ASCO GI: Phase III Bevacizumab Results of the AVEX and TRIBE Trials

Plus: Avastin gets new indication from FDA for second-line treatment

By Anna Azvolinsky, PhD¹ | January 28, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

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The same week that bevacizumab (Avastin) received a new indication for the treatment of metastatic colorectal cancer, results from two phase III trials involving the drug were presented at the American Society of Clinical Oncology 2013 Gastrointestinal Cancers Symposium (ASCO GI) held January 24–26 in San Francisco.

TRIBE Trial Results at ASCO GI 2013

Results of the phase III TRIBE trial—comparing bevacizumab plus FOLFOXIRI with bevacizumab plus FOLFIRI—for metastatic colorectal cancer patients who have not been previously treated with chemotherapy were presented at ASCO GI (abstract #336). First-line FOLFOXIRI combined with bevacizumab showed better efficacy compared with the combination with FOLFIRI. A phase II trial had initially showed promise of this combination.

(MORE: ASCO GI: Oral Chemo S-1 Increases Survival in Pancreatic Cancer, Japanese Study Shows)

Among 35 Italian centers, 508 patients were randomized one to one to either arm, which both included up to 12 cycles of 5 mg/kg bevacizumab followed by bevacizumab plus fluorouracil as a maintenance therapy.
The study met its primary endpoint—a median progression-free survival of 11.9 months was seen in the FOLFOXIRI arm compared with 9.5 months in the FOLFIRI arm (hazard ratio [HR] = 0.72; P = .001). Response rates were also higher for the FOLFOXIRI combination—64% compared with 53% in the FOLFIRI group (P = .015). Toxicities were as expected and comparable in the two groups.

AVEX Trial Results at ASCO GI 2013

Another bevacizumab phase III trial reported at the meeting was the AVEX trial of elderly metastatic colorectal cancer patients. The AVEX trial compared bevacizumab in combination with capecitabine or capecitabine alone in previously untreated patients 70 years or older (abstract #337).
According to the study researchers, this is the first randomized, prospective trial that has analyzed the benefit of bevacizumab specifically in elderly patients. The results show the combination may be a better treatment that improves elderly patient outcomes. The results validate the use of bevacizumab with capecitabine, a fluoropyrimidine, in elderly patients.
“[These results] confirm a benefit with increased response and tumor control,” said David Cunningham, MD, head of the gastrointestinal unit at the Royal Marsden Hospital in the United Kingdom, and the presenter of the study.
The open-label trial administered bevacizumab to one half of the patients at a 7.5 mg/kg dose every 3 weeks. A total of 280 patients (median age of 76) in 10 countries were part of the trial, which showed the combination prolonged progression-free survival compared with chemotherapy alone. Progression-free survival was 9.1 months for patients taking the combination compared with 5.1 months in the chemotherapy alone arm (HR = 0.53; P < .001).
Overall survival was also improved, but the difference between the two arms was not statistically significant—median overall survival was 20.7 months in the combination arm compared with 16.8 months for the capecitabine arm (HR = 0.79; P = .182). Grade 3 and higher adverse events were more frequent in the combination arm, but researchers said the regimen was generally well tolerated. Grade 3 or higher toxicities were seen in 59% of patients taking bevacizumab plus capecitabine compared with 44.1% of patients taking capecitabine alone.
“This trial result emphasizes that with appropriate selection, patients with advanced colorectal cancer, regardless of age, may benefit from chemotherapy and that the combination of capecitabine and bevacizumab represents a good option that has a favorable balance between efficacy against side effects,” said Cunningham.

Avastin Gets New FDA Indication for Second-Line Treatment

The US Food and Drug Administration (FDA) approved the use of bevacizumab (Avastin) as part of a new combination treatment for the second-line treatment of metastatic colorectal cancer. The drug is now approved in combination with a fluoropyrimidine-based irinotecan or oxaliplatin chemotherapy for metastatic colorectal cancer patients whose cancer has progressed after first-line treatment with a regimen that contains bevacizumab (ie, second-line treatment of bevacizumab/oxaliplatin for patients who received prior therapy of bevacizumab/irinotecan and vice versa).
Patients receiving the combination lived longer compared with those who switched to chemotherapy alone as a second-line treatment. Results showed a 19% risk of death reduction for patients on the combination therapy compared with standard chemotherapy alone (HR = 0.81; P = .0057) in the phase III ML18147 trial. The median overall survival was 11.2 months compared with 9.8 months. The results are published in the Lancet Oncology.
Bevacizumab is already approved in combination with chemotherapy as a first-line therapy for metastatic colorectal cancer patients and also as a second-line treatment in combination with FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin).

DIET FAILURES

With any kind of diet, by the time you reach the 6-12 week mark,  the selected strategy has given you its maximum benefit.  Hopefully, by then you will have achieved the 10% reduction of your total weight which is the realistic goal to pursue.  If you did it right, 1-2 pound per week of weight loss, you would have lost at least 10 pound by now.  After this, maintenance is the challenge and your body's response is even more of a challenge.
The body wants to get back to the size it knows you can achieve.  Make no mistake, size is the major killer.  Just look at the tumor, when it gets too big, areas of necrosis soon happen because some areas will suffer ischemia.

