https://www.medicalnewstoday.com/articles/323444.php
https://ascopubs.org/doi/full/10.1200/JCO.2008.16.0333
https://journals.lww.com/co-hematology/Abstract/2007/03000/Influence_of_new_molecular_prognostic_markers_in.5.aspx
Influence of new molecular prognostic markers in patients with karyotypically normal acute myeloid leukemia: recent advances
Mrózek, Krzysztofa; Döhner, Hartmutb; Bloomfield, Clara Da
Current Opinion in Hematology: March 2007 - Volume 14 - Issue 2 - p 106–114
doi: 10.1097/MOH.0b013e32801684c7
Myeloid disease
Purpose of review Molecular study of cytogenetically normal acute myeloid leukemia is among the most active areas of leukemia research. Despite having the same normal karyotype, adults with de-novo cytogenetically normal acute myeloid leukemia who constitute the largest cytogenetic group of acute myeloid leukemia, are very diverse with respect to acquired gene mutations and gene expression changes. These genetic alterations affect clinical outcome and may assist in selection of proper treatment. Herein we critically summarize recent clinically relevant molecular genetic studies of cytogenetically normal acute myeloid leukemia.
Recent findings NPM1 gene mutations causing aberrant cytoplasmic localization of nucleophosmin have been demonstrated to be the most frequent submicroscopic alterations in cytogenetically normal acute myeloid leukemia and to confer improved prognosis, especially in patients without a concomitant FLT3 gene internal tandem duplication. Overexpressed BAALC, ERG and MN1 genes and expression of breast cancer resistance protein have been shown to confer poor prognosis. A gene-expression signature previously suggested to separate cytogenetically normal acute myeloid leukemia patients into prognostic subgroups has been validated on a different microarray platform, although gene-expression signature-based classifiers predicting outcome for individual patients with greater accuracy are still needed.
Summary The discovery of new prognostic markers has increased our understanding of leukemogenesis and may lead to improved prognostication and generation of novel risk-adapted therapies.
http://www.bloodjournal.org/content/127/1/53?sso-checked=true
An update of current treatments for adult acute myeloid leukemia
Hervé Dombret and Claude Gardin
Abstract
Recent advances in acute myeloid leukemia (AML) biology and its genetic landscape should ultimately lead to more subset-specific AML therapies, ideally tailored to each patient's disease. Although a growing number of distinct AML subsets have been increasingly characterized, patient management has remained disappointingly uniform. If one excludes acute promyelocytic leukemia, current AML management still relies largely on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), at least in younger patients who can tolerate such intensive treatments. Nevertheless, progress has been made, notably in terms of standard drug dose in ...
A sample of an annotated bibliography entry for HCM402, using the .docxblondellchancy
A sample of an annotated bibliography entry for HCM402, using the guidelines on page 11, and addressing at least one bullet per section
Peter Pronovost, M.D., Ph.D., Dale Needham, M.D., Ph.D., Sean Berenholtz, M.D., David Sinopoli, M.P.H., M.B.A., Haitao Chu, M.D., Ph.D., Sara Cosgrove, M.D., Bryan Sexton, Ph.D., Robert Hyzy, M.D., Robert Welsh, M.D., Gary Roth, M.D., Joseph Bander, M.D., John Kepros, M.D., and Christine Goeschel, R.N., M.P.A. An Intervention to Decrease Catheter-Related Bloodstream Infections in the ICU N Engl J Med 2006;355:2725-32.
This study is closely related to the previous literature, which is cited. The review of earlier work is recent and complete as of the time this article was written.
The problem statement is clear: Can catheter-related bloodstream infections occurring in the intensive care unit (ICU) be reduced using training protocols and checklists?
The hypothesis is clearly stated: catheter-related bloodstream infections occurring in the intensive care unit (ICU) will be reduced using training protocols and checklists.
Method: independent and dependent variables are clearly stated, and are, respectively, the intervention of training protocols/checklists, and the rates of catheter related bloodstream infections.
The sample was 108 hospital ICUs in Michigan that agreed to participate in the study, and of these, 103 reported data. The analysis included 1981 ICU-months of data and 375,757 catheter-days. This sample should be representative of hospitals in other states in the United States
Results and Discussion are related to the hypotheses. The median
rate of catheter-related bloodstream infection per 1000 catheter-days decreased
from 2.7 infections at baseline to 0 at 3 months after implementation of the study
intervention (P≤0.002), and the mean rate per 1000 catheter-days decreased from
7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002). The regression model
showed a significant decrease in infection rates from baseline, with incidence-rate
ratios continuously decreasing from 0.62 (95% confidence interval [CI], 0.47 to 0.81)
at 0 to 3 months after implementation of the intervention to 0.34 (95% CI, 0.23 to
0.50) at 16 to 18 months.
The list of references was current at the time the article was written.
The report is clearly written and understandable.
Running head: ACUTE MYELOID LEUKEMIA: A CONCISE REVIEW 1
ACUTE MYELOID LEUKEMIA: A CONCISE REVIEW 8Acute Myeloid Leukemia
Ruth Ivy
HCM 402
July 14, 2019
Acute Myeloid Leukemia
The body is made up of million cells that undergo cell cycle that allows them to grow then they divide and die. For you to be able to understand the concept around this, you will need to know about cancer whereby cells grow uncontrollably. In that case, cells grow but they do not die like other normal cells. This occurs by first damaging the DNA of the cells. Leukemia starts in the organs that make up the blood, called the bone marrow. Acute cancer will need to be ...
A sample of an annotated bibliography entry for HCM402, using the .docxblondellchancy
A sample of an annotated bibliography entry for HCM402, using the guidelines on page 11, and addressing at least one bullet per section
Peter Pronovost, M.D., Ph.D., Dale Needham, M.D., Ph.D., Sean Berenholtz, M.D., David Sinopoli, M.P.H., M.B.A., Haitao Chu, M.D., Ph.D., Sara Cosgrove, M.D., Bryan Sexton, Ph.D., Robert Hyzy, M.D., Robert Welsh, M.D., Gary Roth, M.D., Joseph Bander, M.D., John Kepros, M.D., and Christine Goeschel, R.N., M.P.A. An Intervention to Decrease Catheter-Related Bloodstream Infections in the ICU N Engl J Med 2006;355:2725-32.
This study is closely related to the previous literature, which is cited. The review of earlier work is recent and complete as of the time this article was written.
The problem statement is clear: Can catheter-related bloodstream infections occurring in the intensive care unit (ICU) be reduced using training protocols and checklists?
The hypothesis is clearly stated: catheter-related bloodstream infections occurring in the intensive care unit (ICU) will be reduced using training protocols and checklists.
Method: independent and dependent variables are clearly stated, and are, respectively, the intervention of training protocols/checklists, and the rates of catheter related bloodstream infections.
The sample was 108 hospital ICUs in Michigan that agreed to participate in the study, and of these, 103 reported data. The analysis included 1981 ICU-months of data and 375,757 catheter-days. This sample should be representative of hospitals in other states in the United States
Results and Discussion are related to the hypotheses. The median
rate of catheter-related bloodstream infection per 1000 catheter-days decreased
from 2.7 infections at baseline to 0 at 3 months after implementation of the study
intervention (P≤0.002), and the mean rate per 1000 catheter-days decreased from
7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002). The regression model
showed a significant decrease in infection rates from baseline, with incidence-rate
ratios continuously decreasing from 0.62 (95% confidence interval [CI], 0.47 to 0.81)
at 0 to 3 months after implementation of the intervention to 0.34 (95% CI, 0.23 to
0.50) at 16 to 18 months.
The list of references was current at the time the article was written.
The report is clearly written and understandable.
Running head: ACUTE MYELOID LEUKEMIA: A CONCISE REVIEW 1
ACUTE MYELOID LEUKEMIA: A CONCISE REVIEW 8Acute Myeloid Leukemia
Ruth Ivy
HCM 402
July 14, 2019
Acute Myeloid Leukemia
The body is made up of million cells that undergo cell cycle that allows them to grow then they divide and die. For you to be able to understand the concept around this, you will need to know about cancer whereby cells grow uncontrollably. In that case, cells grow but they do not die like other normal cells. This occurs by first damaging the DNA of the cells. Leukemia starts in the organs that make up the blood, called the bone marrow. Acute cancer will need to be ...
Acute myeloid leukemia originates in the bone marrow from immature white blood cells, specifically granulocytes or monocytes.
In the realm of drug therapy, the potential market for AML Type (AML with t(8;21)(q22;q22); (RUNX1;RUNX1T1)) was valued at USD$ 22.21 million in 2020. This particular AML subtype market is anticipated to exhibit a compound annual growth rate (CAGR) of 6.3% from 2021 to 2030.
Notably, Novartis is directing its attention toward newly diagnosed patients with FLT3-mutated acute myeloid leukemia. The key therapeutic solution on the horizon is Midostaurin 50 mg, expected to be launched in the coming years, promising advancements in treatment options for this patient group.
Acute myeloid leukemia (AML) is classified into various groups or systems, including the French-American-British (FAB) system and the World Health Organization (WHO) system.
The FAB system categorizes AML based on the appearance of leukemia cells under the microscope and the presence of specific antibody proteins on these cells. In contrast, the WHO system classifies AML by considering myeloid cells and the presence of abnormal chromosomal (genetic) changes within these cells.
The WHO system is commonly referenced, as it places a significant emphasis on the genetic makeup of leukemia cells, making it a valuable tool for predicting prognosis. Molecular biomarkers are employed for this purpose and to forecast responses to approved targeted therapies in AML patients.
A variety of molecular biomarkers and genetic alterations, including karyotypes, chromosomal translocations, inversions, deletions, and gene mutations, have been identified as prognostic indicators in AML.
Second-line induction therapy is the quickest path to regulatory approval for adult patients with relapsed or refractory AML. Notably, Annamycin has shown promise as a second-line induction therapy for these patients.
The FDA has approved several therapies for refractory or relapsed AML, such as Enasidenib (Idhifa®), Gemtuzumab ozogamicin (MylotargTM), Ivosidenib (Tibsovo®), and Gilteritinib (Xospata®).
Effective pricing is essential to ensure that these drugs are accessible to patients.
Clinical effectiveness plays a crucial role in shaping the drug market for AML treatments.
Industry players are placing increased focus on specific mutations, as evidenced by clinical studies conducted by companies like Arog Pharmaceuticals, Inc. (founded in 2010), which is currently studying AML patients with FLT3 activation mutations (Clinical Trial Identifier: NCT01657682).
Cancer chemotherapy for medical studentstaklo simeneh
Cancer chemotherapy has been presented in detail for medical students. It can be used for other health students by modifying it based on their curriculum and time given.
One of my best friends (when I was a teenager) died of leukemia. Several advances have been made in the ensuing decades (see attached document). Watch this space for additional notes.
httpswww.azed.govoelaselpsUse this to see the English Lang.docxpooleavelina
https://www.azed.gov/oelas/elps/
Use this to see the English Language Proficiency Standards of Arizona-Pick a grade level
https://cms.azed.gov/home/GetDocumentFile?id=54de1d88aadebe14a87070f0
http://www.corestandards.org/ELA-Literacy/introduction/how-to-read-the-standards/
how to read standards
Week 04
Acquisition and Customer Lifetime Value (CLV)
https://www.smh.com.au/politics/federal/nbn-customers-face-higher-prices-or-poorer-internet-connection-audit-warns-20190813-p52go7.html
Customer Relationship Management?
CRM is the process of carefully managing detailed information about individual
customers and all customer touch points to maximize customer loyalty.
Now closely associated with data warehousing and mining
Relationship
Relationship
Identifying good customers: RFM Model
Recency
Frequency
Monetary Value
Time/purchase occasions since the last purchase
Number of purchase occasions since first purchase
Amount spent since the first purchase
R
F
M
Total RFM Score: R Score + F score + M Score
CASE: Database for BookBinders Book Club
Predict response to a mailing for the book, Art History of Florence, based on the
following variables accumulated in the database and the responses to a test mailing:
Gender
Amount purchased
Months since first purchase
Months since last purchase
Frequency of purchase
Past purchases of art books
Past purchases of children’s books
Past purchases of cook books
Past purchases of DIY books
Past purchases of youth books
Recency
Frequency
Monetary
Example: RFM Model Scoring Criteria
R
Months from last
purchase
13-max 10-12 7-9 3-6 0-2
Score 5pts 10 15 20 25
F
Frequency > 30 21-30 16-20 11-15 0-10
Score 25pts 20 15 10 5
M
Amount
purchased
> 400 301-400 201-300 101- 200 100
Score 50 45 30 15 10
Implement using Nested If statements in Excel
Decile Classification
• Standard Assessment Method
• Apply the results of approach and
calculate the “score” of each individual
• Order the customers based on “score”
from the highest to the lowest
• Divide into deciles
• Calculate profits per deciles
Customer 1 Score 1.00
Customer 2 Score 0.99
….
Customer 230 Score 0.92
Customer 2300 Score 0.00
Decile1
Decile10
…
..
…
..
Output for Bookbinders club
Decile Score RFM No. of Mailings Cost of mailing RFM Units sold RFM Profit
10 17.6% 5000 $3,250 783 $4,733
20 34.8% 10000 $6,500 1,543 $9,243
30 46.1% 15000 $9,750 2,043 $11,093
40 53.4% 20000 $13,000 2,370 $11,170
50 65.2% 25000 $16,250 2,891 $13,241
60 77.9% 30000 $19,500 3,457 $15,757
70 83.3% 35000 $22,750 3,696 $14,946
80 91.7% 40000 $26,000 4,065 $15,465
90 97.5% 45000 $29,250 4,326 $14,876
100 100.0% 50000 $32,500 4,435 $12,735
Note: Market Potential = 4435 units and margin = $10.20
Leaky bucket
New customer
acquisition
Purchase increase by
current customers
Purchase decrease by
current customers
Lost customers
Lost customers
Credit Card Rewards Program ...
httpfmx.sagepub.comField Methods DOI 10.117715258.docxpooleavelina
http://fmx.sagepub.com
Field Methods
DOI: 10.1177/1525822X04269550
2005; 17; 30 Field Methods
Don A. Dillman and Leah Melani Christian
Survey Mode as a Source of Instability in Responses across Surveys
http://fmx.sagepub.com/cgi/content/abstract/17/1/30
The online version of this article can be found at:
Published by:
http://www.sagepublications.com
can be found at:Field Methods Additional services and information for
http://fmx.sagepub.com/cgi/alerts Email Alerts:
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at SAGE Publications on September 9, 2009 http://fmx.sagepub.comDownloaded from
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http://fmx.sagepub.com
10.1177/1525822X04269550FIELD METHODSDillman, Christian / SURVEY MODE AS SOURCE OF INSTABILITY
Survey Mode as a Source of Instability
in Responses across Surveys
DON A. DILLMAN
LEAH MELANI CHRISTIAN
Washington State University
Changes in survey mode for conducting panel surveys may contribute significantly to
survey error. This article explores the causes and consequences of such changes in
survey mode. The authors describe how and why the choice of survey mode often
causes changes to be made to the wording of questions, as well as the reasons that
identically worded questions often produce different answers when administered
through different modes. The authors provide evidence that answers may change as a
result of different visual layouts for otherwise identical questions and suggest ways
to keep measurement the same despite changes in survey mode.
Keywords: survey mode; questionnaire; panel survey; measurement; survey error
Most panel studies require measurement of the same variables at different
times. Often, participants are asked questions, several days, weeks, months,
or years apart to measure change in some characteristics of interest to the
investigation. These characteristics might include political attitudes, satis-
faction with a health care provider, frequency of a behavior, ownership of
financial resources, or level of educational attainment. Whatever the charac-
teristic of interest, it is important that the question used to ascertain it perform
the same across multiple data collections.
In addition, declining survey response rates, particularly for telephone
surveys, have encouraged researchers to use multiple modes of data collec-
tion during the administration of a single cross-sectional survey. Encouraged
by the availability of more survey modes than in the past and evidence that a
change in modes produces higher response rates (Dillman 2002), surveyors
This is a revision of a paper presented at t ...
More Related Content
Similar to httpswww.medicalnewstoday.comarticles323444.phphttpsasco.docx
Acute myeloid leukemia originates in the bone marrow from immature white blood cells, specifically granulocytes or monocytes.
In the realm of drug therapy, the potential market for AML Type (AML with t(8;21)(q22;q22); (RUNX1;RUNX1T1)) was valued at USD$ 22.21 million in 2020. This particular AML subtype market is anticipated to exhibit a compound annual growth rate (CAGR) of 6.3% from 2021 to 2030.
Notably, Novartis is directing its attention toward newly diagnosed patients with FLT3-mutated acute myeloid leukemia. The key therapeutic solution on the horizon is Midostaurin 50 mg, expected to be launched in the coming years, promising advancements in treatment options for this patient group.
Acute myeloid leukemia (AML) is classified into various groups or systems, including the French-American-British (FAB) system and the World Health Organization (WHO) system.
The FAB system categorizes AML based on the appearance of leukemia cells under the microscope and the presence of specific antibody proteins on these cells. In contrast, the WHO system classifies AML by considering myeloid cells and the presence of abnormal chromosomal (genetic) changes within these cells.
The WHO system is commonly referenced, as it places a significant emphasis on the genetic makeup of leukemia cells, making it a valuable tool for predicting prognosis. Molecular biomarkers are employed for this purpose and to forecast responses to approved targeted therapies in AML patients.
