomes would exist if the rater and child shared the same racial/ethnic background. Additionally, most research in the United States that involved cross-cultural comparisons has used White and Hispanic boys. Few empirical studies have examined differences between Black and White boys.
The present study sought to address several limitations in the field. Most notably, cross-cultural comparisons between Black and White boys were included instead of Hispanic and White children. Next, maternal figures, rather than teachers, were included as the informants.
The present study was developed using a similar methodology that examined Hispanic and White boys’ behavior from the perspective of Hispanic and White teachers (Dominguez de Ramirez & Shapiro, 2005). In sum, we sought to determine if there were differences in how Black and White maternal figures rated Black and White boys who were demonstrating the same level/type of behavior (i.e., sub-clinical levels of 