Your body will start asking for food, will try to tell you that just this small thing will not be harmful, and it will tell this throughout the day.   TIMING, WHEN YOU CAN AFFORD TO EAT SOMETHING IS AN IMPORTANT STRATEGY TO PUT IN PLACE.  KEEP CONTROL OVER THIS.  REMEMBER ONE THING IS FOR SURE: BY THIS TIME, GROWTH HAS STOPPED AND THAT THIS IS ALREADY A GREAT GOAL ACHIEVED. KEEP IT THERE.

To go further down, avoid staying home near the refrigerator.  Go out, walk at the mall without money, just your ID! Or best go to the gym or call your support buddy.  When the diet effect is maximized, that is when you need to exercise the most, and that's when you need Calorie control the most, and your vitamins.  Whatever you do, do not increase your Carbohydrate intake, or any excess calories. Remember, you will not increase your weight doing this.  The body will fight back, trying to use what you have given it to its maximum advantage, using everything to its advantage, constipation will set in to prolong intestinal absorption and reduce stool size, but work on staying "regular".  Constipation is a proven risk of Colon cancer.  Take it out. At this stage, it also is hard to exercise. Your body will tell your brain not to exercise.  Any excuses will come to mind.  Double down and keep exercising.  A walk will be good any time.  Remember, staying home with the refrigerator in the house is one of the brain challenges.  If you do reach for the refrigerator, have safe options.  Very cold water, sweet non sugary options or a fruit.  Dried vegetable chips or low calorie nuts.  Here, frequency to the refrigerator needs to be controlled by a schedule.

So, schedule or time your eating, when you reach to eating, find options that are safe, and keep on moving or exercising; this should be your strategy.  And remember, if you do not increase your weight, that's an objective success already.  We will keep trying to find more and let you know!

OVEREXPRESSION OF SQLE GENE ON CHROMOSOME 8,  MARKER OF PROLIFERATION?

One of the gene marked as proliferation genes is the SQLE, This gene located  at 8q24 was puzzling to me because it has a role in Sterol Biosynthesis.  I wonder why this gene was in the proliferation section.  Then it occurs to me that new cells need new cellular membranes.  Of course, you need to over-express this.
I should confess that sterol biosynthesis is a tremendous opportunity for cancer cure because research is advanced in this area.  I know the Trypanosome has been fought through this media.  Silencing SQLE.  Who would have thought....!

SPEAKING SLEEPING SICKNESS, MEDICATIONS USED TO TREAT THIS DISEASE INCLUDE ARSENIC DERIVATIVES.  IN AN EFFORT TO POTENTIATE THE ARSENICALS, COMBINATION WITH DFMO HAD BEEN TRIED, I WONDER IF ONE CAN USE THIS COMBINATION FOR TREATMENT IN ACUTE PROMYELOCYTIC LEUKEMIA?  WILL LOOK INTO THIS!

NOMENCLATURE OF THE GENES OF PROLIFERATION, STILL THE 3RD LAW,

1. ZWINT:

During cell division, separation of chromosome or chromosome  movement is not random, and follows microtubule tracks through an attachment at the Kinetochore. Kinetochore attaches the chromosome at its inner section, and the micotubule at the outer section.   protein components of the the Kinetochore include Dynein, a cytoplasmic protein that need to be recruited (phosphorylated) to the Kinetochore.  The ZWINT (at 10q21)with its interactor ZW10, serves as a substrate to AURORA B, helps globally with the Dynein recruitment  at the Kinetochore.   Disruption at the Kinetochore will foil cell division.
Expression of the ZWINT marks a proliferative phase in the cancerous process.

2. TTK
CANNOT DESCRIBE IT BETTER
"

This gene encodes a dual specificity protein kinase with the ability to phosphorylate tyrosine, serine and threonine. Associated with cell proliferation, this protein is essential for chromosome alignment at the centromere during mitosis and is required for centrosome duplication. It has been found to be a critical mitotic checkpoint protein for accurate segregation of chromosomes during mitosis. Tumorigenesis may occur when this protein fails to degrade and produces excess centrosomes resulting in aberrant mitotic spindles. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

Genomic context

Location :

6q13-q21"

SOURCE  NCBI

 ------------------------------

RELATED GENES : THE CYCLIN DEPENDENT KINASE AND PLK-1

RELATED PATHWAY pRb PATHWAY.

THIS IS PROLIFERATION AT IT BEST, CANCER MUTATES THESE TO ESCAPE PROLIFERATION CONTROL

Can Metastasis of Triple-Negative Breast Cancer Be Thwarted?

By Anna Azvolinsky, PhD¹ | January 24, 2013

¹Freelance Science Writer and Cancer Network Contributor. Follow Her on Twitter

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Researchers have demonstrated how a particularly aggressive type of breast cancer, triple-negative disease, spreads to other parts of the body. The results may lead to new therapies that could treat metastatic breast cancer. The findings are published in Cancer Cell.

Breast cancer cells; H&E stain

Triple-negative breast cancer (TNBC) readily spreads to other parts of the body and has few treatment options—there are currently no therapies specifically for TNBC approved by the US Food and Drug Administration. Approximately 15% to 25% of all breast cancers are TNBC.