A variety of molecular biomarkers and genetic alterations, including karyotypes, chromosomal translocations, inversions, deletions, and gene mutations, have been identified as prognostic indicators in AML.
Second-line induction therapy is the quickest path to regulatory approval for adult patients with relapsed or refractory AML. Notably, Annamycin has shown promise as a second-line induction therapy for these patients.
The FDA has approved several therapies for refractory or relapsed AML, such as Enasidenib (Idhifa®), Gemtuzumab ozogamicin (MylotargTM), Ivosidenib (Tibsovo®), and Gilteritinib (Xospata®).
Effective pricing is essential to ensure that these drugs are accessible to patients.
Clinical effectiveness plays a crucial role in shaping the drug market for AML treatments.
Industry players are placing increased focus on specific mutations, as evidenced by clinical studies conducted by companies like Arog Pharmaceuticals, Inc. (founded in 2010), which is currently studying AML patients with FLT3 activation mutations (Clinical Trial Identifier: NCT01657682).
Cancer chemotherapy for medical studentstaklo simeneh
Cancer chemotherapy has been presented in detail for medical students. It can be used for other health students by modifying it based on their curriculum and time given.
One of my best friends (when I was a teenager) died of leukemia. Several advances have been made in the ensuing decades (see attached document). Watch this space for additional notes.
httpswww.azed.govoelaselpsUse this to see the English Lang.docxpooleavelina
https://www.azed.gov/oelas/elps/
Use this to see the English Language Proficiency Standards of Arizona-Pick a grade level
https://cms.azed.gov/home/GetDocumentFile?id=54de1d88aadebe14a87070f0
http://www.corestandards.org/ELA-Literacy/introduction/how-to-read-the-standards/
how to read standards
Week 04
Acquisition and Customer Lifetime Value (CLV)
https://www.smh.com.au/politics/federal/nbn-customers-face-higher-prices-or-poorer-internet-connection-audit-warns-20190813-p52go7.html
Customer Relationship Management?
CRM is the process of carefully managing detailed information about individual
customers and all customer touch points to maximize customer loyalty.
Now closely associated with data warehousing and mining
Relationship
Relationship
Identifying good customers: RFM Model
Recency
Frequency
Monetary Value
Time/purchase occasions since the last purchase
Number of purchase occasions since first purchase
Amount spent since the first purchase
R
F
M
Total RFM Score: R Score + F score + M Score
CASE: Database for BookBinders Book Club
Predict response to a mailing for the book, Art History of Florence, based on the
following variables accumulated in the database and the responses to a test mailing:
Gender
Amount purchased
Months since first purchase
Months since last purchase
Frequency of purchase
Past purchases of art books
Past purchases of children’s books
Past purchases of cook books
Past purchases of DIY books
Past purchases of youth books
Recency
Frequency
Monetary
Example: RFM Model Scoring Criteria
R
Months from last
purchase
13-max 10-12 7-9 3-6 0-2
Score 5pts 10 15 20 25
F
Frequency > 30 21-30 16-20 11-15 0-10
Score 25pts 20 15 10 5
M
Amount
purchased
> 400 301-400 201-300 101- 200 100
Score 50 45 30 15 10
Implement using Nested If statements in Excel
Decile Classification
• Standard Assessment Method
• Apply the results of approach and
calculate the “score” of each individual
• Order the customers based on “score”
from the highest to the lowest
• Divide into deciles
• Calculate profits per deciles
Customer 1 Score 1.00
Customer 2 Score 0.99
….
Customer 230 Score 0.92
Customer 2300 Score 0.00
Decile1
Decile10
…
..
…
..
Output for Bookbinders club
Decile Score RFM No. of Mailings Cost of mailing RFM Units sold RFM Profit
10 17.6% 5000 $3,250 783 $4,733
20 34.8% 10000 $6,500 1,543 $9,243
30 46.1% 15000 $9,750 2,043 $11,093
40 53.4% 20000 $13,000 2,370 $11,170
50 65.2% 25000 $16,250 2,891 $13,241
60 77.9% 30000 $19,500 3,457 $15,757
70 83.3% 35000 $22,750 3,696 $14,946
80 91.7% 40000 $26,000 4,065 $15,465
90 97.5% 45000 $29,250 4,326 $14,876
100 100.0% 50000 $32,500 4,435 $12,735
Note: Market Potential = 4435 units and margin = $10.20
Leaky bucket
New customer
acquisition
Purchase increase by
current customers
Purchase decrease by
current customers
Lost customers
Lost customers
Credit Card Rewards Program ...
httpfmx.sagepub.comField Methods DOI 10.117715258.docxpooleavelina
http://fmx.sagepub.com
Field Methods
DOI: 10.1177/1525822X04269550
2005; 17; 30 Field Methods
Don A. Dillman and Leah Melani Christian
Survey Mode as a Source of Instability in Responses across Surveys
http://fmx.sagepub.com/cgi/content/abstract/17/1/30
The online version of this article can be found at:
Published by:
http://www.sagepublications.com
can be found at:Field Methods Additional services and information for
http://fmx.sagepub.com/cgi/alerts Email Alerts:
http://fmx.sagepub.com/subscriptions Subscriptions:
http://www.sagepub.com/journalsReprints.navReprints:
http://www.sagepub.com/journalsPermissions.navPermissions:
http://fmx.sagepub.com/cgi/content/refs/17/1/30 Citations
at SAGE Publications on September 9, 2009 http://fmx.sagepub.comDownloaded from
http://fmx.sagepub.com/cgi/alerts
http://fmx.sagepub.com/subscriptions
http://www.sagepub.com/journalsReprints.nav
http://www.sagepub.com/journalsPermissions.nav
http://fmx.sagepub.com/cgi/content/refs/17/1/30
http://fmx.sagepub.com
10.1177/1525822X04269550FIELD METHODSDillman, Christian / SURVEY MODE AS SOURCE OF INSTABILITY
Survey Mode as a Source of Instability
in Responses across Surveys
DON A. DILLMAN
LEAH MELANI CHRISTIAN
Washington State University
Changes in survey mode for conducting panel surveys may contribute significantly to
survey error. This article explores the causes and consequences of such changes in
survey mode. The authors describe how and why the choice of survey mode often
causes changes to be made to the wording of questions, as well as the reasons that
identically worded questions often produce different answers when administered
through different modes. The authors provide evidence that answers may change as a
result of different visual layouts for otherwise identical questions and suggest ways
to keep measurement the same despite changes in survey mode.
Keywords: survey mode; questionnaire; panel survey; measurement; survey error
Most panel studies require measurement of the same variables at different
times. Often, participants are asked questions, several days, weeks, months,
or years apart to measure change in some characteristics of interest to the
investigation. These characteristics might include political attitudes, satis-
faction with a health care provider, frequency of a behavior, ownership of
financial resources, or level of educational attainment. Whatever the charac-
teristic of interest, it is important that the question used to ascertain it perform
the same across multiple data collections.
In addition, declining survey response rates, particularly for telephone
surveys, have encouraged researchers to use multiple modes of data collec-
tion during the administration of a single cross-sectional survey. Encouraged
by the availability of more survey modes than in the past and evidence that a
change in modes produces higher response rates (Dillman 2002), surveyors
This is a revision of a paper presented at t ...
https://iexaminer.org/fake-news-personal-responsibility-must-trump-intellectual-laziness/
Fake news: Personal responsibility must trump intellectual laziness
By Matt Chan January 4, 2017
Where do you get your news? That question has become incredibly important given the results of our Presidential Election. How many times have you heard, “I read a news story on Facebook and …” The problem: Facebook is not a news service; it’s a “social media” site whose purpose is to connect like-minded friends and family, to provide you with social connections, and online entertainment.
For Asian Americans social media provides an important and useful way of connecting socially and in some cases politically, but there is a downside. The downside is how social media actually works. These sites employ elaborate algorithms to track and analyze your posts, likes, and dislikes to provide you with a custom experience unique to you. The truth is you are being marketed to, not informed. What looks like news, is not really news, it’s personal validation. All in an attempt to keep you on the site longer, to click a few more things, to make you feel good about what you’re reading. It makes it seem like most people agree with you because you’re only fed information and stories that validate your worldview.
On the other hand, real news is hard work. Its fact-based information presented by people who have checked, researched, and documented what they are presenting as the truth. Real news can be verified.
“Fake News” is, well, fake, often times entirely made-up or containing a hint of truth. Social media was largely responsible for pushing “fake news” stories that were entirely made up to drive clicks on websites. These clicks in turn generated money for the people promoting the stories. The more outrageous the story, the more clicks, the more revenue. When you factor in the algorithms that feed you what you like, you can clearly see the more “fake news” you consume on social media, the more is pushed your way. There’s an abundance of pseudo news sites that merely re-post and curate existing stories, adding their bias to validate their audience’s beliefs, no matter how crazy or mainstream. It is curated solely for you. Now factor in that nearly 44% of Americans obtain some or most of their news from social media and you have a very toxic mix.
The mainstream news media has also fallen into this validation trap. You have one news network that solely reflects the right wing, others that take the view of the left-center leaning, and what is lost are the facts and context, the balance we need to evaluate, learn, and understand the world. People seeking fact-based journalism lose, because the more extreme the media becomes to entice consumers with provocative headlines and click-bait to earn more money, the less their news is fact-based and becomes more opinion driven.
There was a time when fact-based reporting was required of broadcast news. It was called “The Fairness Doctrin ...
http1500cms.comBECAUSE THIS FORM IS USED BY VARIOUS .docxpooleavelina
http://1500cms.com/
BECAUSE THIS FORM IS USED BY VARIOUS GOVERNMENT AND PRIVATE HEALTH PROGRAMS, SEE SEPARATE INSTRUCTIONS ISSUED BY
APPLICABLE PROGRAMS.
NOTICE: Any person who knowingly files a statement of claim containing any misrepresentation or any false, incomplete or misleading information may
be guilty of a criminal act punishable under law and may be subject to civil penalties.
REFERS TO GOVERNMENT PROGRAMS ONLY
MEDICARE AND CHAMPUS PAYMENTS: A patient’s signature requests that payment be made and authorizes release of any information necessary to process
the claim and certifies that the information provided in Blocks 1 through 12 is true, accurate and complete. In the case of a Medicare claim, the patient’s signature
authorizes any entity to release to Medicare medical and nonmedical information, including employment status, and whether the person has employer group health
insurance, liability, no-fault, worker’s compensation or other insurance which is responsible to pay for the services for which the Medicare claim is made. See 42
CFR 411.24(a). If item 9 is completed, the patient’s signature authorizes release of the information to the health plan or agency shown. In Medicare assigned or
CHAMPUS participation cases, the physician agrees to accept the charge determination of the Medicare carrier or CHAMPUS fiscal intermediary as the full charge,
and the patient is responsible only for the deductible, coinsurance and noncovered services. Coinsurance and the deductible are based upon the charge
determination of the Medicare carrier or CHAMPUS fiscal intermediary if this is less than the charge submitted. CHAMPUS is not a health insurance program but
makes payment for health benefits provided through certain affiliations with the Uniformed Services. Information on the patient’s sponsor should be provided in those
items captioned in “Insured”; i.e., items 1a, 4, 6, 7, 9, and 11.
BLACK LUNG AND FECA CLAIMS
The provider agrees to accept the amount paid by the Government as payment in full. See Black Lung and FECA instructions regarding required procedure and
diagnosis coding systems.
SIGNATURE OF PHYSICIAN OR SUPPLIER (MEDICARE, CHAMPUS, FECA AND BLACK LUNG)
I certify that the services shown on this form were medically indicated and necessary for the health of the patient and were personally furnished by me or were furnished
incident to my professional service by my employee under my immediate personal supervision, except as otherwise expressly permitted by Medicare or CHAMPUS
regulations.
For services to be considered as “incident” to a physician’s professional service, 1) they must be rendered under the physician’s immediate personal supervision
by his/her employee, 2) they must be an integral, although incidental part of a covered physician’s service, 3) they must be of kinds commonly furnished in physician’s
offices, and 4) the services of nonphysicians must be included on the physician’s bills.
For CHA ...
httpstheater.nytimes.com mem theater treview.htmlres=9902e6.docxpooleavelina
https://theater.nytimes.com/ mem/ theater/ treview.html?res=9902e6db1639f931a25753c1a962948260
THEATER: WILSON'S 'MA RAINEY'S' OPENS
By FRANK RICH
Published: October 12, 1984, Friday
LATE in Act I of ''Ma Rainey's Black Bottom,'' a somber, aging band trombonist (Joe Seneca) tilts his head heavenward to sing the blues. The setting is a dilapidated Chicago recording studio of 1927, and the song sounds as old as time. ''If I had my way,'' goes the lyric, ''I would tear this old building down.''
Once the play has ended, that lyric has almost become a prophecy. In ''Ma Rainey's Black Bottom,'' the writer August Wilson sends the entire history of black America crashing down upon our heads. This play is a searing inside account of what white racism does to its victims - and it floats on the same authentic artistry as the blues music it celebrates. Harrowing as ''Ma Rainey's'' can be, it is also funny, salty, carnal and lyrical. Like his real-life heroine, the legendary singer Gertrude (Ma) Rainey, Mr. Wilson articulates a legacy of unspeakable agony and rage in a spellbinding voice.
The play is Mr. Wilson's first to arrive in New York, and it reached here, via the Yale Repertory Theater, under the sensitive hand of the man who was born to direct it, Lloyd Richards. On Broadway, Mr. Richards has honed ''Ma Rainey's'' to its finest form. What's more, the director brings us an exciting young actor - Charles S. Dutton - along with his extraordinary dramatist. One wonders if the electricity at the Cort is the same that audiences felt when Mr. Richards, Lorraine Hansberry and Sidney Poitier stormed into Broadway with ''A Raisin in the Sun'' a quarter-century ago.
As ''Ma Rainey's'' shares its director and Chicago setting with ''Raisin,'' so it builds on Hansberry's themes: Mr. Wilson's characters want to make it in white America. And, to a degree, they have. Ma Rainey (1886-1939) was among the first black singers to get a recording contract - albeit with a white company's ''race'' division. Mr. Wilson gives us Ma (Theresa Merritt) at the height of her fame. A mountain of glitter and feathers, she has become a despotic, temperamental star, complete with a retinue of flunkies, a fancy car and a kept young lesbian lover.
The evening's framework is a Paramount-label recording session that actually happened, but whose details and supporting players have been invented by the author. As the action swings between the studio and the band's warm-up room - designed by Charles Henry McClennahan as if they might be the festering last- chance saloon of ''The Iceman Cometh'' - Ma and her four accompanying musicians overcome various mishaps to record ''Ma Rainey's Black Bottom'' and other songs. During the delays, the band members smoke reefers, joke around and reminisce about past gigs on a well-traveled road stretching through whorehouses and church socials from New Orleans to Fat Back, Ark.
The musicians' speeches are like improvised band solos - variously fiz ...
https://fitsmallbusiness.com/employee-compensation-plan/
The puzzle of motivation | Dan Pink [Video file]. Retrieved from https://www.youtube.com/watch?v=rrkrvAUbU9Y
Refining the total rewards package through employee input at MillerCoors [Video file]. Retrieved from https://www.youtube.com/watch?v=_I7nv0B4_NU&feature=youtu.be
How to design an employee compensation plan [SlideShare slides]. Retrieved from http://www.slideshare.net/FitSmallBusiness/how-to-design-a-compensation-plan-dave?ref=http://fitsmallbusiness.com/how-to-pay-employees/
Compensation strategies [Video file]. Retrieved from https://youtu.be/U2wjvBigs7w
· Expectations for Power Point Presentations in Units IV and V
I would like to provide information about what needs to be included in presentations. Please review the rubric prior to submitting any assignment. If you don't know where to find this, please contact me.
1. You need a title slide.
2. You need an overview of the presentation slide (slide after the title slide). This is how you would organize a presentation if you were presenting it at work.
3. You need a summary slide (before the reference slide); same reason as above.
4. Please do not forget to cite on slides where you are writing about something related to what you have read. Please consider each slide a paragraph. You can cite on the slides or in the notes. If you do not cite, you will not get credit for the slide.
- Direct quotes should not be used in this presentation as they are not analysis.
5. Remember, all I can evaluate is what you submit, so please consider using notes to explain what you are writing in further detail. Bullets are great and you can use these but then provide more detail in the notes.
6. Graphics - Please include graphics/charts/graphs as this is evaluated in the rubric (quality of the presentation).
7. References - For all references, you need citations. For all citations, you need references. They must match. All must be formatted using APA requirements. Please review the Quick Reference Guide that was posted in the announcements.
Please never hesitate to email me with any questions. If you need further clarification about feedback or if you do not agree with any of the feedback, please contact me. My door is always open.
Assignment 1
Positioning Statement and Motto
Use the provided information, as well as your own research, to assess one (1) of the stated brands (Tesla, SmoothieKing, Suave, or Nintendo) by completing the questions below with an ORIGINAL response to each. At the end of the worksheet, be sure to develop a new ORIGINAL positioning statement and motto for the brand you selected. Submit the completed template in the Week 4 assignment submission link.
