Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835+, 2 ITD+), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD+, 2 D835+), 5 who were all originally ITD+ had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease

Characterization of a novel variant BCR–ABL1 fusion transcript in a patient with chronic myeloid leukemia: Implications for molecular monitoring

AbstractMolecular monitoring of BCR–ABL1 transcript levels using quantitative polymerase chain reaction is an essential part of the modern management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Establishing the diagnostic BCR–ABL1 fusion transcript is necessary in order to select appropriate primers and probes for such monitoring. A case is described in which quantitative polymerase chain reaction failed to detect the presence of BCR–ABL1 fusion transcript in a Philadelphia chromosome-positive chronic myeloid leukemia patient. Further investigation demonstrated a novel in-frame BCR–ABL1 fusion transcript with a breakpoint in BCR exon 13 and insertion of a sequence of ABL1 intron 1, therefore enabling subsequent molecular monitoring. This case highlights the requirement for characterization of the BCR–ABL1 transcript type at chronic myeloid leukemia diagnosis. Issues concerning standardized methodological approaches and interpretation of transcript levels in such rare cases are discussed

Barriers and Disparities in Emergency Medical Services 911 Calls for Stroke Symptoms in the United States Adult Population: 2009 BRFSS Survey

Introduction: This study examines barriers and disparities in the intentions of American citizens, when dealing with stroke symptoms, to call 911. This study hypothesizes that low socioeconomic populations are less likely to call 911 in response to stroke recognition. Methods: The study is a cross-sectional design analyzing data from the Centers for Disease Control’s 2009 Behavioral Risk Factor Surveillance Survey, collected through a telephone-based survey from 18 states and the District of Columbia. The study identified the 5 most evident stroke-warning symptoms based on those given by the American Stroke Association. We conducted appropriate weighting procedures to account for the complex survey design. Results: A total of 131,988 respondents answered the following question: “If you thought someone was having a heart attack or a stroke, what is the first thing you would do?” A majority of those who said they would call 911 were insured (85.1%), had good health (84.1%), had no stroke history (97.3%), had a primary care physician (PCP) (81.4%), and had no burden of medical costs (84.9%). Those less likely to call 911 were found in the following groups: 65 years or older, men, other race, unmarried, less than or equal to high school degree, less than $25,000 family income, uninsured, no PCP, burden of medical costs, fair/poor health, previous history of strokes, or interaction between burden of medical costs and less than$50,000 family income (p\u3c0.0001 by X2 tests). The only factors significantly associated with “would call 911” were age, sex, race/ethnicity, marital status, and previous history of strokes. Conclusion: Barriers and disparities exist among subpopulations of different socioeconomic statuses. This study suggests that some potential stroke victims could have limited access to EMS services. Greater effort targeting certain populations is needed to motivate citizens to call 911. [West J Emerg Med. 2014;15(2):251–259]

Inter-Laboratory Evaluation of a Next-Generation Sequencing Panel for Acute Myeloid Leukemia

INTRODUCTION: Acute myeloid leukemia (AML) is a heterogeneous clonal disorder often associated with dismal overall survival. The clinical diversity of AML is reflected in the range of recurrent somatic mutations in several genes, many of which have a prognostic and therapeutic value. Targeted next-generation sequencing (NGS) of these genes has the potential for translation into clinical practice. In order to assess this potential, an inter-laboratory evaluation of a commercially available AML gene panel across three diagnostic centres in the UK and Ireland was performed.METHODS: DNA from six AML patient samples was distributed to each centre and processed using a standardised workflow, including a common sequencing platform, sequencing chips and bioinformatics pipeline. A duplicate sample in each centre was run to assess inter- and intra-laboratory performance.RESULTS: An average sample read depth of 2725X (range 629-5600) was achieved using six samples per chip, with some variability observed in the depth of coverage generated for individual samples and between centres. A total of 16 somatic mutations were detected in the six AML samples, with a mean of 2.7 mutations per sample (range 1-4) representing nine genes on the panel. 15/16 mutations were identified by all three centres. Allelic frequencies of the mutations ranged from 5.6 to 53.3 % (median 44.4 %), with a high level of concordance of these frequencies between centres, for mutations detected.CONCLUSION: In this inter-laboratory comparison, a high concordance, reproducibility and robustness was demonstrated using a commercially available NGS AML gene panel and platform.</p

A RETROSPECTIVE ANALYSIS OF CLAIMS DATA TO DETERMINE SYMPTOMS ASSOCIATED WITH OVARIAN CANCER

According to the American Cancer Society, approximately twenty percent (20% of women with ovarian cancer are diagnosed at an early stage (e.g. stage I or II), which subsequently means eighty percent (80%) of women diagnosed with this disease are at the late stage (e.g. stage III or IV) and are likely not to survive. No cure exists and, concurrently, studies show mixed results in utilizing blood tests and transvaginal ultrasounds to screen for ovarian cancer. While symptoms are not easily discernable, some oncologists have validated there are common symptoms women experience prior to diagnosis. As these symptoms are not routinely recognized by general practitioners as an indicator to detect ovarian cancer, we conducted a retrospective study to determine whether certain types of symptoms are evident prior to the diagnosis. Our two specific aims included: (1) conduct an exploratory study to determine if certain symptoms were prevalent in women that are diagnosed with ovarian cancer; and (2) assess and compare symptoms experienced by women diagnosed with ovarian cancer to women that have not been diagnosed with any type of cancer. The symptoms were identified by forty-seven (47) International Classification of Disease, 9th revision (ICD-9), diagnosis codes and categorized into four primary groups: (i) abdominal-pelvis; (ii) bladder; (iii) digestive; and (iv) pain. In conjunction with identifying the type of symptoms experienced, reoccurrence and combination of symptoms were also analyzed. The data to support this study was derived from health insurance claims between 2008 through 2013 from a commercial payer. All subjects for both studies were residents in the state of Texas and were a minimum of 24 years old. The analysis of the first aim of the study was primarily descriptive to assess symptoms and frequencies experienced prior to diagnosis. Of the 3,601 women diagnosed with ovarian cancer, 2,292 (64%) experienced a related symptom prior to or at diagnosis. Over 60% (n=1544) of women experienced a first symptom associated with abdomen and pelvis and 85% of overall complaints were associated with this group of symptoms. Pain was the second most frequent complaint at 45%, followed by digestive at 24% and bladder at 18%. This was also confirmed in women who experienced a combination of symptoms where abdomen and pelvis along with pain was shown to be the highest complaint at 41%. The results of the first study consequently led to pursue the second aim which included a nested case control study comparing a subset of 789 women diagnosed with ovarian cancer to women who did not have any history of cancer. The results supported statistical significance in symptoms experienced specific to abdomen and pelvis in conjunction with pain as well as digestive. While these symptoms are ordinary and are difficult to distinguish as having an association with ovarian cancer, the findings of this research appear to affirm that a symptom index may prove to be a useful method when recurring complaints are presented in women