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Researchers at the Weill Cornell Medical College of Cornell University in New York and colleagues have identified a microRNA (miRNA), the small RNA molecules that regulate gene expression, called miR-708 that is repressed in metastatic breast cancer. Expression of the miRNA in breast cancer mouse models specifically blocked metastasis, but did not affect primary tumor growth. The study shows that miR-708 normally functions as a metastatic tumor inhibitor.
“These studies suggest that miR-708 has the potential in the treatment of extraordinarily high-risk breast cancer patients,” said lead study author Vivek Mittal, PhD, associate professor of cell and developmental biology at Weill Cornell Medical College, referring to patients with TNBC whose cancer has metastasized. “TNBC is almost like a death sentence for these patients.”
The study of the miRNA also presents a theory for why TNBC is more malignant compared with other breast cancer types. Using primary and metastatic breast cancer patient tumor samples, Mittal and colleagues showed that miR-708 is present in all types of primary breast tumors, but is not expressed in metastatic breast tumors. However, miR-708 was downregulated (expressed less) in TNBC compared with other breast cancer types. “We think that TNBC is the most metastatic because the primary tumor itself may contain more metastatic, stem-like cells.” Earlier studies have suggested this to be the case.
MiR-708 normally functions to decrease intracellular calcium levels, resulting in activation of the ERK/FAK pathway that impairs the ability of cells to migrate and, therefore, metastasize. When miR-708 is inhibited, the cells can readily migrate and invade other organs. Higher calcium levels trigger migratory pathways that help cancer cells travel to other organs and can lead to metastasis.
When the researchers delivered synthetically made miR-708 to mice with primary TNBC tumors, the miRNA was able to block metastasis development of the TNBC tumor cells in the lungs of the mice.
“The surprising part is that miR-708 does not affect primary tumor growth, but impacts metastasis alone, suggesting its exclusive role in later metastasis pathways,” said Mittal.
The study also identified the protein complex that inhibits expression of miR-708. The complex works to remodel proteins to epigenetically silence certain genes.
“Our finding is significant,” said Mittal. “Since previously discovered breast cancer miRNAs targeted primary tumor growth by affecting proliferation and apoptosis, it was difficult to discern their role following metastatic dissemination.”
According to Mittal, two approaches to target the miR-708 miRNA are ongoing. One is using an epigenetic therapeutic approach by inhibiting one of the complexes that silences miR-708. Another is directly adding back miR-708 miRNA using either liposomes or nanoparticles for delivery.
If targeted agents against miR-708 are developed, they would be among the first that would restore the normal function of an miRNA and the first to specifically target cancer metastasis.
The current study identified miR-708 using a next-generation miRNA sequencing approach. Had a microarray approach been used, the miR-708 miRNA would not have been identified, as it was not available on any of the microarray platforms, said Mittal. “MiRNA sequencing is powerful and allows discovery of known and novel miRNAs.” Whether miR-708 also has a role in metastasis in other cancers has yet to be addressed.

UPDATE ON TREATMENTS OF PERIPHERAL T CELL LYMPHOMA

3 AGGRESSIVE TYPES:
==================
1. PTLC- NOS
2. AITL: AngioImmunoblastic
3ALCL (Anaplastic large cell  (ALK +)  6% AND     alk NEGATIVE
CD30 , t(2,5)(p23,q25)
---------------------------------------------------------------------------------
1 Peripheral T cell lymphoma not otherwise specified
-PET
-Gene Profiling
treat it with EPOCH (CHOEP) or Etoposide based regimen followed by transplant
consider Romidepsin (upfront in Europe)
followed by Gemcitabine, Navelbine (Doxil)

Europeans give ACVBP +/- Romidepsin (Vindesin not available in the US)

refractory disease" FDA has released 3 drugs, their role and position is being evaluated"
=============
Romidepsin
Pralatrexate
CD30 positive - BRENTUXIMAB VEDOITIN
----------------------------------------------------------------------------------------------
2. some T cell lymphoma are clearly Indolent i.e Mycosis Fungoides (MF)
-------------------------------------------------------------------------------
3. Anaplastic Large cell Lymphoma
ALK negative
for Europeans ACVBP followed by transplant

USA, same paradigm as in PTCL NOS

FOR ALK POSITIVE -- CHOP  ALONE IS THE BEST NO TRANSPLANT (NO ETOPOSIDE NEEDED)   (THE GERMAN STUDY WAS RETROSPECTIVE )
CRIZOTINIB

PRALATREXATE AND ROMIDEPSIN HAVE BEEN USED IN CLINICAL TRIAL
---------------------------------------------------------------------------------------------------------
4. ANGIOIMMUNOBLASTIC

STEROIDS
SOME CLAIM CYCLOSPORINE (PARTICULARLY WHEN HEMOLYTIC ANEMIA)

IN EUROPE CHOP-ROMIDEPSIN

IN USA, GEMZAR
FOR THOSE WITH A COMPONENT OF CD20 POSITIVE, RITUXAN +STEROID

WHATEVER YOU DO, DON'T GIVE ADRIAMYCIN!

sCD163 and sTARC are disease response biomarkers for Hodgkin's lymphoma

As published in Clinical Cancer Research, combined sCD163 and sTARC are better markers of disease response in patients with Hodgkin's lymphoma undergoing first-line therapy than either marker alone. sCD163 reflected tumor burden during treatment, while sTARC was more significant upon completion of therapy.