Name:
Professor’s Name:
Course Title:
Date:
Company/Brand Selected (Tesla, SmoothieKing, Suave or Nintendo):
1. Target Customers/Users
Who are the target customers for the company/brand? Make sure you tell why you selected each item that you did. (NOTE: DO NO ...
http://hps.org/documents/pregnancy_fact_sheet.pdf
https://www.asge.org/docs/default-source/education/practice_guidelines/doc-5c7150fd-910a-4181-89bf-bc697b369103.pdf?sfvrsn=6
http://hps.org/hpspublications/articles/pregnancyandradiationexposureinfosheet.html
Data Science
and
Big Data Analytics
Chapter 12: The Endgame, or Putting It All Together
1
Chapter Contents
12.1 Communicating and Operationalizing an Analytics Project
12.2 Creating the Final Deliverables
Developing core material for multiple audiences, project goals, main findings, approach, model description, key points supported with data, model details, recommendations, tips on final presentation, providing technical specifications and code
12.3 Data Visualization Basics
Key points supported with data, evolution of a graph, common representation methods, how to clean up a graphic, additional considerations
Summary
2
12.1 Communicating and Operationalizing an Analytics Project
3
12.1 Communicating and Operationalizing an Analytics Project
Deliverables and Stakeholders
4
12.1 Communicating and Operationalizing an Analytics Project
Deliverables
General Deliverables – from Textbook
Presentation for Project Sponsors
Presentation for Analysts
Code
Technical Specifications
Deliverables For This Course
Presentation for Analysts – half hour per team, next week
Technical Paper for Research Day Conference
Submit CD – Presentation, Paper, Data or URL, Code
5
12.2 Creating the Final Deliverables
Case Study – Fictional Bank Churn Prediction
This section describes a scenario of a fictional bank and a churn prediction model of its customers
The analytic plan contains components that can be used as inputs for writing the final presentations
scope
underlying assumptions
modeling techniques
initial hypotheses
and key findings
6
12.2 Creating the Final Deliverables
Case Study – Fictional Bank Churn Prediction
7
12.2 Creating the Final Deliverables
Case Study – Fictional Bank Analytics Plan
8
12.2 Creating the Final Deliverables
12.2.1 Developing Core Material for Multiple Audiences
Some project components have dual use
Create core materials used for both analyst and business audiences
Three areas on the next slide used for both audiences
Sections after the following overview slide
12.2.2 – Project Goals
12.2.3 – Key Findings
12.2.4 – Approach
12.2.5 – Model Description
12.2.6 – Key Points Supported by Data
12.2.7 – Model Details
12.2.8 – Recommendations
12.2.9 – Additional Tips on the Final Presentation
12.2.10 – Providing Technical Specifications and Code
9
12.2 Creating the Final Deliverables
12.2.1 Developing Core Material for Multiple Audiences
10
12.2 Creating the Final Deliverables
12.2.2 Project Goals
The project goals portion of the final presentation is generally the same for sponsors and analysts
The project goals are described first to lay the groundwork for the solution and recommendations
Generally, the goals are agreed on earl ...
https://www.worldbank.org/en/country/vietnam/overview
-------------- Context ----------------
Vietnam’s development over the past 30 years has been remarkable. Economic and political reforms under Đổi Mới, launched in 1986, have spurred rapid economic growth, transforming what was then one of the world’s poorest nations into a lower middle-income country. Between 2002 and 2018, more than 45 million people were lifted out of poverty. Poverty rates declined sharply from over 70% to below 6% (US$3.2/day PPP), and GDP per capita increased by 2.5 times, standing over US$2,500 in 2018.
In the medium-term, Vietnam’s economic outlook is positive, despite signs of cyclical moderation in growth. After peaking at 7.1% in 2018, real GDP growth in 2019 is projected to slightly decelerate in 2019, led by weaker external demand and continued tightening of credit and fiscal policies. Real GDP growth is projected to remain robust at around 6.5% in 2020 and 2021. Annual headline inflation has been stable for the seven consecutive years – at single digits, trending towards 4% and below in recent years. The external balance remains under control and should continue to be financed by strong FDI inflows which reached almost US$18 billion in 2018 – accounting for almost 24% of total investment in the economy.
Vietnam is experiencing rapid demographic and social change. Its population reached 97 million in 2018 (up from about 60 million in 1986) and is expected to expand to 120 million before moderating around 2050. Today, 70% of the population is under 35 years of age, with a life expectancy of 76 years, the highest among countries in the region at similar income levels. But the population is rapidly aging. And an emerging middle class, currently accounting for 13% of the population, is expected to reach 26% by 2026.
Vietnam ranks 48 out of 157 countries on the human capital index (HCI), second in ASEAN behind Singapore. A Vietnamese child born today will be 67% as productive when she grows up as she could be if she enjoyed complete education and full health. Vietnam’s HCI is highest among middle-income countries, but there are some disparities within the country, especially for ethnic minorities. There would also be a need to upgrade the skill of the workforce to create productive jobs at a large scale in the future.
Over the last thirty years, the provision of basic services has significantly improved. Access of households to modern infrastructure services has increased dramatically. As of 2016, 99% of the population used electricity as their main source of lighting, up from 14 % in 1993. Access to clean water in rural areas has also improved, up from 17% in 1993 to 70% in 2016, while that figure for urban areas is above 95%.
Vietnam performs well on general education. Coverage and learning outcomes are high and equitably achieved in primary schools — evidenced by remarkably high scores in the Program for International Student Assessment (PISA) in 2012 and 2015, ...
HTML WEB Page solutionAbout.htmlQuantum PhysicsHomeServicesAbou.docxpooleavelina
HTML WEB Page solution/About.htmlQuantum PhysicsHomeServicesAboutContact Me
This website gives a detail inward look in quantam physics as it is a evolving field now-a-days and has many upcoming changes that is going to leave the world in shock. There has been a lot of confusion lately related to this topics in people so it is encourage that people visit this website and get to know more about this field and explore the horizons there is yet to come.
HTML WEB Page solution/FirstLastHomePage.htmlQuantum PhysicsHomeServicesAboutContact Me
Definition
Quantum mechanics is the part of material science identifying with the little.
It brings about what may have all the earmarks of being some extremely peculiar decisions about the physical world. At the size of particles and electrons, a significant number of the conditions of old style mechanics, which depict how things move at ordinary sizes and speeds, stop to be helpful. In traditional mechanics, objects exist in a particular spot at a particular time. Be that as it may, in quantum mechanics, protests rather exist in a fog of likelihood; they have a specific possibility of being at point An, another possibility of being at point B, etc.Three revolutionary principles
Quantum mechanics (QM) created over numerous decades, starting as a lot of questionable scientific clarifications of tests that the math of old style mechanics couldn't clarify. It started at the turn of the twentieth century, around a similar time that Albert Einstein distributed his hypothesis of relativity, a different numerical unrest in material science that portrays the movement of things at high speeds. In contrast to relativity, nonetheless, the sources of QM can't be credited to any one researcher. Or maybe, various researchers added to an establishment of three progressive rules that bit by bit picked up acknowledgment and exploratory confirmation somewhere in the range of 1900 and 1930. They are:
Quantized properties:
Certain properties, for example, position, speed and shading, can once in a while just happen in explicit, set sums, much like a dial that "clicks" from number to number. This tested a crucial presumption of old style mechanics, which said that such properties should exist on a smooth, ceaseless range. To portray the possibility that a few properties "clicked" like a dial with explicit settings, researchers begat the word "quantized".
Particles of light:
Light can now and again act as a molecule. This was at first met with unforgiving analysis, as it negated 200 years of trials indicating that light acted as a wave; much like waves on the outside of a quiet lake. Light acts comparatively in that it ricochets off dividers and twists around corners, and that the peaks and troughs of the wave can include or counteract. Included wave peaks bring about more splendid light, while waves that counterbalance produce obscurity. A light source can be thought of ...
https://www.huffpost.com/entry/online-dating-vs-offline_b_4037867
For your initial post, provide a sentence to share which article you are referring to so that you can best communicate with your peers. Include a link to your selection.
· Explain how the argument contains or avoids bias.
i. Provide specific examples to support your explanation.
ii. What assumptions does it make?
· Discuss the credibility of the overall argument.
i. Were the resources the argument was built upon credible?
ii. Does the credibility support or undermine the article’s claims in any important ways?
In response to your peers, provide an additional resource to support or refute the argument your peer makes. Do you agree with their claims of credibility? Are there any other possible bias not identified?
Response #1
Allysa Tantala posted Sep 22, 2019 10:17 PM
Subscribe
The article that I am looking at is Online Dating Vs. Offline Dating: Pros and Cons.It was written by Julie Spira, an online dating expert, bestselling author, and CEO of Cyber-Dating Expert. The name of the article is spot on in describing what it is about. The author goes through the pros and cons of dating online and offline in today’s day and age. The author avoids bias because she looks at both options in both their positive and negative attributes. She comes at the issues from both angles and I believe she does a very good job at remaining unbiased. She states that “if you're serious about meeting someone special, you must include a combination of both online and offline dating in your routine” (Spira, 2013, par. 18). She’s stating that both options have their pros and cons and that really a combination of both is needed to find someone. The only bias I could see anyone pointing out would be that she is a woman, so you do not get the male perspective on these things. That being said, I one hundred percent think she covers all of the questions people may have about online and offline dating in today’s world. The only assumption being made here is that the reader wants to be out in the dating world and they need to know what is best. But, the title of the article is pretty self-explanatory so if someone did not want to know these things, they would not have to waste their time reading it all because they could tell what it would be about by the title.
The resource that she used was herself, and like I stated above, she is an online dating expert, bestselling author, and CEO of Cyber-Dating Expert; so she is more than qualified to give her perspective on these issues. I find her to be credible and thought provoking. Her credibility supports everything the article says and makes the reader feel like they are being told the truth by someone who completely understands all of the pros and cons.
Resource:
Spira, J. (2013, December 3). Online Dating Vs. Offline Dating: Pros and Cons. Retrieved from https://www.huffpost.com/entry/online-dating-vs-offline_b_4037867
Response #2
Jennifer Caforio posted Se ...
https://www.vitalsource.com/products/comparative-criminal-justice-systems-harry-r-dammer-jay-s-v9781285630779
THE ASSIGNMENT IS BASED ON CHAPTER 1 (ONE)
Login : [email protected]
Password: Greekyogurt13!
1
3Defining the Problem
Rigina CochranMPA/593
August 19, 2019
Peter ReevesDefining the Problem
The health care system in Colorado is a composition of medical professionals providing services such as diagnosis, treatment, as well as preventive measures to mental illness and injuries ("Healthcare policy in Colorado - Ballotpedia," 2019). Health care policy involves the establishment and implementation of legislation and other regulations that the states use to manage its health care system effectively. Further, this sector consists of other participants, such as insurance and health information technology. The cost citizens pay for medical care and also the access to quality care influence the overall health care providers in Colorado. Therefore, the need for the creation and implementation of laws that help the state maintain efficiency in the health sector in Colorado.
Problem Statement
The declining standards of medical care within the United States has caused significant concern in the world. Due to these rising concerns, there have been various policies implemented, leading to mixed reactions among the different states. Some of the active policies implemented offer a long-term solution to this problem including Medicaid and Medicare. After acquiring state control, the Republicans dismissed the idea to expand and create medical insurance for Medicaid in Colorado. Sustaining the structure of the health care payroll calls for the deductions from the employees and the employers, which may lead to loss of jobs and increased burden of expenditure (Garcia, 2019).
Identify the Methodology
The main objective of this policy plan is to investigate the role of legislation in the management of the health care sector in the United States. Due to the need for achieving in-depth exploration, this paper uses a combination of both qualitative and quantitative methods of data collection by addressing both practical and theoretical aspects of the research. Based on the answers that the policy requires, choosing survey as the research design. This method involves collecting and analyzing data from a few people who represent the principal group within health care. However, the survey method faces some challenges such as attitudes and perception of the health workers leading to the delimitation of the study. The target population for the study includes the nurses within the health sectors in Colorado. The selection of the participants involved in the use of stratified random sampling.
Identify your Stakeholders
The major stakeholders in the creation and implementation of the policy plan include the legislatures, local government, patients, and other private parties such as the insurance companies. Collectively, these bodies are involved in the makin ...
https://www.nationaleatingdisorders.org/learn/by-eating-disorder/arfid
AVOIDANT RESTRICTIVE FOOD INTAKE DISORDER (ARFID)
Avoidant Restrictive Food Intake Disorder (ARFID) is a new diagnosis in the DSM-5, and was previously referred to as “Selective Eating Disorder.” ARFID is similar to anorexia in that both disorders involve limitations in the amount and/or types of food consumed, but unlike anorexia, ARFID does not involve any distress about body shape or size, or fears of fatness.
Although many children go through phases of picky or selective eating, a person with ARFID does not consume enough calories to grow and develop properly and, in adults, to maintain basic body function. In children, this results in stalled weight gain and vertical growth; in adults, this results in weight loss. ARFID can also result in problems at school or work, due to difficulties eating with others and extended times needed to eat.
DIAGNOSTIC CRITERIA
According to the DSM-5, ARFID is diagnosed when:
· An eating or feeding disturbance (e.g., apparent lack of interest in eating or food; avoidance based on the sensory characteristics of food; concern about aversive consequences of eating) as manifested by persistent failure to meet appropriate nutritional and/or energy needs associated with one (or more) of the following:
· Significant weight loss (or failure to achieve expected weight gain or faltering growth in children).
· Significant nutritional deficiency.
· Dependence on enteral feeding or oral nutritional supplements.
· Marked interference with psychosocial functioning.
· The disturbance is not better explained by lack of available food or by an associated culturally sanctioned practice.
· The eating disturbance does not occur exclusively during the course of anorexia nervosa or bulimia nervosa, and there is no evidence of a disturbance in the way in which one’s body weight or shape is experienced.
· The eating disturbance is not attributable to a concurrent medical condition or not better explained by another mental disorder. When the eating disturbance occurs in the context of another condition or disorder, the severity of the eating disturbance exceeds that routinely associated with the condition or disorder and warrants additional clinical attention.
RISK FACTORS
As with all eating disorders, the risk factors for ARFID involve a range of biological, psychological, and sociocultural issues. These factors may interact differently in different people, which means two people with the same eating disorder can have very diverse perspectives, experiences, and symptoms. Researchers know much less about what puts someone at risk of developing ARFID, but here’s what they do know:
· People with autism spectrum conditions are much more likely to develop ARFID, as are those with ADHD and intellectual disabilities.
· Children who don’t outgrow normal picky eating, or in whom picky eating is severe, appear to be more likely to develop ARFID.
· Many children with ARFID ...
https://www.youtube.com/watch?time_continue=59&v=Bh_oEYX1zNM&feature=emb_logo
BA 325 Pivot Table Assignment Answer Sheet
Name:
Before you do anything fill out your name on the assignment and save your file as BA325 Firstname Lastname (use your actual name).
The table has all of the questions from the DuPont Assignment. Fill in your answers to the questions in the corresponding cell in the Answer column. Below the table there is a spot for the Screen Clippings from both the Practice Assignment, and the DuPont Assignment.
After you have filled out all of the answers and Screen Clippings submit the file to the Assignments folder in D2L.
Q Number
Question
Answer
Q1
How much was American Airlines’ Net Revenues in 2013?
Q2
What was the Return on Equity for Apple in 2015?
Q3
Which company had the highest Net Income and in which year? What was the value?
Q4
Which company had the lowest Net Income and in which year? What was the value?
Q5
How many unique companies in your sample had Net Losses exceeding one billion dollars? Which companies, and what years?
Q6
What was the Sum of the Net Income for all companies in the sample for 2015?
Q7
Which company had the highest total Net Income over the three year period? What was the value?
Q8
Which company had the lowest total Net Income over the three year period? What was the value?
Q9
Which industry had the highest Average Profit Margin over the three year period? What was the value?
Q10
In which year was the Average Profit Margin the highest for the entire sample? What was the value?
Q11
For how many companies do you have Profit Margin ratio data in 2013?
Q12
For what Industry do you have the most Profit Margin ratio data in the sample? What was the value? For that Industry what year was the highest? What was the value?
Q13
Which Industry has the highest Average Asset Turnover over the three year period? What was the value?
Q14
Which of the remaining Industries has the highest Asset Turnover in 2014? What was the value?
Q15
Which Industry has the highest Average Financial Leverage over the three year period? What was the value?
Q16
Which Industry has the lowest Average Financial Leverage that does not include negative numbers in any year? What was the value?
Q17
What is the Average Financial Leverage for the Transportation Industry in 2013?
Note: The answer is odd. You will have to use Data Cleaning to resolve the issue.
Q18
Which Industry has the highest Average Return on Equity over the three year period and which company is the highest within that Industry? What are the values?
Q19
Which two companies in the Public Utilities Industry have the highest Average Return on Equity during the period? What are the values?
Q20
Which Industry had the largest decrease in Average Return on Equity between 2013 and 2014? What was the value?
Q21
Which Industry had the largest increase in Average Return on Equity between 2014 and 2015? What was the value?
Q22
Bonus Question 1: How many industrie ...
https://www.fbi.gov/news/pressrel/press-releases/fbi-expects-a-rise-in-scams-involving-cryptocurrency-related-to-the-covid-19-pandemic
https://www.coindesk.com/bitcoin-bulls-trillions-coronavirus-aid
https://www.forbes.com/sites/walterpavlo/2020/02/25/crime-and-punishment-in-the-cryptocurrency-world/#62232a6748fe
Running head: Bitcoin as a cryptocurrency 1
Bitcoin as a cryptocurrency 8Bitcoin as a Cryptocurrency of Misconduct
Roger F. Lewis
Miami Dade College-North Campus
June 5, 2019
Bitcoin as a Cryptocurrency of Misconduct
In the expansion of cryptocurrencies in particular bitcoins have resulted in providing clients with exceptional advantages, the advantages in this matter have not had their hazards and struggles. In the peculiar free mode in the cryptocurrency arcade, it has been in constant misuse and linked to several illegal activities. Lawmakers globally repetitively stumble upon this very position (Anon,2019). The tendency on allowing a market to settle on its fosters this activity as the lawmakers tend to abstain from events of the market. They cannot also sit by and enable misconduct behaviors to foster in the markets. Tracking the cryptocurrency action has proved to be much more complicated than the standard plugged-in transactions. The bottom line is that these transactions occur globally has established a headache to try and monitor this particular field. The release of the bitcoin in the year two thousand and nine as the world’s pioneer and most profound mode of cryptocurrency was a breakthrough in the industry. Cryptocurrency, on the other hand, is the mode of exchange that occurs only in the digital dimension. Cryptocurrency uses complex codes as a skill of protecting data. Thus, monetary transactions are carried out most safely (Anon,2019). A public ledger is used to know the actual owner of a particular cryptocurrency.
Assets in the digital market portray distinctive characteristics –delegation, simple connections between members as well as the relative use of modern technology, many have the thought or mindset that in time bitcoins will be used as a forthcoming currency. To understand the illegal uses of bitcoins we must first address the non-illegal activities in this field. As earlier stated, there is a possibility that the bitcoins will indeed replace the current custom. One can lawfully use bid coins in the following areas; travels, to pay tuition fee for institutions and can be used as an alternative where the standards of payment are online. The above depicts numerous ways can use bitcoins to settle their bills. The difference in value between the bitcoins and the traditional currency leads to individuals opting to use the bitcoins for exchange in cases or scenarios where a high exchange rate is noted, and alternatively, the opposite is exact. Chargebacks risk is reduced in the event of using bitcoins, therefore easing access to the broader market for traders. In the event of unlawful trades, both ends to ...
We all have good and bad thoughts from time to time and situation to situation. We are bombarded daily with spiraling thoughts(both negative and positive) creating all-consuming feel , making us difficult to manage with associated suffering. Good thoughts are like our Mob Signal (Positive thought) amidst noise(negative thought) in the atmosphere. Negative thoughts like noise outweigh positive thoughts. These thoughts often create unwanted confusion, trouble, stress and frustration in our mind as well as chaos in our physical world. Negative thoughts are also known as “distorted thinking”.
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
In this webinar you will learn how your organization can access TechSoup's wide variety of product discount and donation programs. From hardware to software, we'll give you a tour of the tools available to help your nonprofit with productivity, collaboration, financial management, donor tracking, security, and more.
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
Instructions for Submissions thorugh G- Classroom.pptxJheel Barad
This presentation provides a briefing on how to upload submissions and documents in Google Classroom. It was prepared as part of an orientation for new Sainik School in-service teacher trainees. As a training officer, my goal is to ensure that you are comfortable and proficient with this essential tool for managing assignments and fostering student engagement.
Students, digital devices and success - Andreas Schleicher - 27 May 2024..pptxEduSkills OECD
Andreas Schleicher presents at the OECD webinar ‘Digital devices in schools: detrimental distraction or secret to success?’ on 27 May 2024. The presentation was based on findings from PISA 2022 results and the webinar helped launch the PISA in Focus ‘Managing screen time: How to protect and equip students against distraction’ https://www.oecd-ilibrary.org/education/managing-screen-time_7c225af4-en and the OECD Education Policy Perspective ‘Students, digital devices and success’ can be found here - https://oe.cd/il/5yV
1. https://www.medicalnewstoday.com/articles/323444.php
https://ascopubs.org/doi/full/10.1200/JCO.2008.16.0333
https://journals.lww.com/co-
hematology/Abstract/2007/03000/Influence_of_new_molecular_
prognostic_markers_in.5.aspx
Influence of new molecular prognostic markers in patients with
karyotypically normal acute myeloid leukemia: recent advances
Mrózek, Krzysztofa; Döhner, Hartmutb; Bloomfield, Clara Da
Current Opinion in Hematology: March 2007 - Volume 14 -
Issue 2 - p 106–114
doi: 10.1097/MOH.0b013e32801684c7
Myeloid disease
Purpose of review Molecular study of cytogenetically normal
acute myeloid leukemia is among the most active areas of
leukemia research. Despite having the same normal karyotype,
adults with de-novo cytogenetically normal acute myeloid
leukemia who constitute the largest cytogenetic group of acute
myeloid leukemia, are very diverse with respect to acquired
gene mutations and gene expression changes. These genetic
alterations affect clinical outcome and may assist in selection of
proper treatment. Herein we critically summarize recent
clinically relevant molecular genetic studies of cytogenetically
normal acute myeloid leukemia.
Recent findings NPM1 gene mutations causing aberrant
cytoplasmic localization of nucleophosmin have been
demonstrated to be the most frequent submicroscopic alterations
in cytogenetically normal acute myeloid leukemia and to confer
improved prognosis, especially in patients without a
concomitant FLT3 gene internal tandem duplication.
2. Overexpressed BAALC, ERG and MN1 genes and expression of
breast cancer resistance protein have been shown to confer poor
prognosis. A gene-expression signature previously suggested to
separate cytogenetically normal acute myeloid leukemia patients
into prognostic subgroups has been validated on a different
microarray platform, although gene-expression signature-based
classifiers predicting outcome for individual patients with
greater accuracy are still needed.
Summary The discovery of new prognostic markers has
increased our understanding of leukemogenesis and may lead to
improved prognostication and generation of novel risk-adapted
therapies.
http://www.bloodjournal.org/content/127/1/53?sso-checked=true
An update of current treatments for adult acute myeloid
leukemia
Hervé Dombret and Claude Gardin
Abstract
Recent advances in acute myeloid leukemia (AML) biology and
its genetic landscape should ultimately lead to more subset-
specific AML therapies, ideally tailored to each patient's
disease. Although a growing number of distinct AML subsets
have been increasingly characterized, patient management has
remained disappointingly uniform. If one excludes acute
promyelocytic leukemia, current AML management still relies
largely on intensive chemotherapy and allogeneic hematopoietic
stem cell transplantation (HSCT), at least in younger patients
who can tolerate such intensive treatments. Nevertheless,
progress has been made, notably in terms of standard drug dose
intensification and safer allogeneic HSCT procedures, allowing
a larger proportion of patients to achieve durable remission. In
addition, improved identification of patients at relatively low
risk of relapse should limit their undue exposure to the risks of
HSCT in first remission. The role of new effective agents, such
3. as purine analogs or gemtuzumab ozogamicin, is still under
investigation, whereas promising new targeted agents are under
clinical development. In contrast, minimal advances have been
made for patients unable to tolerate intensive treatment, mostly
representing older patients. The availability of hypomethylating
agents likely represents an encouraging first step for this latter
population, and it is hoped will allow for more efficient
combinations with novel agents.
J Clin Med. 2016 Mar; 5(3): 33.
Published online 2016 Mar 5. doi: 10.3390/jcm5030033
PMCID: PMC4810104
PMID: 26959069
Acute Myeloid Leukemia: A Concise Review
Jennifer N. Saultz1 and Ramiro Garzon2,*
Jennifer N. Saultz
1Medical Oncology/Hematology, Department of Internal
Medicine, Starling-Loving Hall, Room M365, 320 W. 10th
Ave., Columbus, OH 43210, USA; [email protected]
Find articles by Jennifer N. Saultz
Ramiro Garzon
2Division of Hematology, Department of Internal Medicine, 460
W 12th Ave, Columbus, OH 43210, USA
Find articles by Ramiro Garzon
Jeffrey E. Rubnitz, Academic Editor
Author informationArticle notesCopyright and License
informationDisclaimer
1Medical Oncology/Hematology, Department of Internal
Medicine, Starling-Loving Hall, Room M365, 320 W. 10th
Ave., Columbus, OH 43210, USA; [email protected]
5. primary and relapsed tumors, a phenomenon called clonal
evolution has been characterized with both founding clones and
novel subclones, impacting the therapeutic approach [2].
Despite an increased understanding of AML biology, our efforts
to this point in changing treatment strategy have been
disappointing. In this review, we discuss the current diagnostic
and prognostic strategies, current treatment approaches and
novel therapies critical to AML management.
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2. Morphology
Morphologically, AML blasts vary in size from slightly larger
than lymphocytes to the size of monocytes or larger. The nuclei
are large in size, varied in shape and usually contain several
nucleoli. AML blasts express antigens found also on healthy
immature myeloid cells, including common differentiation (CD)
markers CD13, CD33 and CD34 [3]. Other cells markers are
expressed depending on the morphological subtype of AML and
stage of differentiation block such as monocytic differentiation
markers (CD4, CD14, CD11b), erythroid (CD36, CD71) and
megakaryocytes markers (CD41a and CD61). On occasion, AML
blasts also co-express antigens restricted to T or B cell lineages
including Terminal deoxynucleotidyl transferase (TdT), Human
leukocyte antigen-antigen D related (HLA-DR), CD7 and CD19.
Rarely, the blasts can exhibit morphologic and immune-
phenotypic features of both myeloid and lymphoid cells that
make it difficult to classify them as either myeloid or lymphoid
in origin. These cases are classified as mixed phenotypic
leukemia and usually portend a worse overall survival [4]. Bone
marrow aspirate and biopsy, including morphology, immune-
phenotype, cytochemistry and genetics studies (conventional
karyotype and molecular studies) remain essential for diagnosis,
classification and risk stratification.
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3. Classification
Over the years there have been several different classification
systems for AML based on etiology, morphology, immune-
6. phenotype and genetics. In the 1970s, AML was classified
according to the French-American-British classification system
using mainly morphology and immune-phenotype/cytochemical
criteria to define eight major AML subtypes (FAB M0 to M7)
[5]. The World Health Organization (WHO) classification of
AML, replaced the old French-American-British classification
system to become the essential modality for AML classification
today. The WHO classification was updated in 2008 and
identifies seven AML subtypes: (1) AML with recurrent genetic
abnormalities (RUNX1-RUNX1T1 t(8;21)(q22;q22), CBFB-
MYH11 Inv(16)(p13.1q22), t(16;16)(p13.1;q22), PML-RARA
t(15,17)(q22;q12), MLL 11q23 abnormalities, etc.) and with
gene mutations (Nucleophosmin 1 (NPM1) and CEBPA mutated
gene); (2) AML with myelodysplasia-related changes; (3)
Therapy related myeloid neoplasms; (4) AML not otherwise
specified (NOS) (similar to FAB Classification M0–M7 with
others such as acute megakaryoblastic leukemia, acute
panmyelosis with myelofibrosis, and pure erythroleukemia); (5)
Myeloid sarcoma; (6) Myeloid proliferations related to Down
syndrome; and (7) Blastic plasmocytoid dendritic cell neoplasm
[6]. Based on etiology alone, AML can also be subdivided into
three distinct categories: (1) Secondary AML (s-AML)
(associated with antecedent myelodysplastic syndrome (MDS)
or other myeloid proliferative disorder (MPD)); (2) Therapy-
related AML (t-AML) (associated with prior
toxin/chemotherapy exposure) and (3) De novo AML [7].
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4. Cytogenetics
Non-random chromosomal abnormalities (e.g., deletions,
translocations) are identified in approximately 52% of all adult
primary AML patients and have long been recognized as the
genetic events that cause and promote this disease [8]. Certain
cytogenetic abnormalities, including the t(8;21)(q22;q22),
t(15;17)(q22;q12) and inv(16)(p13.1;q22) are associated with
longer remission and survival, while alterations of chromosomes
5, 7, complex karyotype (described as >3 chromosomal
7. abnormalities) and 11q23 are associated with poor response to
therapy and shorter overall survival [1]. In contrast, about 40%–
50% of all AML cases are cytogenetically normal (CN-AML)
when assessed using conventional banding analysis [9].
Although, this group has an intermediate risk of relapse, a
substantial heterogeneity is found in this population in terms of
clinical outcome. Molecular screening of this AML category is
critical for prognostic categorization and treatment strategy.
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5. Molecular Abnormalities
During the last decade, several studies have shown that the
presence or absence of specific gene mutations and/or changes
in gene expression can further classify AML cases and have an
effect on the patients’ prognosis [7,10,11]. As stated above, this
is particularly relevant for patients with CN-AML. With the
advent of next generation sequencing, the genetic landscape of
CN-AML has been more defined with each case having an
average of 13 mutations, eight of which are random “passenger”
mutations and five of which are recurrent “driver” mutations
[10]. Key molecular abnormalities have been identified and are
now used to predict outcome and help guide treatment for AML
patients. In the next sections we will describe the most relevant
AML mutations discussed in relative order of frequency.
5.1. Nucleophosmin 1 (NPM1) Mutations
Nucleophosmin 1 (NPM1) mutations are the most frequent
mutation in AML, occurring in 25%–30% of AML patients, with
female predominance [12,13]. NPM1 mutations result in the
aberrant expression of the NPM1 protein in the cytoplasm rather
than the nucleus, stimulating myeloid proliferation and
leukemia development [13,14,15]. Clinically, the mutation is
associated with monocytic morphology and in the absence of
FMS-like tyrosine kinase 3 or FLT3-ITD, predicts favorable
overall survival (OS). The reason for improved survival remains
unclear however it has been found that NPM1 mutations have
been associated with chemosensitivity to intensive
chemotherapy in both young and old patients, which may
8. account for improved outcome [16]. NPM1 mutations are
associated with other recurrent genetic abnormalities such as
+8, DNMT3A mutations, FLT3-ITD (40% of the time), FLT3-
TKD (10%–15%) and IDH mutations (25% of time) [11,17].
5.2. DNA Methyltansferase 3A (DNMT3A) Mutations
Mutations in the DNA methyltansferase 3A (DNMT3A) gene
occurs in 18%–22% of all AML cases and in about 34% of CN-
AML [18]. Missense mutations affecting arginine codon 882
(R882-DNMT3A) are more common than those affecting other
codons (non-R882-DNMT3A) causing a defect in normal
hematopoiesis and proper methylation [17]. Recently, DNMT3A
mutations have been identified as pre-leukemic mutations,
arising early in AML evolution and persisting in times of
remission [19]. The prognostic significance of DNMT3A
mutations is therefore thought to be adverse. Initial studies
showed unfavorable impact on outcome in CN-AML [17].
However, these effects were age related. Younger patients with
non-R882-DNMT3A mutations had shorter disease free survival
(DFS) and overall survival (OS), whereas older patients with
R882-DNMT3A mutations had shorter DFS and OS after
adjustment for other clinical and molecular prognosticators
[17]. A larger study involving more than 1700 AML cases found
no significant impact of DNMT3A mutations on survival end
points [20]. Recently, it was reported that patients with
DNMT3A-mutated AML have an inferior survival when treated
with standard-dose anthracycline induction therapy. Sehgal et
al., concluded that this group should be considered for high-
dose induction therapy [21]. High-dose daunorubicin, as
compared with standard-dose daunorubicin, improved the rate of
survival among patients with DNMT3A or NPM1 mutations or
MLL translocations (p = 0.001) but not among patients with
wild-type DNMT3A, NPM1, and MLL (p = 0.67) [22].
5.3. Fms-Like Tyrosine Kinase 3 (FLT3) Mutations
First described in 1991, FLT3 was found to be strongly
expressed in hematopoietic stem cells with important roles in
cell survival and proliferation [23,24]. Internal tandem
9. duplications (ITD) in the juxta-membrane (JM) domain or
mutations in the second tyrosine kinase domain (TKD) of the
FLT3 gene have been found in 20% of all AML cases and 30%
to 45% of CN-AML patients [1,25]. Both types of mutations
constitutively activate FLT3 signaling, promoting blast
proliferation [25,26]. Indeed patients with FLT3 mutations often
present with extreme leukocytosis and characteristic prominent
nuclear invagination often described as “cuplike” nucleus
[25,27]. Furthermore, FLT3-ITD mutations have been
associated with increased risk of relapse, while the prognostic
relevance of FLT3-TKD mutations is controversial [28]. The
degree to which FLT3-ITD is a biomarker associated with poor
outcome is determined by the binding site and FLT3-ITD allelic
burden [25,28,29]. Studies have shown that non-JM ITD are
worse than JM domain ITD and higher mutant to wild-type
allelic ratios were significantly associated with lower complete
remission (CR) rates [28,29]. Currently, tyrosine kinase
inhibitors (TKI) are being tested in FLT3 mutated AML
patients. Unfortunately, when used alone, TKIs showed only a
transient reduction of blasts, and even if initially effective,
subsequent acquisition of secondary mutations induces
resistance over time [30].
5.4. Isocitrate Dehydrogenase (IDH) Mutations
Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 gene
are gain-of-function mutations which cause loss of the
physiologic enzyme function and create a novel ability of the
enzymes to convert α-ketoglutarate into 2-hydroxyglutarate.
IDH mutations are oncogenic. Specifically recurrent mutations
affecting the highly conserved arginine (R) residue at codon 132
(R132) of IDH1 and at codons R140 and R172 of IDH2 have
been identified in 15%–20% of all AML and 25% to 30% of
patients with CN-AML [11,22,31]. They are found more
frequently in older patients [32]. IDH mutations, in particular
IDH1, are associated with lower DFS and OS in CN-AML cases
with NPM1 mutations and wild type FLT3 [31,32]. Orally
available, selective, potent inhibitors of mutated IDH are
10. currently being tested in Phase I and II studies in AML with
promising results [33].