Read the article summary now:
http://www.mdlinx.com/oncology/news-article.cfm/4317702/?utm_source=in-house-msg&utm_medium=message&utm_campaign=reactiv-scott

GENETIC MUTATIONS GIVING FURTHER INSIGHT INTO HEMATOLOGIC MALIGNANCIES, POINTING OUT WHERE ABNORMALITIES ARE WHICH WHICH WILL IMPACT SIGNIFICANTLY RESEARCH FOR THERAPY.

While Multiple Myeloma seems to result from amplification of major pathways with Ubiquitinated molecule persistence being one of the major therapeutic interventions (as a result of proteasome inhibitors), most likely by feedback blockage of major pathways and mitotic check point arrests, Myelodysplasia and Leukemia are going purely NUCLEAR.  SF3B1 mutation now associated with Refractory Anemia with ring Sideroblasts and cases of Chronic lymphocytic leukemia, putw us square and fair into the realm of m-RNA splicing.  The new interest in SETBP1 ties some case of mental retardation to elevated risk of Anemia. (Schinzel-Giedion Syndrome).  But remember, the elevated risk of AML in Down Syndrome-Coincidence or similarity, is the question!

Finding abnormality in the PRPF8 gene in dysplasia and leukemia brings back and re-enforces that splicing abnormality may be a significant driver in these conditions.  These findings cast doubt that researchers pushing drugs treating myeloma in Leukemia treatment  may meet disappointment.  It is another animal all around!

Abnormality in CSMD1 gene (regulator in the complement system) caught our attention. Is this an insight into immunodeficiency in Dysplastic syndrome...?  we will follow-up!

Another gene PPFIA2 is down regulated by Androgen therapy in prostate cancer, if it is significant, can we use this as predictive indicator in a therapeutic strategy?

We can't seriously finish without talking about the RUNX-1: what a major target since differentiation lays here.  But is differentiation a meaningful target?  Remember, allowing these cells to fully mature may lead them to Apoptosis... so let's weigh this one! 

The future is exciting in Research!

Adrenaline Funk by Clement Albert on Ubetoo

by Clement Albert
Adrenaline rushing in my veins


http://www.ubetoo.com/clementalbert/54807#.UQQiUGhzo7o.email
copy the link if it does not work!
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A little music for relaxation can only do good!

PRELIMINARY DISCUSSION ON THE 4TH LAW. THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.

THE 4TH LAW IS BEST UNDERSTOOD AS THE SET OF FORCES THAT DRIVE THE CELL FUNCTIONS IN A PARTICULAR ELECTED DIRECTION.
At molecular level, this is enforced by GENE AMPLIFICATION.  That is if the cell is going toward differentiation, the cell will make cellular processes to direct all the cellular function to that aim.  for specific cancer this equivalent to the notion of DRIVER Mutation.   Cellular functions are not totally random and living things do not stay still!  life is always on the go, and on the go for survival.  And once it has chosen a direction, it direct its functions toward an overall goal which at cellular level is to ensure survival.  The drive, the stamina, the direction is battery powered and purposeful!
In the cell that drive is powered and to ensure that it has direction,  AMPLIFICATION GENES go to work.

One good example of this is what happens with some Viruses.  A number of viruses when the enter the host cell, will incorporate their viral genome into the genome of the host to manage to use the host survival machinery to their advantage.  Insertion in the genome of the host sometimes is not enough to trigger the use of the Viral genome in the host machinery, the Virus has to recruit a "growth factor" most of the time called FACTOR-1 to ensure amplification of its genetic material.  (this is known for HIV infection)

In cancer cells, there are amplification genes toward the completion and survival of the cancerous process.
In lung and thyroid cancers, TTF-1 represent such a gene.  found amplified in about 10 % of tumors.  Scientist have had trouble defining its role.  But they know its AMPLIFICATION is bad news for the host.  It is a driver gene for the cancerous process.   In the cell, there are several levels of GENE AMPLIFICATIONS.

The first level is mission driven.  If the mission is to differentiate, this 4th law push to achieve the mission.
if the mission is to grow a cancer, the cell uses all its resources to make a "perfect cancer."  This means, tolerate error in the DNA multiplication, down-regulate the repair mechanism, down-regulate or mutate the  regulator of P53, MDM2. Amplify VGEF so that the tumor has plenty of good blood vessels.

The second level of amplification is actually originating from the stimulus, the cause of the transformation.  the cause could be a change in Oxygen level, a break of shorten Telomerase tail, Tumor growth factor (FGF-1), Cyclins, or an oncogenic mutation or break of DNA strands.  This will ultimately stimulate receptors with subsequent signal transduction pathways flow that could be amplified by way of  intensity of the signals, but also enzymatic up-regulation and nuclear transcription amplification.   Amplification can be then cancerous based, but also stimuli caused.

the 3rd amplification is what occurs at the DRIVER Mutation due to growth factors or increased catalytic rate from related enzymes.

It is hard to measure cancer driven gene Amplification.  Most of the study keeps taking Metothrexate and its mechanism of Resistance because amplification of Dehydrofolate Reductase is the mechanism of resistance.  every body focus on this enzyme to measure resistance.   But when you look at amplification at this various levels, it is not  hard to see that these measurements are missing the point or are just misleading.

We will discuss the relevant Genes under the section or Rubric "NOMENCLATURE".  Frankly speaking, we have not finished yet the genes for the 3rd law.