5.5. Ten–Eleven Translocation 2 (TET2) Mutations
The ten–eleven translocation oncogene family member 2 (TET2)
is found mutated in about 9%–23% of AML patients [34]. TET1
is an enzyme involved in the conversion of 5-methylcytosine
(5mC) to 5-hydroxymethylcytosine (5hmC) in DNA, which is a
process thought to play an important role in DNA demethylation
[34]. In general, TET2 mutations are loss-of-function mutations.
Overall, despite several studies their prognostic significance
remains unclear. Metzeler et al., reported TET2 mutations as an
adverse factor for CR and OS [35]. However Gaidzik et al., did
not show a prognostic effect with TET2 mutations [36].
5.6. Runt-Related Transcription Factor (RUNX1) Mutations
Runt-related transcription factor (RUNX1) has been shown to be
essential in normal hematopoiesis [37]. Also known as AML1
protein or core-binding factor subunit α-2 (CBFA2), RUNX1 is
located at chromosome 21 and is frequently translocated with
the ETO/MTG8/RUNX1T1 gene located on chromosome 8q22,
creating a fusion protein AML-ETO or t(8;21)(q22;q22) AML
[38]. In addition to chromosome translocations, RUNX1
mutations are found in 5%–13% of AML and are commonly
associated with trisomy 13, trisomy 21, absence of NPM1 and
older CN-AML [11]. In general, studies have shown RUNX1
mutations are associated with resistance to standard induction
therapy with inferior overall survival for both younger and older
patients [39].
5.7. CCAAT Enhancer Binding Protein α (CEBPA) Mutations
The differentiation-inducing transcription factor CCAAT
enhancer binding protein α (CBPA) mutations are found in 6%–
10% of all AML and 15%–19% of CN-AML, commonly in
association with del(9q) [1,40]. CEBPA is a critical
transcription factor that controls gene expression during
hematopoiesis [41]. In AML, CEBPA mutations commonly
harbor two mutations or double mutations, which frequently
involve both a combination of an N-terminal and a bZIP gene
11. mutation. Importantly, only bi allelic mutation, not single,
CEBPA mutations predicted a higher complete response (CR)
and favorable OS, occurring in 4%–5% of AML [42]. AML with
a single CEBPA mutation is associated with survival similar to
that of AML with wild-type CEBPA [11,43].
5.8. Additional Sex Comb-Like 1 (ASXL1) Mutations
Additional sex comb-like 1 (ASXL1) mutations are loss-of-
function mutations that occur in 5%–11% of AML cases [44].
The function of ASXL1 protein is not fully understood, but it is
suggested that it may be involved in epigenetic regulation (DNA
and/or histone modifications) [36]. ASXL1 mutations are five
times more common in older (≥60 years) patients (16.2%) than
those younger than 60 years (3.2%; p < 0.001) [44]. Among
older patients, ASXL1 mutations are associated with t(8;21),
wild-type NPM1, absence of FLT3-ITD, mutated CEBPA, and
overall inferior complete remission and overall survival [45,46].
5.9. Mixed Lineage Leukemia (MLL) Mutations
The mixed lineage leukemia (MLL) gene at chromosome 11q23
encodes for a protein that has histone methyltransferase activity
that coordinates chromatin modification as part of a regulatory
complex [47]. Translocations affecting the MLL gene lead to
aggressive acute lymphoblastic and myeloid leukemia with poor
prognosis that is characterized by HOX gene overexpression
[37]. In addition to translocations, partial in tandem
duplications (PTD) of the MLL gene (MLL-PTD) have been
demonstrated most often in adult de novo CN-AML and in
trisomy 11 AML cases [48,49]. In adult CN-AML, the frequency
of MLL rearrangement is 11% with the presence of the MLL-
PTD associated with a worse prognosis (i.e., shorter duration of
remission) when compared with CN-AML without the MLL-
PTD [50].
5.10. Tumor Protein p53 (TP53) Mutations
The tumor suppressor gene TP53 is found in 8%–14% of AML
cases. These mutations and deletions are primarily associated in
AML with complex karyotype (69%) and are rare in patient
without chromosomal deletions. In general, TP53 mutations
12. confer a very adverse prognosis with documented
chemoresistance [51].
5.11. c-KIT Mutations
The KIT tyrosine kinase receptor is a 145 kDa transmembrane
protein critical to normal hematopoiesis [52]. This mutation is
rare in AML (<5%) however present approximately 22%–29%
of the time in CBF mutations (i.e., AML harboring
t(8;21)(q22;q22) or inv(16)(p13.1q22) or corresponding
respective fusion genes RUNX1/RUNX1T1 and
CBFB/MYH11).KIT mutations have been shown to confer
higher relapse risk and lower OS. The KIT mutation in the
codon D816 in particular has been associated with unfavorable
DFS and OS, particularly in t(8;21)(q22;q22) patients [53].
Prospective studies later confirmed that patients with CBF AML
harboring KIT mutations have shorter OS than patients with
wild type KIT for t(8;21)(q22;q22) but not for patients with
inv(16)(p13.1q22) [54]. Remarkably KIT could be targeted
pharmacologically by using tyrosine kinase inhibitors, such as
dasatinb [52]. Preliminary results were presented recently at the
American Society of Hematology Annual Meeting from a phase
II trial that combined the KIT inhibitor, dasatinib with standard
chemotherapy for newly diagnosed patients with CBF AML.
After a median follow-up of 21 months, patients with KIT
mutations who received dasatinib with standard chemotherapy
showed similar outcomes to that of wild type KIT patients [55].
Unfortunately, no survival benefit was found with maintenance
dasatinib in a phase II study completed by Boissel et al.,
Interestingly, at relapse there was disappearance of the KIT
subclone which is hypothesized to be dasatinib driven [56].
More studies are needed to evaluate the long term outcomes of
KIT inhibitors in CBF AML.
5.12. Spilicing Factor Gene Mutations and Mutations in
Cohesion Complex Members
Often considered founding mutations, spilicing factor gene
mutations have been found to be associated with pre-leukemic
conditions such as MDS. The most common genes reported
13. include SF3B1, U2AF1, SRSF2 and ZRSR2 [7]. In newly
diagnosed AML patients, splicesome mutations including
SRSF2, F3B1, U2AF1, or ZRSR2 are now considered
pathognomonic of secondary AML developing from precedent
MDS [57]. Somatic cohesion complex mutations were identified
in roughly 20% of patients with high-risk MDS and secondary
AML. Relevant mutations include STAG2, TAD21 and SMC3
which are important in regulating gene expression and DNA-
loop formation. Mutations in cohesion complex members are
associated with poor overall survival [58].
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6. Prognosis/Risk Stratification
Age and performance status in addition to chromosomal and
molecular aberrations remain the most important tools for
outcome prediction in AML. In 2010, the European
LeukemiaNet (ELN) classification scheme was created in an
effort to standardize risk stratification in adult AML patients by
incorporating cytogenetic and known molecular abnormalities
[59]. Patients are classified into one of four risk groups:
favorable, intermediate 1, intermediate 2 and adverse (Table 1).
Favorable prognosis is associated with acute promyelocytic
leukemia (APL) t(15;17)(q22;q12), balanced abnormalities of
t(8;21)(q22;q22), inv(16)(p13.1q22), t(16;16)(p13.1;q22),
mutated NPM1 without FLT3-ITD and biallelic mutated
CEBPA. Intermediate 1 includes mutated NPM1 with FLT3-
ITD, wild-type NPM1 with or without FLT3-ITD. The
intermediate -2 category includes t(9;11), MLLT3-MLL and
cytogenetic abnormality neither favorable nor adverse. Complex
karyotype, inv(3)(q21q26)/t(3;3)(q21;q26), RPN1-EVI1, DEK-
NUP214 t(6,9)(p23;q34), t(6;11), −5 or del(5q), −7 or abnormal
(17p) and monosomal karyotype are associated with poor
prognosis [59,60]. Patients with monosomal karyotype (defined
as having two of more distinct monosomies or one monosomy
and another structural abnormality) have a very poor prognosis
(less than 4% survival at four years) [61]. Studies have shown
that age >60 is an independent predictor of poor outcomes
14. regardless of the ELN classification [60].
APL is risk stratified according to the risk of relapse based on
initial white blood count (WBC) and platelet count at diagnosis.
The following patient categories are: (1) low-risk: presenting
WBC count below or equal to 10 × 109/L and platelet count
above 40 × 109/L; (2) intermediate-risk: presenting WBC and
platelet counts below or equal to 10 × 109 and 40 × 109/L,
respectively; and (3) high-risk group: presenting WBC greater
than 10 × 109/L. Treatment strategy varies depending on risk
stratification at diagnosis however, the inclusion of arsenic
trioxide (ATO) in frontline therapy seems to benefit all-risk
category APL patients [62].
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7. Therapeutics
7.1. Induction Therapy
Since 1970, the backbone of intensive induction chemotherapy
remains unchanged. For young adults (age < 60 years) and fit
elderly patients (especially those harboring NPM1 mutations
and CBF leukemia) the intensive anthracycline and cytarabine
regimen, “7 + 3”, induction therapy is the standard of care. The
typical dose and schedule includes either daunorubicin (60 or 90
mg/m2 on days 1, 2 and 3) or idarubicin (10–12 mg/m2 on days
1, 2 and 3) given with seven days of continuous cytarabine
infusion (100 mg/m2/daily for one week (days 1 through 7). The
goal of induction chemotherapy is to achieve morphologic
complete remission (CR), which is defined as: (1) <5% blasts in
bone marrow aspirate sample with marrow spicules and with a
count of ≥200 nucleated cells (no blasts with Auer rods or
persistence of extramedullary disease); (2) absolute neutrophil
count (ANC) >1000/µL, and (3) platelets ≥ 100,000/µL [63].
Young, de novo, AML patients achieve CR in 65%–73% using
standard induction with “7 + 3” while only 38%–62% of
patients over 60 years of age with AML achieve CR [64,65,66].
Several trials have now shown that higher dose of anthracycline
(90 versus 45 mg/m2) in both younger and older fit adults (from
60 to 65) results in higher CR rates and increases the duration
15. of OS [65,66]. Concerns about toxicity of high-dose
daunorubicin and the wide use of the 60-mg/m2 dose as a newer
“standard,” led the United Kingdom (UK) National Cancer
Research Council (NCRC) to conduct a prospective randomized
trial with the goal to compare daunorubicin at 60 vs. 90 mg/m2
in the induction of 1206 AML patients [67]. In this study there
was no benefit of using higher dosing (90 mg/m2) over 60
mg/m2 across all subgroups [67]. However there are some
caveats to consider in this trial. In particular, the cumulative
dose of anthracyclines in the low dose arm (60 mg/m2) was
equivalent in the United Kingdom National Cancer Research
Institute (UK NCRC) trial to the higher dose (90 mg/m2) of the
other clinical trials due to multiple courses of anthracycline. In
addition the UK NCRC trial has a shorter follow up [68]. Thus,
it is clear that 45 mg/m2 of daunorubicin seems insufficient and
60 mg/m2 is not inferior to 90 mg/m2 with less associated
toxicity. Patients found to have a FLT3 mutation should be
treated with a FLT3 inhibitor (discussed in more detail below),
such as midostaurin, added to standard induction therapy [69].
Characterizing fitness in the adult population is important when
deciding treatment strategy. In particular, appropriate therapy in
the elderly AML patient should be determined based on
“patient-specific fitness” using geriatric assessments to
determine fitness, vulnerable and frail status regardless of age
[70]. In older adults, deemed not fit for intensive induction
therapy especially harboring complex karyotype without NPM1
mutations, the use of hypomethylating agents including
decitabine and azacitidine has shown to be beneficial
[70,71,72]. Both agents, commonly used to treat myelodisplasia,
have activity in AML as initial induction therapy and in the
relapsed setting. Several phase II and III studies using
azacitadine and decitabine have been conducted [71,72,73]. A
study of 82 patients with AML, median age of 72 years, who
received azacitidine as part of a compassionate use program
showed CR/incomplete CR in 11 of the 35 untreated patients
(31%). The median overall response duration was 13 months
16. with the one-year and two-years overall survival rates of 58%
and 24%, respectively [73]. Blum et al. showed an even higher
complete remission rate of 47% and overall response rate of
64% with 10 days of low-dose decitabine at 20 mg/m2
intravenous over 1 h [72]. This treatment was well tolerated
with CR achieved in 52% of subjects presenting with CN-AML
and in 50% of those with complex karyotypes [72]. Older
patients receiving induction decitabine usually require a median
of two to four cycles of therapy to have an optimal response.
Patients with suspected acute promyelocytic leukemia (APL)
should be treated with all-trans retinoic acid (ATRA) even
before the diagnosis is confirmed. Early use of ATRA decreases
the risk of APL induced coagulopathy, development of
disseminated intravascular coagulation (DIC) and mortality. For
patients with low-to-intermediate-risk APL (WBC ≤ 10 × 109/L)
outcomes are excellent with the use of ATRA with arsenic
(ATO) [74]. In this non-inferiority study, the ATO-ATRA
combination showed CR rates in all 77 patients (100%) and in
75 of 79 patients (95%) in the ATRA-idarubicin group. The
two-year event-free survival and OS rates were significantly
improved (97% and 99%) in the ATO-ATRA arm than for those
in the ATRA–chemotherapy arm (86% and 91%) [74]. For high-
risk patients (WBC > 10 × 109/L), chemotherapy with
idarubicin should be initiated once the diagnosis is confirmed in
addition to ATO-ATRA for rapid control of leukocytosis.
During induction treatment it is recommended that WBC,
fibrinogen level, prothrombin time and partial thromboplastin
time be monitored at least twice daily with aggressive
transfusion support (platelet count ≥ 30 × 109/L and fibrinogen
level ≥ 1.5 g/L). Prophylactic steroids are also recommended, in
particular when using ATRA/ATO combination for induction in
patients with high WBC count to prevent differentiation
syndrome [74,75].
7.2. Consolidation Strategies
Consolidation or post-induction therapy is given to prevent
relapse and eradicate minimal residual leukemia (MRD) in the
17. bone marrow after induction as a bridge to transplant or to
achieve cure. Assessment of minimal residual disease using
real-time PCR or Next Generation Sequencing (NGS) is
increasingly being used to help track treatment response and has
been shown to be superior than morphology alone in predicting
impending relapse [76,77]. Despite this powerful information,
the heterogentiy of AML in general has made following
mutational clones difficult to determine absolute risk of
leukemia development as some clones can persist in patient in
long-term remission following treatment, such as DNMT3A
[19]. In general, there are two main strategies for consolidation;
chemotherapy (including targeted agents) and hematopoietic
stem cell transplantation [64]. Both strategies could be used
alone or most commonly in combination depending on the type
of leukemia, the fitness of the patient and the availability of a
stem cell donor. Post induction chemotherapy using
intermediate-dose cytarabine 1.5 g/m2 twice daily on days 1, 3
and 5 given in three to four cycles is an effective and
established regimen to prolong remission and improve survival
in favorable risk young adults (<60 year of age) [8]. These
patients are usually treated with chemotherapy alone and
transplantation is reserved only at relapse [64]. In 2013, Burnett
et al. challenged this dose schedule for adults <60 year old and
showed that higher dose (3 g/m2) as compared to lower dose
(1.5 g/m2) cytarabine for three courses led to identical
outcomes [78]. Thus, low dose cytarabine at 1.5 g/m2 became
the standard of care. High-dose cytarabine is still used for
patients with CBF AML [e.g., t(8:21); or inv(16)] and NPM1
mutated AML [8,78]. In elderly patients (>60 year of age) there
was no benefit with high dose cytarabine with increased and
sometimes irreversible neurotoxicity noted [79], therefore 500–
1000 mg/m2 is standardly used [1].
For other prognostic groups, in particular fit patients with
intermediate risk or high risk disease after achieving CR,
allogeneic hematopoietic stem cell transplantation remains the
most effective long term therapy for AML with cure in 50% to
18. 60% of patients in first CR [80,81]. Despite this, several
patients never become eligible for transplant given co-
morbidities, failure to achieve CR or lack of suitable donor
[80]. While waiting for transplant it is standard practice to give
post induction chemotherapy to maintain CR and keep the
leukemia burden low. Decisions regarding consolidation rather
than moving straight to transplant should be individualized as
consolidation therapy poses risk of morbidity and mortality,
which may hinder eventual curative transplant. Recent evidence
unanimously confirms that age should no longer be used as the
sole criteria for transplant eligibility [80,82]. Rather eligibility
should be decided upon based on pre-transplant performance
status, co-morbidities and current remission. The most widely
recognized and validated tool for assessing comorbidity
includes the Hematopoietic Cell Transplantation Comorbidity
Index (HCT-CI) [82]. The higher the comorbidity index score,
the worse the clinical outcome. Improvements in supportive
care, increased donor options (haplo-identical donors and cord
grafts) and reduced intensity preparation regimens for HCT
have increased the success of transplant in all age groups. It is
for this reason that we advocate for early patient discussion,
risk assessment and tissue typing at diagnosis. Conditioning
regimen should be decided based on patient fitness, transplant
options and disease characteristics. Although risk of relapse is
higher, long term outcomes of reduced-intensity allogeneic
hematopoietic stem cell transplant in patients who were
ineligible for myeloablative transplant are promising [81]. The
results of a prospective multicenter phase II trial conduced by
the Alliance for Clinical Trials in Oncology (formerly Cancer
and Leukemia Group B) and the Blood and Marrow Transplant
Clinical trial Network showed reduced intensity conditioning-
based hematopoietic stem cell transplant (HSCT) to be an
effective strategy for suitable older patients with an available
matched donor with a disease-free survival and OS at two years
after transplant of 42% and 48%, respectively [83]. Reduced
intensity transplants are therefore becoming more common and
19. clinically accepted.