We are working hard at CRBCM!

Medscape Medical News

New Norovirus Strain Hits US

Robert Lowes

Jan 24,2013

Editors' Recommendations

• CDC Links Norovirus to Most Gastroenteritis Outbreaks
• Emerging and Reemerging Infectious Diseases News & Perspectives

Drug & Reference Information

• Norwalk Virus
• Viral Gastroenteritis
• Food Poisoning

In the middle of a punishing influenza season, a new strain of norovirus from Australia has come on the scene, and it is not yet clear how nasty this bug will be, the Centers for Disease Control and Prevention (CDC) announced today.
In its latest Morbidity and Mortality Weekly Report, the CDC identified the Aussie newcomer as GII.4 Sydney. First spotted in March 2012, the strain already has triggered acute gastroenteritis outbreaks in the United Kingdom and other countries. During the last 4 months of 2012, GII.4 Sydney accounted for 53% of 266 norovirus outbreaks in the United States reported through an electronic laboratory surveillance system called CaliciNet. Roughly half of the Sydney outbreaks resulted from direct person-to-person transmission; another 20% were foodborne.
Two thirds of the US outbreaks of GII.4 Sydney have occurred in long-term care facilities.
The CDC stated that GII.4 Sydney appears to have replaced a previously dominant strain called GII.4 New Orleans. In general, GII.4 strains are associated with higher rates of hospitalization and death.

GII.4 Sydney strain of norovirus

The emergence of a new norovirus strain such as GII.4 Sidney often leads to "increased outbreak activity," but not all the time, according to the CDC. The agency said that it is premature to assess the relative magnitude of GII.4 Sydney because during the previous 3 winters, "the peak in reported norovirus outbreaks occurred in January." However, the CDC urged clinicians to be on the lookout for a potential rise in norovirus cases in the coming weeks.
"Proper hand hygiene, environmental disinfection, and isolation of ill persons remain the mainstays of norovirus prevention and control," the CDC noted.
The foremost clinical hazard of any norovirus infection — especially for the elderly — is dehydration caused by vomiting and diarrhea, said William Schaffner, MD, an infectious disease expert at Vanderbilt University Medical Center in Nashville, Tennessee.
In severe cases, Dr. Schaffner told Medscape Medical News, oral fluids and electrolyte replacement may need to give way to intravenous fluids. Patients also require attentive care lest a rush to the bathroom together with faint-headedness lead to a stumble, a fall, and a head injury, he said.
Morb Mortal Wkly Rep. 2013;62:55. Full text

Latest in Infectious Diseases

• CDC Urges Tamiflu Rx to Curb Flu Death Rate
• U.S. Researchers Find New Disease Carried by Deer Ticks
• FDA Okays Novel Flu Vaccine Made Without Eggs, Viruses
• CDC: Flu Hitting Harder, Too Early to Tell If It's Peaking
• Gonorrhea Resistant to Cefixime Found in North America

Medscape Medical News © 2013  WebMD, LLC


Send comments and news tips to news@medscape.net.

Cite this article: New Norovirus Strain Hits US. Medscape. Jan 24, 2013.

Op Ed from Vice Chair Barbara Canales

	3:14 PM (49 minutes ago)
to me

The Cancer Prevention and Research Institute of Texas Foundation serves as the connecting link for public policy, community, and business leaders and is committed to strengthening and expanding the fight against cancer in Texas. Is this email not displaying correctly? View it in your browser. Below is the Op Ed from CPRIT Foundation Vice Chair Barbara Canales  that ran in the Houston Chronicle today. The CPRIT Foundation  continues to operate under a process of integrity, intelligence and  efficiency. We are encouraged by the strength and confidence of  our Board, staff, and supporters. Cancer Agency Committed to Clarity, Transparency In recent months, the Cancer Prevention and Research Institute of  Texas has come under the scrutiny of state leaders and Texas citizens. In an effort to make all facts known and available to the public, the   CPRIT Foundation - the nonprofit created to support the mission  of the institute - has found it imperative to make its role and  purpose clear. First, it is crucial to know that no taxpayer money is used to support  the activities of the CPRIT Foundation. The foundation is funded  entirely by private donations. In an effort to provide complete transparency, a list of foundation  donors has been made public and provided to members of the  Texas Legislature, other public officials and members of the media. Originally, the foundation adopted a donor bill of rights to protect  the confidentiality of its donors. This is standard practice for  foundations so that contributors are not added to call lists or  targeted by other organizations seeking financial support. However,  in light of recent developments, the foundation took this important  step. It is also important to note that the foundation plays no role in the  institute's grant application or review process. It has made every  effort available to the foundation to address potential donor  conflicts, including prohibiting foundation donors from receiving  grants from the institute. In fact, contributions have been returned in cases where it has been determined a possible conflict may exist. The CPRIT Foundation was established by the Legislature for good  reason; to support the work of the institute by supplementing  executive salaries, coordinating an annual scientific conference  and promoting cancer prevention and research efforts alongside  business and community leaders. The foundation exists solely  for these administrative purposes. As organizations other than  CPRIT have found, this model is necessary, and not uncommon,  in achieving goals that are restricted by state agency regulations. For example, the state Legislature correctly contemplated that  CPRIT would not be able to attract the caliber of scientists needed  to make it a first-class institute with the salaries allowed by the  state of Texas. To recruit the best scientific minds in the country,  CPRIT needs to offer a competitive salary, and that is only achieved  by having a separate foundation that can supplement that  compensation. The CPRIT Foundation also coordinates and directs CPRIT's annual  conference using private funds. This conference attracts the most accomplished and highly respected scientists in the world and  nearly 1,000 attendees to our state to discuss the most advanced  and cutting-edge developments in cancer prevention and research. Throughout the year, the foundation staff also travels across the  state to conduct meetings with advocates and community leaders.  The foundation also organizes Cancer Day at the Capitol to raise  awareness among state legislators and has coordinated an annual  meeting in Washington to build relationships to recruit support  and federal grants into our state. The consulting firm selected to direct the efforts of the foundation,  JHL Company, was chosen because of its proven success in  fundraising and project management for both public and private  entities. The retainer for their services, which includes all operating  expenses and overhead associated with the foundation, is  less than 17 percent of the foundation's total income over a  three-year period. This is comparable to other, similar foundations. Members of the CPRIT Oversight Committee and the CPRIT  Foundation Board of Directors serve as uncompensated volunteers.  I serve on both, within the parameters of the original bylaws,  because of my own personal connection to this terrible disease. As an organization created to supplement the efforts of such an  important cause, the foundation is committed to providing clarity, transparency and anything else that will help the institute continue  its hard work in the fight against cancer.  follow on Twitter | friend on Facebook | forward to a friend  Copyright © 2013 CPRIT Foundation, All rights reserved. You are receiving this email because you opted in at our website or are a friend of CPRIT. Our mailing address is: CPRIT Foundation P.O. Box 12631 Austin, TX 78711 Add us to your address book  unsubscribe from this list | update subscription preferences