7.3. Relapsed Disease
Of the patients who relapse, only a small fraction achieve
successful second remission using salvage chemotherapy
followed by allogeneic stem cell transplant with curative intent
[64]. Studies examining clonal evolution of relapse show that
relapse can occur from expansion of major or minor clones
present at diagnosis or through newly acquired mutations over
time [2]. Therefore, clinical trial is the preferred treatment
approach especially in light of novel targeted therapies. Early
relapse (occurring within the first six months after CR1)
portends a poor overall survival. Salvage regimes include
intermediate dose cytarabine (500–1500 mg/m2 intravenously
every 12 h on days 1–3); MEC (Mitoxantrone 8 mg/m2 on days
1–5, Etoposide 100 mg/m2 on days 1–5, and Cytarabine 100
mg/m2 on days 1–5) or lastly, FLAG-IDA (Fludarabine 30
mg/m2, intravenously on days 1–5 (20 mg/m2 in patient >60
years old), Cytarabine 1500 mg/m2 (500–1000 mg/m2 in
patients >60 year) intravenously, 4 h after fludarabine infusion,
on days 1–5; Idarubicin 8 mg/m2, intravenously, on days 3–5;
Granulocyte colony-stimulating factor 5 μg/kg, subcutaneously,
from day 6 to white-cell count >1 g/L (FLAG-IDA) [1]. The
likelihood of achieving a second CR is best in patients with a
long first remission, younger age and in those with favorable
cytogenetics [84]. In cases of APL, re-induction with ATO with
or without ATRA remains the standard. CR rates with single
agent ATO are good at roughly 85% [85].
Go to:
8. Novel Targets
8.1. Fms-Like Tyrosine Kinase 3 (FLT3) Inhibitors
Several FLT3 small molecule inhibitors have been developed
with mixed results. First generation drugs include multi-kinase
inhibitors such as midostaurin, lestaurtinib, tandutinib sunitinib
and sorafenib. When used as single agents they have limited
anti-leukemia activity mostly showing only transient reduction
of blood and bone marrow blasts and increased toxicity [86]. In
20. a randomized trial of 224 patients with FLT3 mutated AML in
first relapse lestaurtinib did not increase the response rate or
prolong survival [87]. Single agent use with midostantrum,
tandutinib and KW2449 in phase I/II trials were also not
clinically effective [88,89,90]. Combination therapy using FLT3
inhibitors with chemotherapy have also been conducted. Serve
et al. reported a randomized trial of 201 newly diagnosed older
AML patients, using the addition of sorafenib to induction and
consolidation therapy. Unfortunately, sorafenib did not improve
outcomes and patients did worse in the sorafenib arm due to
higher treatment-related mortality and lower CR rates [91]. A
recent phase II study of sorafenib in combination with 5-
azacitadine in relapsed/refractory FLT3-ITD mutant AML
demonstrated a response rate of 46%, mostly consisting of CR
or CR with incomplete count recovery [92]. Sunitinib added to
induction and consolidation chemotherapy in older patients with
AML and FLT3 activating mutations showed some effectiveness
with CR rates 53% (8/15) and 71% (5/7) for patients with FLT3-
ITD and FLT3-TKD mutations, respectively. The 13 patients
who achieved CR went on to be consolidated with high dose
cytarabine and 7/13 received sunitinib maintenance. The median
overall survival in this study was 18.8 months [93]. The largest
randomized, phase III clinical trial in FLT3-mutated AML
conduced to date was recently presented at the 2015 American
Society of Hematology (ASH) Plenary session showing the
benefit of midostaurin added to induction chemotherapy
(RATIFY trial) in which patients receiving midostaurin had
significantly longer median OS than those receiving placebo:
74.7 versus 25.6 months (p = 0.0076) [94]. Second generation
agents, promising to have better potency and less side effects
include quizartinib and crenolanib are still undergoing clinical
investigation. One trial, using quizartinib (AC220), did show
better blast count clearance however also noted the development
of secondary resistance. Drug resistance has since become the
major challenge in treating patients with a single FLT3
inhibitor. The point mutations identified which lead to
21. resistance include N676, F691, and D835 within the kinase
domain of FLT3-ITD [95]. The novel FLT3 inhibitors, G-749
and ASP2215 (active against both FLT3 ITD and D835
mutations), have recently been shown to provide sustained
inhibition of FLT3 phosphorylation and increased ability to
overcome drug resistance in pre-clinical trials but further
studies are needed to determine if it will have clinical efficacy
[96,97].
8.2. Isocitrate Dehydrogenase (IDH) Inhibitors
The IDH1 inhibitor AG-120 and the IDH2 inhibitor AG-221
have demonstrated promising response rates in patients with
AML in two separate phase I clinical trials [98,99]. Preliminary
results were recently presented for both trials. The objective
response rate (ORR) with AG-221 was 40% and 31% with AG-
120 in relapsed/refractory AML patients. More interestingly the
duration of the responses for AG-221 and AG-120 were more
than 15 and 11 months at the analysis, and remained ongoing.
Overall, 76% of responses lasted longer than six months. Based
on these data, the Food and Drug Administration (FDA) have
granted the medication an orphan drug designation for patients
with AML.
8.3. Nuclear Exporter Inhibitors
The anti-leukemic efficacy of reversible inhibitors of the major
nuclear export receptor, chromosome region maintenance 1
(CRM1, also termed XPO1) has brought much excitement.
CRM1 is a major nuclear exporter protein which mediates the
export and inactivation of several tumor suppressors such as
p53, p73, FOXO1, RB1 and p21 (CDKN1A) among others
[100]. CRM1 has been shown to be upregulated in a range of
solid tumors and hematological malignancies, including AML
[101,102]. Preclinical studies indicate that treatment of AML
cell lines, patient samples and AML xenografts with novel
CRM1 inhibitors (Selinexor) induces strong anti-leukemic
effects [103,104]. Based on these studies, Phase I/II clinical
trials are currently ongoing to assess the safety, tolerability and
activity of selinexor in AML patients.
22. 8.4. Immune Therapies
Novel antibody therapies are revolutionary in the treatment
leukemia and currently under development in AML. Monoclonal
antibodies being explored include CD33 (Gemtuzumab
ozogamicin) [105] and bispecific antibodies such as AMG 330
(anti-CD33 and CD3) [106]. Chimeric antigen receptor (CAR)-
transduced T cells (CARTs) are T cells engineered to express a
specific antigen receptor target designed against a specific cell-
surface antigen. CD123 has been found to be expressed on the
majority of AML blasts but also normal hematopoietic cells.
Preclinical data shows that targeting CD123 via CARTs results
in rejection of human AML and myeloablation in the mouse
models [107].
9. Conclusions
AML is complex disease with a diverse genetic landscape. The
field is rapidly expanding with increased understanding of the
biology as well as potential new drug targets. Despite our best
efforts at targeted therapy, it has become apparent that single
drug options may be less likely to succeed over multiple drug
targets. Relapse disease remains the highest cause of mortality
after HCT. Immunotherapy is also an exciting new therapeutic
approach which may offer long term cures for relapsed patients.
We remain hopeful that the therapeutic options will continue to
improve, with less toxicity and improved efficacy.
References
1. Döhner H., Weisdorf D.J., Bloomfield C.D. Acute myeloid
leukemia. N. Engl. J. Med. 2015;373:1136–1152. [PubMed]
[Google Scholar]
2. Ding L., Ley T.J., Larson D.E., Miller C.A., Koboldt D.C.,
Welch J.S., Ritchey J.K., Young M.A., Lamprecht T., McLellan
M.D., et al. Clonal evolution in relapsed acute myeloid
leukaemia revealed by whole-genome sequencing. Nature.
2012;481:506–510. doi: 10.1038/nature10738. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
23. 3. Campos L., Guyotat D., Archimbaud E., Devaux Y., Treille
D., Larese A., Maupas J., Gentilhomme O., Ehrsam A., Fiere D.
Surface marker expression in adult myeloid leukemia:
Correlations with initial characteristics, morphology and
response to therapy. Br. J. Haematol. 1989;72:161–166. doi:
10.1111/j.1365-2141.1989.tb07677.x. [PubMed] [CrossRef]
[Google Scholar]
4. Wolach O., Stone R.M. How I treat mixed-phenotype acute
leukemia. Blood. 2015;125:2477–2485. doi: 10.1182/blood-
2014-10-551465. [PubMed] [CrossRef] [Google Scholar]
5. Bennett J.M., Catovsky D., Daniel M.T., Flandrin G., Galton
D.A., Gralnick H.R., Sultan C. Proposals for the classification
of the acute leukaemias. French-American-British (FAB) co-
operative group. Br. J. Haematol. 1976;33:451–458. doi:
10.1111/j.1365-2141.1976.tb03563.x. [PubMed] [CrossRef]
[Google Scholar]
6. Vardiman J.W., Thiele J., Arber D.A., Brunning R.D.,
Borowitz M.J., Porwit A., Harris N.L., le Beau M.M.,
Hellstrom-Lindberg E., Tefferi A., et al. The 2008 revision of
the World Health Organization (WHO) classification of myeloid
neoplasms and acute leukemia: Rationale and important
changes. Blood. 2009;114:937–951. doi: 10.1182/blood-2009-
03-209262. [PubMed] [CrossRef] [Google Scholar]
7. Lindsley R.C., Mar B.G., Mazzola E., Grauman P.V., Shareef
S., Allen S.L., Pigneux A., Wetzler M., Stuart R.K., Erba H.P.,
et al. Acute myeloid leukemia ontogeny is defined by distinct
somatic mutations. Blood. 2015;125:1367–1376. doi:
10.1182/blood-2014-11-610543. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
8. Byrd J.C., Mrózek K., Dodge R.K., Carroll A.J., Edwards
C.G., Arthur D.C., Pettenati M.J., Patil S.R., Rao K.W., Watson
M.S., et al. Pretreatment cytogenetic abnormalities are
predictive of induction success, cumulative incidence of
relapse, and overall survival in adult patients with de novo
acute myeloid leukemia: Results from Cancer and Leukemia
Group B (CALGB 8461) Blood. 2002;100:4325–4336. doi:
24. 10.1182/blood-2002-03-0772. [PubMed] [CrossRef] [Google
Scholar]
9. Gaidzik V., Dohner K. Prognostic implications of gene
mutations in acute myeloid leukemia with normal cytogenetics.
Semin. Oncol. 2008;35:346–355. doi:
10.1053/j.seminoncol.2008.04.005. [PubMed] [CrossRef]
[Google Scholar]
10. Cancer Genome Atlas Research Network Genomic and
epigenomic landscapes of adult de novo acute myeloid
leukemia. N. Engl. J. Med. 2013;368:2059–2074. [PMC free
article] [PubMed] [Google Scholar]
11. Marcucci G., Haferlach T., Dohner H. Molecular genetic of
adult acute myeloid leukemia: Prognostic and therapeutic
implications. J. Clin. Oncol. 2011;29:475–486. doi:
10.1200/JCO.2010.30.2554. [PubMed] [CrossRef] [Google
Scholar]
12. Schnittger S., Schoch C., Kern W., Mecucci C., Tschulik C.,
Martelli M.F., Haferlach T., Hiddemann W., Falini B.
Nucleophosmin gene mutations are predictors of favorable
prognosis in acute myelogenous leukemia with a normal
karyotype. Blood. 2005;106:3733–3739. doi: 10.1182/blood-
2005-06-2248. [PubMed] [CrossRef] [Google Scholar]
13. Falini B., Nicoletti I., Martelli M.F., Mecucci C. Acute
myeloid leukemia carrying cytoplasmic/mutated nucleophosmin
(NPMc + AML): Biologic and clinical features. Blood.
2007;109:874–885. doi: 10.1182/blood-2006-07-012252.
[PubMed] [CrossRef] [Google Scholar]
14. Falini B., Bolli N., Shan J., Martelli M.P., Liso A.,
Pucciarini A., Bigerna B., Pasqualucci L., Mannucci R., Rosati
R., et al. Both carboxy-terminus NES motif and mutated
tryptophan(s) are crucial for aberrant nuclear export of
nucleophosmin leukemic mutants in NPMc + AML. Blood.
2006;107:4514–4523. doi: 10.1182/blood-2005-11-4745.
[PubMed] [CrossRef] [Google Scholar]
15. Cheng K., Sportoletti P., Ito K., Clohessy J.G., Teruya-
Feldstein J., Kutok J.L., Pandolfi P.P. The cytoplasmic NPM
25. mutant induces myeloproliferation in a transgenic mouse model.
Blood. 2010;115:3341–3345. doi: 10.1182/blood-2009-03-
208587. [PMC free article] [PubMed] [CrossRef] [Google
Scholar]
16. Dohner K., Schlenk R.F., Habdank M., Scholl C., Rucker
F.G., Corbacioglu A., Bullinger L., Frohling S., Dohner H.
Mutant nucleophosmin (NPM1) predicts favorable prognosis in
younger adults with acute myeloid leukemia and normal
cytogenetics: Interaction with other gene mutations. Blood.
2005;106:3740–3746. doi: 10.1182/blood-2005-05-2164.
[PubMed] [CrossRef] [Google Scholar]
17. Marcucci G., Metzeler K.H., Schwind S., Becker H.,
Maharry K., Mrozek K., Radmacher M.D., Kohlschmidt J.,
Nicolet D., Whitman S.P., et al. Age-related prognostic impact
of different types of DNMT3A mutations in adults with primary
cytogenetically normal acute myeloid leukemia. J. Clin. Oncol.
2012;30:742–750. doi: 10.1200/JCO.2011.39.2092. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
18. Ley T.J., Ding L., Walter M.J., McLellan M.D., Lamprecht
T., Larson D.E., Kandoth C., Payton J.E., Baty J., Welch J., et
al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J.
Med. 2010;363:2424–2433. doi: 10.1056/NEJMoa1005143.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
19. Shlush L.I., Zandi S., Mitchell A., Chen W.C., Brandwein
J.M., Gupta V., Kennedy J.A., Schimmer A.D., Schuh A.C., Yee
K., et al. Identification of pre-leukaemic haematopoietic stem
cells in acute leukaemia. Nature. 2014;506:328–333. doi:
10.1038/nature13038. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]
20. Gaidzik V.I., Schlenk R.F., Paschka P., Stölzle A., Späth D.,
Kuendgen A., von Lilienfeld-Toal M., Brugger W., Derigs H.G.,
Kremer S., et al. Clinical impact of DNMT3A mutations in
younger adult patient with acute myeloid leukemia: A
comprehensive analysis of the AML study Group (AMLSG)
Blood. 2013;121:4769–4777. doi: 10.1182/blood-2012-10-
461624. [PubMed] [CrossRef] [Google Scholar]
26. 21. Sehgal A.R., Gimotty P.A., Zhao J., Hsu J.M., Daber R.,
Morrissette J.D., Luger S., Loren A.W., Carroll M. DNMT3A
mutational status affects the results of dose-escalated induction
therapy in acute myelogenous leukemia. Clin. Cancer Res.
2015;21:1614–1620. doi: 10.1158/1078-0432.CCR-14-0327.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Patel J.P., Gonen M., Figueroa M.E., Fernandez H., Sun Z.,
Racevskis J. Prognostic relevance of integrated genetic
profiling in acute myeloid leukemia. N. Engl. J. Med.
2012;366:1079–1089. doi: 10.1056/NEJMoa1112304. [PMC free
article] [PubMed] [CrossRef] [Google Scholar]
23. Maroc N., Rottapel R., Rosnet O., Marchetto S., Lavezzi C.,
Mannoni P., Birnbaum D., Dubreuil P. Biochemical
characterization and analysis of the transforming potential of
the FLT3/FLK2 receptor tyrosine kinase. Oncogene.
1993;8:909–918. [PubMed] [Google Scholar]
24. Gilliland D.G., Griffin J.D. The roles of FLT3 in
hematopoiesis and leukemia. Blood. 2002;100:1532–1542. doi:
10.1182/blood-2002-02-0492. [PubMed] [CrossRef] [Google
Scholar]
25. Kelly L.M., Liu Q., Kutok J.L., Williams I.R., Boulton C.L.,
Gilliland D.G. FLT3 internal tandem duplication mutations
associated with human acute myeloid leukemias induce
myeloproliferative disease in a murine bone marrow transplant
model. Blood. 2002;99:310–318. doi: 10.1182/blood.V99.1.310.
[PubMed] [CrossRef] [Google Scholar]
26. Kayser S., Schlenk R.F., Londono M.C., Breitenbuecher F.,
Wittke K., Du J., Groner S., Späth D., Krauter J. Insertion of
FLT3 internal tandem duplication in the tyrosine kinase domain-
1 is associated with resistance to chemotherapy and inferior
outcome. Blood. 2009;114:2386–2392. doi: 10.1182/blood-
2009-03-209999. [PubMed] [CrossRef] [Google Scholar]
27. Kussick S.J., Stirewalt D.L., Yi H.S., Sheets K.M.,
Pogosova-Agadjanyan E., Braswell S., Norwood T.H., Radich
J., Wood B.L. A distinctive nuclear morphology in acute
myeloid leukemia is strongly associated with loss of HLA-DR
27. expression and FLT3 internal tandem duplication. Leukemia.