FDA Approves Imatinib for Pediatric ALL

Nick Mulcahy

DisclosuresJan 25, 2013

 

Editors' Recommendations

• Surprising Results in Children With ALL Who Fail Induction
• Acute Leukemia News & Perspectives

Drug & Reference Information

• Genetics of Non-Small Cell Lung Cancer
• Pediatric Acute Lymphoblastic Leukemia
• Chemoprevention Strategies in Head and Neck Cancer

The US Food and Drug Administration (FDA) today approved imatinib (Gleevec, Novartis) for the treatment of newly diagnosed pediatric acute lymphoblastic leukemia (ALL) that is Philadelphia chromosome (Ph) positive.
"We are pleased that the number of cancer medications for children is on the rise," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, in a press statement.
In 2011, imatinib was approved to treat children newly diagnosed with Ph-positive chronic myeloid leukemia (CML).
However, ALL is the most common type of pediatric cancer, affecting approximately 2900 children annually, according to the FDA.
The safety and effectiveness of imatinib for pediatric patients with Ph-positive ALL were established in a clinical trial that enrolled children (1 year and older) and young adults with very-high-risk ALL (>45% chance of experiencing complications from their disease within 5 years of treatment).
The 92 patients with Ph-positive ALL enrolled in the trial were divided into 5 treatment groups, with each successive group receiving imatinib plus chemotherapy for a longer period.
Fifty of the Ph-positive ALL patients received imatinib for the longest period, and 70% of these patients did not experience relapse or death within 4 years. In addition, patient deaths decreased with the increasing duration of imatinib treatment in combination with chemotherapy, according to the FDA.
The most common adverse effects observed in children with Ph-positive ALL treated with imatinib plus chemotherapy were decreased neutrophil levels, decreased blood platelets levels, liver toxicity, and infection.
Imatinib is a tyrosine kinase inhibitor that blocks cancer-promoting proteins, and should be used in combination with chemotherapy to treat pediatric Ph-positive ALL.

Imatinib has been a practice-changing drug in this setting, according to the Children's Oncology Group, which conducted the pivotal clinical trial.
According to the group's Web site, the preferred treatment for Ph-positive ALL before imatinib was stem cell transplantation followed by 3 to 6 months of chemotherapy. However, cure rates were less than 50% with this approach. Imatinib in combination with chemotherapy has doubled cure rates, and stem cell transplantation is no longer automatically considered to be the best way to treat children with Ph-positive ALL.
Imatinib was granted accelerated approval in 2001 by the FDA to treat patients with blast-crisis, accelerated-phase, or chronic-phase Ph-positive CML who have failed interferon-alpha therapy. The drug was also approved in 2012 for the treatment of adults whose Kit (CD117)-positive gastrointestinal stromal tumors (GIST) had been surgically removed.

 

Latest in Hematology-Oncology

• Supreme Court to Hear Challenge to BRCA Gene Patents Again
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• Bosutinib in CML Cleared for Approval in Europe
• US Cancer Mortality Down by 20%, More for Major Cancers
• California Soon to Have Breast Density Notification Law

FREE CPRIT MOVEMENT HAS BEEN CREATED!
PEOPLE AND INSTITUTIONS NEEDING FUNDING FOR CANCER RESEARCH CAN'T WAIT TO SEE CPRIT FREED FROM POWERS !
TALK TO YOUR LEGISLATORS ABOUT CPRIT FREEDOM!