2004;18:1591–1598. doi: 10.1038/sj.leu.2403458. [PubMed]
[CrossRef] [Google Scholar]
28. Gale R.E., Green C., Allen C., Mead A.J., Burnett A.K.,
Hills R.K., Linch D.C., Medical Research Council Adult
Leukaemia Working Party The impact on FLT3 internal tandem
duplication mutant level, number, size and interaction with
NPM1 mutation in a large cohort of young adult patient with
acute myeoid leukemia. Blood. 2008;111:2776–2784. doi:
10.1182/blood-2007-08-109090. [PubMed] [CrossRef] [Google
Scholar]
29. Pratcorona M., Brunet S., Nomdedeu J., Ribera J.M., Tormo
M., Duarte R., Escoda L., Guàrdia R., Queipo de Llano M.P.,
Salamero O., et al. Favorable outcome of patients with acute
myeloid leukemia harboring a low-allelic burden LFT3-ITD
mutation and concomitant NPM1 mutations: Relevance to post-
remission therapy. Blood. 2013;121:2734–2738. doi:
10.1182/blood-2012-06-431122. [PubMed] [CrossRef] [Google
Scholar]
30. Small D. Targeting FLT3 for the treatment of leukemia.
Semin. Hematol. 2008;45:S17–S21. doi:
10.1053/j.seminhematol.2008.07.007. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
31. Marcucci G., Maharry K., Wu Y.Z., Radmacher M.D.,
Mrózek K., Margeson D., Holland K.B., Whitman S.P., Becker
H., Schwind S., et al. IDH1 and IDH2 gene mutations identify
novel molecular subsets within de novo cytogenetically normal
acute myeloid leukemia: A cancer and leukemia group B study.
J. Clin. Oncol. 2010;28:2348–2355. doi:
10.1200/JCO.2009.27.3730. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
32. Paschka P., Schlenk R.F., Gaidzik V.I., Habdank M.,
Krönke J., Bullinger L., Späth D., Kayser S., Zucknick M.,
Götze K., et al. IDH1 and IDH2 mutations are frequent genetic
alterations in acute myeloid leukemia and confer adverse
prognosis in cytogenetically normal acute myeloid leukemia
28. with NPM1 mutation without FLT3 internal tandem duplication.
J. Clin. Oncol. 2010;28:3636–3643. doi:
10.1200/JCO.2010.28.3762. [PubMed] [CrossRef] [Google
Scholar]
33. Fathi A.T., Wander S.A., Faramand R., Emadi A.
Biochemical, epigenetic, and metabolic approaches to target
IDH mutations in acute myeloid leukemia. Semin. Hematol.
2015;52:165–171. doi: 10.1053/j.seminhematol.2015.03.002.
[PubMed] [CrossRef] [Google Scholar]
34. Chou W.C., Chou S.C., Liu C.Y., Chen C.Y., Hou H.A., Kuo
Y.Y., Lee M.C., Ko B.S., Tang J.L., Yao M., et al. TET2
mutation is an unfavorable prognostic factor in acute myeloid
leukemia patients with intermediate-risk cytogenetics. Blood.
2011;118:3803–3810. doi: 10.1182/blood-2011-02-339747.
[PubMed] [CrossRef] [Google Scholar]
35. Metzeler K.H., Maharry K., Radmacher M.D., Mrozek K.,
Margeson D., Becker H. TET2 mutations improve the new
European LeukemiaNet risk classification of acute myeloid
leukemia: A cancer and leukemia group B study. J. Clin. Oncol.
2011;29:1373–1381. doi: 10.1200/JCO.2010.32.7742. [PMC
free article] [PubMed] [CrossRef] [Google Scholar]
36. Gaidzik V.I., Paschka P., Spath D., Habdank M., Kohne
C.H., Germing U., von Lilienfeld-Toal M., Held G., Horst H.A.,
Haase D., et al. TET2 mutations in acute myeloid leukemia
(AML): Results from a comprehensive genetic and clinical
analysis of the AML study group. J. Clin. Oncol. 2012;30:1350–
1357. doi: 10.1200/JCO.2011.39.2886. [PubMed] [CrossRef]
[Google Scholar]
37. Meyers S., Downing J.R., Hiebert S.W. Identification of
AML-1 and the (8;21) translocation protein (AML-1/ETO) as
sequence-specific DNA-binding proteins: The runt homology
domain is required for DNA binding and protein-protein
interactions. Mol. Cell Biol. 1993;13:6336–6345. doi:
10.1128/MCB.13.10.6336. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
38. Tang J.L., Hou H.A., Chem C.Y., Liu C.Y., Chou W.C.,
29. Tseng M.H. AML1/RUNX1 mutations in 470 adult patients with
de novo acute myeloid leukemia: Prognostic implication and
interaction with other gene alternations. Blood. 2009;114:5352–
5361. doi: 10.1182/blood-2009-05-223784. [PubMed]
[CrossRef] [Google Scholar]
39. Mendler J.H., Maharry K., Radmacher M.D., Mrozek K.,
Becker H., Metzeler K.H. RUNX1 mutations are associated with
poor outcome in younger and older patients with cytogenetically
normal acute myeloid leukemia and with distinct gene and
MicroRNA expression signatures. J. Clin. Oncol. 2012;30:3109–
3118. doi: 10.1200/JCO.2011.40.6652. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
40. Mrózek K., Marcucci G., Paschka P., Whitman S.P.,
Bloomfield C.D. Clinical relevance of mutations and gene-
expression changes in adult acute myeloid leukemia with normal
cytogenetics: Are we ready for a prognostically prioritized
molecular classification? Blood. 2007;109:431–448. doi:
10.1182/blood-2006-06-001149. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
41. Koschmieder S., Halmos B., Levantini E., Tenen D.G.
Dysregulation of the C/EBPα differentiation pathway in human
cancer. J. Clin. Oncol. 2009;27:619–628. doi:
10.1200/JCO.2008.17.9812. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
42. Fasan A., Haferlach C., Alpermann T., Jeromin S.,
Grossmann V., Eder C., Weissmann S., Dicker F., Kohlmann A.,
Schindela S., et al. The role of different genetic subtypes of
CEBPA mutated AML. Leukemia. 2014;28:794–803. doi:
10.1038/leu.2013.273. [PubMed] [CrossRef] [Google Scholar]
43. Wouters B.J., Lowenberg B., Erpelinck-Verschueren C.A.,
van Putten W.L., Valk P.J., Delwel R. Double CEBPA
mutations, but not single CEBPA mutations, define a subgroup
of acute myeloid leukemia with a distinctive gene expression
profile that is uniquely associated with a favorable outcome.
Blood. 2009;113:3088–3091. doi: 10.1182/blood-2008-09-
179895. [PMC free article] [PubMed] [CrossRef] [Google
30. Scholar]
44. Metzeler K.H., Becker H., Maharry K., Radmacher M.D.,
Kohlschmidt J., Mrózek K., Nicolet D., Whitman S.P., Wu Y.Z.,
Schwind S., et al. ASXL1 mutations identify a high risk
subgroup of older patients with primary cytogenetically normal
AML within the ELN Favorable genetic category. Blood.
2011;118:6920–6929. doi: 10.1182/blood-2011-08-368225.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
45. Alpermann T., Haferlach C., Eder C., Nadarajah N.,
Meggendorfer M., Kern W., Haferlach T., Schnittger S. AML
with gain of chromosome 8 as the sole chromosomal
abnormality (+8sole) is associated with a specific molecular
mutation pattern including ASXL1 mutation in 46.8% of the
patients. Leuk. Res. 2015;39:265–272. doi:
10.1016/j.leukres.2014.11.026. [PubMed] [CrossRef] [Google
Scholar]
46. Micol J.B., Duployez N., Boissel N., Petit A., Geffroy S.,
Nibourel O., Lacombe C., Lapillonne H., Etancelin P., Figeac
M., et al. Frequent ASXL2 mutations in acute myeloid leukemia
patients with t(8;21)/RUNX1-RUNX1T1 chromosomal
translocations. Blood. 2014;124:1445–1449. doi:
10.1182/blood-2014-04-571018. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
47. Ernest P., Wang J., Korsmeyer S.J. The role of MLL in
hematopoiesis and leukemia. Curr. Opin. Hematol. 2002;9:282–
287. doi: 10.1097/00062752-200207000-00004. [PubMed]
[CrossRef] [Google Scholar]
48. Caligiuri M.A., Schichman S.A., Strout M.P., Mrózek K.,
Baer M.R., Frankel S.R., Barcos M., Herzig G.P., Croce C.M.,
Bloomfield C.D. Molecular rearrangement of the ALL-1 gene in
acute myeloid leukemia without cytogenetic evidence of 11q23
chromosomal translocations. Cancer Res. 1994;54:370–373.
[PubMed] [Google Scholar]
49. Caligiuri M.A., Strout M.P., Lawrence D., Arthur D.C.,
Baer M.R., Yu F., Knuutila S., Mrozek K., Oberkircher A.R.,
Marcucci G., et al. Rearrangement of ALL1 (MLL) in acute
31. myeloid leukemia with normal cytogenetics. Cancer Res.
1998;58:55–59. [PubMed] [Google Scholar]
50. Dohner K., Tobis K., Ulrich R., Frohling S., Benner A.,
Schlenk R.F., Dohner H. Prognostic significance of partial
tandem duplications of the MLL gene in adult patients 16 to 60
years old with acute myeloid leukemia and normal cytogenetics:
A study of the acute myeloid leukemia study group Ulm. J. Clin.
Oncol. 2002;20:3254–3261. doi: 10.1200/JCO.2002.09.088.
[PubMed] [CrossRef] [Google Scholar]
51. Haferlach C., Dicker F., Herholz H., Schnittger S., Kern W.,
Haferlach T. Mutations of the TP53 gene in acute myeloid
leukemia are strongly associated with a complex aberrant
karyotype. Leukemia. 2008;22:1539–1541. doi:
10.1038/leu.2008.143. [PubMed] [CrossRef] [Google Scholar]
52. Sattler M., Salgia R. Targeting c-Kit mutations: Basic
science to novel therapies. Leuk. Res. 2004;28:S11–S20. doi:
10.1016/j.leukres.2003.10.004. [PubMed] [CrossRef] [Google
Scholar]
53. Paschka P., Marcucci G., Ruppert A.S., Mrozek K., Chen
H., Kittles R.A., Vukosavljevic T., Perrotti D., Vardiman J.W.,
Carroll A.J., et al. Adverse prognostic significance of KIT
mutations in adult acute myeloid leukemia with inv(16) and
t(8;21): A cancer and leukemia group B study. J. Clin. Oncol.
2006;24:3904–3911. doi: 10.1200/JCO.2006.06.9500. [PubMed]
[CrossRef] [Google Scholar]
54. Boissel N., Leroy H., Brethon B., Philippe N., de Botton S.,
Auvrignon A., Raffoux E., Leblanc T., Thomas X., Hermine O.,
et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras
gene mutations in core binding factor acute myeloid leukemia
(CBF-AML) Leukemia. 2006;20:965–970. doi:
10.1038/sj.leu.2404188. [PubMed] [CrossRef] [Google Scholar]
55. Marcucci G., Geyer S., Zhao W., Caroll A.J., Bucci D., Uy
G.L., Blum W., Pardee T., Wetzler M., Stock W., et al. Adding
KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the
negative impact of KIT mutation/over-expression in core
binding factor (CBF) acute myeloid leukemia (AML): Results
32. from CLGB 10801 (Alliance) Blood. 2014;124:8. [Google
Scholar]
56. Boissel N., Renneville A., Leguay T., Lefebvre P.C., Recher
C., Lecerf T., Delabesse E., Berthon C., Blanchet O., Prebet T.,
et al. Dasatinib in high-risk core binding factor acute myeloid
leukemia in first complete remission: A french acute myeloid
leukemia intergroup trial. Haematologica. 2015;100:780–785.
doi: 10.3324/haematol.2014.114884. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
57. Cazzola M., Della Porta M.G., Malcovati L. The genetic
basis of myelodysplasia and its clinical relevance. Blood.
2013;122:4021–4034. doi: 10.1182/blood-2013-09-381665.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Thota S., Viny A.D., Makishima H., Spitzer B.,
Radivoyevitch T., Przychodzen B., Sekeres M.A., Levine R.L.,
Maciejewski J.P. Genetic alterations of the cohesin complex
genes in myeloid malignancies. Blood. 2014;124:1790–1798.
doi: 10.1182/blood-2014-04-567057. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
59. Dohner H., Estey E.H., Amadori S., Appelbaum F.R.,
Buchner T., Burnett A.K., Dombret H., Fenaux P., Grimwade
D., Larson R.A., et al. Diagnosis and management of acute
myeloid leukemia in adults: Recommendations from an
international expert panel, on behalf of the European
LeukemiaNet. Blood. 2010;115:453–474. doi: 10.1182/blood-
2009-07-235358. [PubMed] [CrossRef] [Google Scholar]
60. Mrozek K., Marcucci G., Nicolet D., Maharry K.S., Becker
H., Whitman S.P., Metzeler K.H., Schwind S., Wu Y.Z.,
Kohlschmidt J., et al. Prognostic significance of the European
LeukemiaNet standardized system for reporting cytogenetic and
molecular alterations in adults with acute myeloid leukemia. J.
Clin. Oncol. 2012;30:4515–4523. doi:
10.1200/JCO.2012.43.4738. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
61. Medeiros B.C., Othus M., Fang M., Roulston D., Appelbaum
F.R. Prognostic impact of monosomal karyotype in young adult
33. and elderly acute myeloid leukemia: The South-west Oncology
Group (SWOG) experience. Blood. 2010;116:2224–2228. doi:
10.1182/blood-2010-02-270330. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
62. Sanz M.A., Lo Coco F., Martin G., Avvisati G., Rayon C.,
Barbui T., Diaz-Mediavilla J., Fioritoni G., Gonzalez J.D., Liso
V., et al. Definition of relapse risk and role of nonanthracycline
drugs for consolidation in patients with acute promyelocytic
leukemia: A joint study of the PETHEMA and GIMEMA
cooperative groups. Blood. 2000;96:1247–1253. [PubMed]
[Google Scholar]
63. Cheson B.D., Bennett J.M., Kopecky K.J., Buchner T.,
Willman C.L., Estey E.H., Schiffer C.A., Doehner H., Tallman
M.S., Lister T.A., et al. Revised recommendations of the
international working group for diagnosis, standardization of
response criteria, treatment outcomes, and reporting standards
for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol.
2003;21:4642–4649. doi: 10.1200/JCO.2003.04.036. [PubMed]
[CrossRef] [Google Scholar]
64. Estey E., Döhner H. Acute myeloid leukaemia. Lancet.
2006;368:1894–1907. doi: 10.1016/S0140-6736(06)69780-8.
[PubMed] [CrossRef] [Google Scholar]
65. Lowenberg B., Ossenkoppele G.J., van Putten W., Schouten
H.C., Graux C., Ferrant A., Sonneveld P., Maertens J., Jongen-
Lavrencic M., von Lilienfeld-Toal M., et al. High-dose
daunorubicin in older patients with acute myeloid leukemia. N.
Engl. J. Med. 2009;361:1235–1248. doi:
10.1056/NEJMoa0901409. [PubMed] [CrossRef] [Google
Scholar]
66. Fernandez H.F., Sun Z., Yao X., Litzow M.R., Luger S.M.,
Paietta E.M., Racevskis J., Dewald G.W., Ketterling R.P.,
Bennett J.M., et al. Anthracycline Dose Intensification in Acute
Myeloid Leukemia. N. Engl. J. Med. 2009;361:1249–1259. doi:
10.1056/NEJMoa0904544. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
67. Burnett A.K., Russell N.H., Hills R.K., Kell J., Cavenagh J.,
34. Kjeldsen L., McMullin M., Cahalin P., Dennis M., Friis L., et
al. A randomized comparison of daunorubicin 90 mg/m2 vs 60
mg/m2 in AML Induction: Results from the UK NCRI AML17
Trial in 1206 Patients. Blood. 2015;125:3878–3885. doi:
10.1182/blood-2015-01-623447. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
68. Fernandez H.F. Beyond the first glance: Anthracyclines in
AML. Blood. 2015;125:3828–3829. doi: 10.1182/blood-2015-
04-639419. [PubMed] [CrossRef] [Google Scholar]
69. Stone R.M., O’Donnell M.R., Sekeres M.A. Acute myeloid
leukemia. Hematol. Am. Soc. Hematol. Educ. Program.
2004;2004:98–117. doi: 10.1182/asheducation-2004.1.98.
[PubMed] [CrossRef] [Google Scholar]
70. Klepin H. Geriatric perspective: How to assess fitness for
chemotherapy in acute myeloid leukemia. Hematol. Am. Soc.
Hematol. Educ. Program. 2014;2014:8–13. doi:
10.1182/asheducation-2014.1.8. [PubMed] [CrossRef] [Google
Scholar]
71. Quintas-Cardama A., Ravandi F., Liu-Dumlao T., Brandt
M., Faderl S., Pierce S., Borthakur G., Garcia-Manero G.,
Cortes J., Kantarjian H. Epigenetic therapy is associated with
similar survival compared with intensive chemotherapy in older
patients with newly diagnosed acute myeloid leukemia. Blood.
2012;120:4840–4845. doi: 10.1182/blood-2012-06-436055.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
72. Blum W., Garzon R., Klisovic R.B., Schwind S., Walker A.,
Geyer S., Liu S., Havelange V., Becker H., Schaaf L., et al.