In the meantime, Senator Kevin Eltife from Tyler is introducing legislation to stop CPRIT funding through sale of bonds.  He believes that CPRIT should plead its case yearly asking for general fund with a dance before the Finance and and Appropriation Committee. He reportedly believes tha,t with that dance, the scrutiny level will increase.  This point is as debatable as can be and may miss the point all together.   The Senate was there with their eyes opened when the deals were going on!  Somehow an annual report to the Senate cannot be hiding the bad deed?  No, you need just good old honesty in CPRIT leaders and fair balanced processes to solve the issues at hand at CPRIT!   One thing for sure, the Senator is reported to be consistent. He had similar position reportedly before the creation and passage of the law about CPRIT.  Give him that!

NICE QUOTES FROM THE LANCET!

VOLTAIRE :  "The art of Medicine consists of amusing the patient while nature cures the disease".
                even then, the new the truth, we have been found out!  patient have build in defense! we are just distracting him.....

PARCELSUS : "The art of healing comes from nature and not from the physician; Therefore, the physician must start from nature with an open mind"....

And here I am throwing the kitchen sink of chemotherapy instead of Target therapy.  Cure will come from the mastering of law of nature at cellular level . READ CAREFULLY!  CURE IS WITH US, LET'S OPEN OUR MIND!

CREDIT TO DANIEL KRELL, JUSTIN STEBBING!

IN DEPTH INVESTIGATION, BRAIN INJURY--CRBCM
(THIS IS PART OF A PROTOCOL SUBMITTED FOR RESEARCH)

After a trauma to the brain, and in a mature brain, excitatory messages or stimuli lead to the release of Glutamate at the pre-synaptic membrane.  Glutamate released forthwith, will go on to stimulate those well known post-synaptic ionotropic receptors (AMPAR and NMDAR).
The intensity of the post-synaptic stimulation is in fact related to the amount of  receptors clustered in the involved region of the post-synaptic membrane, and the intensity of the ion traffic in the ionotropic channels, leading to variation in the voltage dependent activation of post synaptic events.  This variation of activation and electric status linked to ion displacement has been summarized in the concept: "SYNAPTIC PLASTICITY".

Depending on the nature of subunits of the post-synaptic Receptor (content in NR2B), the post-synaptic event can be inhibitory or activating.  A global positive influx of Calcium through the channels mentioned above lead ultimately to a post-synaptic phosphorylation of the powerful ERK-MAP-Kinase signal transduction pathways with significant physiological consequences.

See, when stress is the initiating event, a particular member of the MAPK family called the C-jun will be awakened up.  The C-Jun terminal protein (JNK) will unveil all its might and strike by way of phosphorylation various substrates in the Nucleus, the Mitochondria and right there in the Cytosol.

In the Mitochondria, the stress and toxic induced C-jun lead to loss of MMP and induce  Cytochrome C release into the Cytosol with resulting activation of the Caspase cascade which leads to Apoptosis or NEURONAL DEATH.

At Nuclear and Cytoplasmic levels, C-jun downregulate Bcl-2, (and MCL-1), up regulate BAX which are pro-Apototic moves or processes, but it also induce pro-inflammatory (TNF alpha, Interleukin 6,8) Cyclins to cause death by Necrosis.  At Glial level, these pro-inflammatory cyclins leads to Neuro-Degeneration.

At CRBCM we believe that in this day in age, letting neurodegeneration set in without intervention is not only ignorant, but not responsible!!!!!  We got to act...respond somehow...our leaders are holding funds and holding us back!    SAY SOMETHING!!  MY READERS !

FREE CPRIT MOVEMENT HAS BEEN CREATED!

QUIZARTINIB ALLOWS TO BUY TIME BEFORE TRANSPLANT IN AML.
In AML patient with FLT3-ITD
46% complete response reported
27% partial response
--------------------------------------
73% total response rate per this account

IF you do not have the FLT3-ITD
32% CR
16% PR
----------------------------------
48% RR

Median duration of response 3 months for FLT3 positive
and 1.5 month for FLT3 negative

the drug is reported to be well tolerated.

*> In other Major news,
Eribulin had failed to best Xeloda overall
there was a positive trend  in triple negative breast cancer which is the focus of CRBCM

*Apixaban may become a valid option for DVT treatment
since it does not require monitoring
and it is not cleared by the Kidneys and therefore could be used in kidney failure patients!

SHORT NEWS FROM ASCO POST

*For years we have been telling women that 5 years of Tamoxifen is all they needed in the treatment of ER positive breast cancer.  We went on to tell them that prolonging the duration of Tamoxifen could only lead to more side effect.  So it is a bit of a surprise that all of the sudden the Oncology community has quickly embraced the new 10 years being recommended without any questions raised.  Had we been lying to women all this time?  who has been giving Tamoxifen for 10 years behind our back?

Published results suggest : "617 recurrences in women taking Tamoxifen for 10 years Vs 711 recurrences in women treated for 5 years".  Total observation time 10-14 years.   SO standard today is 10 years of Tamoxifen, no question asked!

*Ponatinib is the new Darling drug in CML and Philadelphia positive ALL
In a study published by DR Cortes 267 evaluated patients
56 % of those in Chronic phase CML achieved Major Cytogenetic response (Most of these were resistant to TKI.
and 57% of those in accelerated phase achieved a major hematologic response and 34% of those in Blast phase responded.
Remember the FDA has already approved the drug!