Clinical response and miR-29b predictive significance in older
AML patients treated with a 10-day schedule of decitabine.
Proc. Natl. Acad. Sci. USA. 2010;107:7473–7478. doi:
10.1073/pnas.1002650107. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
73. Maurillo L., Venditti A., Spagnoli A., Gaidano G., Ferrero
D., Oliva E., Lunghi M., D'Arco A.M., Levis A., Pastore D., et
al. Azacitidine for the treatment of patients with acute myeloid
leukemia: Report of 82 patients enrolled in an Italian
35. Compassionate Program. Cancer. 2012;118:1014–1022. doi:
10.1002/cncr.26354. [PubMed] [CrossRef] [Google Scholar]
74. Lo-Coco F., Avvisati G., Vignetti M., Thiede C., Orlando
S.M., Iacobelli S., Ferrara F., Fazi P., Cicconi L., Di Bona E.,
et al. Retinoic acid and arsenic trioxide for acute promyelocytic
leukemia. N. Engl. J. Med. 2013;369:111–121. doi:
10.1056/NEJMoa1300874. [PubMed] [CrossRef] [Google
Scholar]
75. Mi J.Q., Li J.M., Shen Z.X., Chen S.J., Chen Z. How to
manage acute promyelocytic leukemia. Leukemia.
2012;26:1743–1751. doi: 10.1038/leu.2012.57. [PubMed]
[CrossRef] [Google Scholar]
76. Grimwade D., Freeman S.D. Defining minimal residual
disease in acute myeloid leukemia: Which platforms are ready
for “prime time”? Blood. 2014;124:3345–3355. doi:
10.1182/blood-2014-05-577593. [PubMed] [CrossRef] [Google
Scholar]
77. Kohlmann A., Nadarajah N., Alpermann T., Grossmann V.,
Schindela S., Dicker F., Roller A., Kern W., Haferlach C.,
Schnittger S., et al. Monitoring of residual disease by next-
generation deep-sequencing of RUNX1 mutations can identify
acute myeloid leukemia patients with resistant disease.
Leukemia. 2014;28:129–137. doi: 10.1038/leu.2013.239.
[PubMed] [CrossRef] [Google Scholar]
78. Burnett A.K., Russell N.H., Hills R.K., Hunter A.E.,
Kjeldsen L., Yin J., Gibson B.E., Wheatley K., Milligan D.
Optimization of chemotherapy for younger patients with acute
myeloid leukemia: Results of the medical research council
AML15 trial. J. Clin. Oncol. 2013;31:3360–3368. doi:
10.1200/JCO.2012.47.4874. [PubMed] [CrossRef] [Google
Scholar]
79. Schiffer C. Optimal dose and schedule of consolidation in
AML: Is there a standard? Best Pract. Res. Clin. Haematol.
2014;27:259–264. doi: 10.1016/j.beha.2014.10.007. [PubMed]
[CrossRef] [Google Scholar]
80. Appelbaum F.R. The current status of hematopoietic cell
36. transplantation. Annu. Rev. Med. 2003;54:491–512. doi:
10.1146/annurev.med.54.101601.152456. [PubMed] [CrossRef]
[Google Scholar]
81. Popat U., de Lima M.J., Saliba R.M., Anderlini P.,
Andersson B.S., Alousi A.M., Hosing C., Nieto Y., Parmar S.,
Khouri I.F., et al. Long-term outcome of reduced-intensity
allogeneic hematopoietic SCT in patients with AML in CR.
Bone Marrow Transplant. 2012;47:212–216. doi:
10.1038/bmt.2011.61. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]
82. Sorror M.L., Maris M.B., Storb R., Baron F., Sandmaier
B.M., Maloney D.G., Storer B. Hematopoietic cell
transplantation (HCT)-specific comorbidity index: A new tool
for risk assessment before allogeneic HCT. Blood.
2005;106:2912–2919. doi: 10.1182/blood-2005-05-2004. [PMC
free article] [PubMed] [CrossRef] [Google Scholar]
83. Devine S.M., Owzar K., Blum W., Mulkey F., Stone R.M.,
Hsu J.W., Champlin R.E., Chen Y.B., Vij R., Slack J., et al.
Phase II Study of Allogeneic Transplantation for Older Patients
With Acute Myeloid Leukemia in First Complete Remission
Using a Reduced-Intensity Conditioning Regimen: Results From
Cancer and Leukemia Group B 100103 (Alliance for Clinical
Trials in Oncology)/Blood and Marrow Transplant Clinical Trial
Network 0502. J. Clin. Oncol. 2015;33:4167–4175. [PMC free
article] [PubMed] [Google Scholar]
84. Breems D.A., Van Putten W.L., Huijgens P.C.,
Ossenkoppele G.J., Verhoef G.E., Verdonck L.F., Vellenga E.,
De Greef G.E., Jacky E., Van der Lelie J., et al. Prognostic
index for adult patients with acute myeloid leukemia in first
relapse. J. Clin. Oncol. 2005;23:1969–1978. doi:
10.1200/JCO.2005.06.027. [PubMed] [CrossRef] [Google
Scholar]
85. Soignet S.L., Maslak P., Wang Z.G., Jhanwar S., Calleja E.,
Dardashti L.J., Corso D., DeBlasio A., Gabrilove J., Scheinberg
D.A., et al. Complete remission after treatment of acute
promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med.
37. 1998;339:1341–1348. doi: 10.1056/NEJM199811053391901.
[PubMed] [CrossRef] [Google Scholar]
86. Sudhindra A., Smith C.C. FLT3 inhibitors in AML: Are we
there yet? Curr. Hematol. Malig. Rep. 2014;9:174–185. doi:
10.1007/s11899-014-0203-8. [PubMed] [CrossRef] [Google
Scholar]
87. Levis M., Ravandi F., Wang E.S., Baer M.R., Perl A.,
Coutre S., Erba H., Stuart R.K., Baccarani M., Cripe L.D., et al.
Results from a randomized trial of salvage chemotherapy
followed by lestaurtinib for patients with FLT3 mutant AML in
first relapse. Blood. 2011;117:3294–3301. doi: 10.1182/blood-
2010-08-301796. [PMC free article] [PubMed] [CrossRef]
[Google Scholar]
88. Stone R.M., DeAngelo D.J., Klimek V., Galinsky I., Estey
E., Nimer S.D., Grandin W., Lebwohl D., Wang Y., Cohen P., et
al. Patients with acute myeloid leukemia and an activating
mutation in FLT3 respond to a small-molecule FLT3 tyrosine
kinase inhibitor, PKC412. Blood. 2005;105:54–60. doi:
10.1182/blood-2004-03-0891. [PubMed] [CrossRef] [Google
Scholar]
89. Smith B.D., Levis M., Beran M., Giles F., Kantarjian H.,
Berg K., Murphy K.M., Dauses T., Allebach J., Small D. Single-
agent cep-701, a novel flt3 inhibitor, shows biologic and
clinical activity in patients with relapsed or refractory acute
myeloid leukemia. Blood. 2004;103:3669–3676. doi:
10.1182/blood-2003-11-3775. [PubMed] [CrossRef] [Google
Scholar]
90. Pratz K.W., Cortes J., Roboz G.J., Rao N., Arowojolu O.,
Stine A., Shiotsu Y., Shudo A., Akinaga S., Small D., et al. A
pharmacodynamic study of the FLT3 inhibitor KW-2449 yields
insight into the basis for clinical response. Blood.
2009;113:3938–3946. doi: 10.1182/blood-2008-09-177030.
[PMC free article] [PubMed] [CrossRef] [Google Scholar]
91. Serve H., Krug U., Wagner R., Sauerland M.C., Heinecke
A., Brunnberg U., Schaich M., Ottmann O., Duyster J., Wandt
H., et al. Sorafenib in combination with intensive chemotherapy
38. in elderly patients with acute myeloid leukemia: Results from a
randomized, placebo-controlled trial. J. Clin. Oncol.
2013;31:3110–3118. doi: 10.1200/JCO.2012.46.4990. [PubMed]
[CrossRef] [Google Scholar]
92. Ravandi F., Alattar M.L., Grunwald M.R., Rudek M.A.,
Rajkhowa T., Richie M.A., Pierce S., Daver N., Garcia-Manero
G., Faderl S., et al. Phase 2 study of azacytidine plus sorafenib
in patients with acute myeloid leukemia and FLT-3 internal
tandem duplication mutation. Blood. 2013;121:4655–4662. doi:
10.1182/blood-2013-01-480228. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
93. Fiedler W., Kayser S., Kebenko M., Krauter J., Salih H.R.,
Götze K., Späth D., Göhring G., Teleanu V., Döhner K., et al.
Sunitinib and intensive chemotherapy in patients with acute
myeloid leukemia and activating flt3 mutations: Results of the
amlsg 10-07 study (clinicaltrials.Gov no. Nct00783653);
Procedings of the 56th ASH Annual Meeting and Exposition;
Atlanta, GA, USA. 8–11 December 2012. [Google Scholar]
94. Stone R.M., Mandrekar S., Sanford B.L., Geyer S.,
Bloomfield C.D., Dohner K., Thiede C., Marcucci G., Lo-CoCo
F., Klisovic R.B., et al. The multi-kinase inhibitor midostaurin
(M) prolongs survival compared with placebo (P) in
combination with daunorubicin (D)/cytarabine (C) induction
(ind), high-dose c consolidation (consol), and as maintenance
(maint) therapy in newly diagnosed acute myeloid leukemia
(AML) patients (pts) age 18–60 with FLT3 mutations (muts):
An international prospective randomized (rand) p-controlled
double-blind trial (CALGB 10603/RATIFY [Alliance]);
Proceedings of the American Society of Hematology Annual
Meeting; Orlando, FL, USA. 5–8 December 2015. [Google
Scholar]
95. Smith C.C., Wang Q., Chin C.S., Salerno S., Damon L.E.,
Levis M.J., Perl A.E., Travers K.J., Wang S., Hunt J.P., et al.
Validation of ITD mutations in FLT3 as a therapeutic target in
human acute myeloid leukemia. Nature. 2012;485:260–263. doi:
10.1038/nature11016. [PMC free article] [PubMed] [CrossRef]
39. [Google Scholar]
96. Lee H.K., Kim H.W., Lee I.Y., Lee J., Lee J., Jung D.S.,
Lee S.Y., Park S.H., Hwang H., Choi J.S., et al. G-749, a novel
FLT3 kinase inhibitor, can overcome drug resistance for the
treatment of acute myeloid leukemia. Blood. 2014;123:2209–
2219. doi: 10.1182/blood-2013-04-493916. [PMC free article]
[PubMed] [CrossRef] [Google Scholar]
97. Altman J.K., Perl A.E., Cortes J.E., Levis M.J., Smith C.S.,
Litzow M.R., Baer M.R., Claxton D.F., Erba H.P., Gill S.C., et
al. Antileukemic Activity and Tolerability of ASP2215 80mg
and Greater in FLT3 Mutation-Positive Subjects with Relapsed
or Refractory Acute Myeloid Leukemia: Results from a Phase
1/2, Open-Label, Dose-Escalation/Dose-Response Study;
Proceedings of the American Society of Hematology Annual
Meeting; Orlando, FL, USA. 5–8 December 2015. [Google
Scholar]
98. Stein E.M., Altman J.K., Collins R., DeAngelo D.J., Fathi
A.T., Flinn I., Frankel A., Levine R.L., Medeiros B.C., Patel
M., et al. AG-221, an Oral, Selective, First-in-Class, Potent
Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces
Durable Remissions in a Phase I Study in Patients with IDH2
Mutation Positive Advanced Hematologic Malignancies;
Procedings of 56th ASH Annual Meeting and Exposition; San
Francisco, CA, USA. 6–9 December 2014; p. 115. [Google
Scholar]
99. Hansen E., Quivoron C., Straley K., Lemieux R.M.,
Popovici-Muller J., Sadrzadeh H., Fathi A.T., Gliser C., David
M., Saada V., et al. AG-120, an Oral, Selective, First-in-Class,
Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG
and Induces Cellular Differentiation in TF-1 R132H Cells and
Primary Human IDH1 Mutant AML Patient Samples Treated Ex
Vivo; Procedings of 56th ASH Annual Meeting and Exposition;
San Francisco, CA, USA. 6–9 December 2014; p. 3734. [Google
Scholar]
100. Fukuda M., Asano S., Nakamura T., Adachi M., Yoshida
M., Yanagida M., Nishida E. CRM1 is responsible for
40. intracellular transport mediated by the nuclear export signal.
Nature. 1997;390:308–311. [PubMed] [Google Scholar]
101. Kojima K., Kornblau S.M., Ruvolo V., Dilip A., Duvvuri
S., Davis R.E., Zhang M., Wang Z., Coombes K.R., Zhang N.,
et al. Prognostic impact and targeting of CRM1 in acute
myeloid leukemia. Blood. 2013;121:4166–4174. doi:
10.1182/blood-2012-08-447581. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
102. Turner J.G., Sullivan D.M. CRM1-mediated nuclear export
of proteins and drug resistance in cancer. Curr. Med. Chem.
2008;15:2648–2655. doi: 10.2174/092986708786242859.
[PubMed] [CrossRef] [Google Scholar]
103. Ranganathan P., Yu X., Na C., Santhanam R., Shacham S.,
Kauffman M., Walker A., Klisovic R., Blum W., Caligiuri M.,
et al. Preclinical activity of a novel CRM1 inhibitor in acute
myeloid leukemia. Blood. 2012;120:1765–1773. doi:
10.1182/blood-2012-04-423160. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
104. Etchin J., Sun Q., Kentsis A., Farmer A., Zhang Z.C.,
Sanda T., Mansour M.R., Barcelo C., McCauley D., Kauffman
M., et al. Antileukemic activity of nuclear export inhibitors that
spare normal hematopoietic cells. Leukemia. 2013;27:66–74.
doi: 10.1038/leu.2012.219. [PMC free article] [PubMed]
[CrossRef] [Google Scholar]
105. Castaigne S., Pautas C., Terré C., Raffoux E., Bordessoule
D., Bastie J.-N., Legrand O., Thomas X., Turlure P., Reman O.,
et al. Effect of gemtuzumab ozogamicin on survival of adult
patients with de-novo acute myeloid leukaemia (ALFA-0701): A
randomised, open-label, phase 3 study. Lancet. 2012;379:1508–
1516. doi: 10.1016/S0140-6736(12)60485-1. [PubMed]
[CrossRef] [Google Scholar]
106. Gasiorowski R.E., Clark G.J., Bradstock K., Hart D.N.J.
Antibody therapy for acute myeloid leukaemia. Br. J. Haematol.
2014;164:481–495. doi: 10.1111/bjh.12691. [PubMed]
[CrossRef] [Google Scholar]
107. Gill S., Tasian S.K., Ruella M., Shestova O., Li Y., Porter
41. D.L., Carroll M., Danet-Desnoyers G., Scholler J., Grupp S.A.,
et al. Preclinical targeting of human acute myeloid leukemia
and myeloablation using chimeric antigen receptor-modified T
cells. Blood. 2014;123:2343–2354. doi: 10.1182/blood-2013-09-
529537. [PMC free article] [PubMed] [CrossRef] [Google
Scholar]
Articles from Journal of Clinical Medicine are provided here
courtesy of Multidisciplinary Digital Publishing
A sample of an annotated bibliography entry for HCM402, using
the guidelines on page 11, and addressing at least one bullet per
section
Peter Pronovost, M.D., Ph.D., Dale Needham, M.D., Ph.D.,
Sean Berenholtz, M.D., David Sinopoli, M.P.H., M.B.A., Haitao
Chu, M.D., Ph.D., Sara Cosgrove, M.D., Bryan Sexton, Ph.D.,
Robert Hyzy, M.D., Robert Welsh, M.D., Gary Roth, M.D.,
Joseph Bander, M.D., John Kepros, M.D., and Christine
Goeschel, R.N., M.P.A. An Intervention to Decrease Catheter-
Related Bloodstream Infections in the ICU N Engl J Med
2006;355:2725-32.
This study is closely related to the previous literature, which is
cited. The review of earlier work is recent and complete as of
the time this article was written.
The problem statement is clear: Can catheter-related
bloodstream infections occurring in the intensive care unit
(ICU) be reduced using training protocols and checklists?
The hypothesis is clearly stated: catheter-related bloodstream
infections occurring in the intensive care unit (ICU) will be
reduced using training protocols and checklists.
Method: independent and dependent variables are clearly
stated, and are, respectively, the intervention of training
protocols/checklists, and the rates of catheter related
bloodstream infections.
42. The sample was 108 hospital ICUs in Michigan that agreed to
participate in the study, and of these, 103 reported data. The
analysis included 1981 ICU-months of data and 375,757
catheter-days. This sample should be representative of hospitals
in other states in the United States
Results and Discussion are related to the hypotheses. The
median
rate of catheter-related bloodstream infection per 1000 catheter-
days decreased
from 2.7 infections at baseline to 0 at 3 months after
implementation of the study
intervention (P≤0.002), and the mean rate per 1000 catheter-
days decreased from
7.7 at baseline to 1.4 at 16 to 18 months of follow-up
(P<0.002). The regression model
showed a significant decrease in infection rates from baseline,
with incidence-rate
ratios continuously decreasing from 0.62 (95% confidence
interval [CI], 0.47 to 0.81)
at 0 to 3 months after implementation of the intervention to 0.34
(95% CI, 0.23 to
0.50) at 16 to 18 months.
The list of references was current at the time the article was
written.
The report is clearly written and understandable.