OMACETAXINE is also active in this disease!

*POMALIDOMIDE is the other wonder but this time in Myeloma
4mg given with 20 mg of Decadron as given in the study!
Also an Oral Proteasome inhibitor MLN9708 is under study with promising results

*For Invasive breast cancer, adjuvant radiation for 3 weeks equivalent to 5 weeks per a UK study!  People are still waiting for the RTOG to conclude its trial.

*Ibrutinib is the new darling drug in CLL
at 26 months, 96% progression survival in chemo-naive CLL
and 75% progression free survival  in relapse/refractory CLL/SLL

*QUIZARTINIB  BUY TIME TO TRANSPLANT

 

ADAR 1

Study: Enzyme Plays Important Role in CML Stem Cell Reprogramming By Dave Levitan | January 18, 2013 Researchers have identified an enzyme that plays an important role in the reprogramming of malignant progenitor cells in chronic myeloid leukemia (CML). The enzyme, adenosine(Drug information on adenosine) deaminase acting on RNA 1 (ADAR1), could represent a target for selecting and eradicating leukemia stem cells, according to a paper published online ahead of print on December 28, 2012, in Proceedings of the National Academy of Sciences. A small, hypolobated megakaryocyte in a bone marrow aspirate, typical of CML; source: Difu Wu, Wikimedia Commons “Although the [chronic phase] of CML often can be controlled for long periods of time with standard TKI therapies, subsequent genetic and epigenetic alterations promote progenitor expansion and the generation of self-renewing leukemia stem cells that fuel disease progression and blast crisis transformation along with TKI resistance,” wrote study senior author Catriona H. M. Jamieson, MD, PhD, of the University of California, San Diego, and colleagues. It is becoming more and more evident that RNA editing enzymes play a role in that promotion of self-renewing CML cells. In this study, researchers used whole-transcriptome sequencing of normal cells, as well as chronic phase and blast phase CML cells, to look for sources for reprogramming of progenitor cells. They found that increased expression of the ADAR1 p150 isoform in blast crisis CML could be related to inflammatory pathway activation, including cytokines and tumor necrosis factors. The investigators also examined whether limiting expression of ADAR1 could affect the self-renewal capacity of leukemia stem cells. They transplanted human CML cells with ADAR1 expression knocked down into mice and compared with control cells; they found an impaired ability to self-renew in the leukemia stem cells. “Although leukemic burden was not diminished significantly, the [leukemia stem cell] self-renewal capacity was irrevocably reduced by ADAR1 knockdown,” the authors wrote. Together, these data suggest that inflammatory mediator-driven expression of ADAR1 contributes to CML progression. In a press release, Dr. Jamieson noted that this adds further weight to inflammation as “an essential driver of cancer relapse and therapeutic resistance.” In particular, the importance of ADAR1 in CML represents a clear target for therapeutic strategies. “ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors,” Dr. Jamieson said. “If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning.”  EMAIL  |    PRINT  |    PDF  |    REPRINT  |    SHARE   Join the Conversation Want to join the conversation? If you're a healthcare professional, we'd like to hear your comments. Just sign in or register today to become part of our growing, online community. Email me when someone comments on this article. CancerNetwork on Facebook

EVENTS GOVERNING CELLULAR LIFE

Overall, life at the cellular level enters a new phase as the sperm enters the Ovocyte, here the activity of life is driven by Nuclear events; cell division (and motility of cells) is the driving trend of forces to be amplified and the Embryo formation (Embryogenesis) is the ultimate objective.  As the embryo is being formed, there a transition of forces from proliferation to tissue differentiation. This transition from PROLIFERATION with an AMPLIFIED MITOSIS AND MOVEMENT OF CELL FOR POSITIONING IN THE BODY OF THE EMBRYO characterizes early life and is driven by promoter genes, amplified pathways, driven metabolism at Ribosome, histone, and genetic levels.  The processing of internal and external stimuli triggers the flow of forces.  A change of stimuli eventually occurs, followed by responses imposed by growth factors, variation in needs, and overall  cellular communications, and soon enough the trend of forces is toward differentiation.  In order to protect future life, SANCTUARY tissues are created to keep DIVISION POTENTIAL ACTIVE (Ovaries, testicles keep proliferative potential and controlled activity).   DIFFERENTIATION becomes the name of the game and is AMPLIFIED.  To commit resouces to this activity exclusively, proliferation is shut down at genes, enzymes, and chromatin levels to shield proliferation related  promoters.  Tissue differentiation is pushed to allow life, survival and adaptation leading to races and other phenotypic differentiation.  Each step is amplified to perfection (whatever the perfection is or implied).  REPRESSION OF A GENE THAT NORMALLY SHOULD BE AMPLIFIED OR STAT TRANSCRIPTION UNDER THESE CIRCUMSTANCES, MEANS ONCOGENIC SUPPRESSION AND A SIGN OF MALIGNANT PROLIFERATION AND POTENTIALLY ASSOCIATED RESUMPTION OF MITOSIS AND MIGRATION (METASTASIS).  IT IS ALSO ASSOCIATED WITH LOSS OF DIFFERENTIATION AND ATYPICAL PHENOTYPIC TRANSFORMATION.

This implies that whenever cancerous trending forces are triggered, they happen in a cell which will de-differentiate, but will switch to proliferation, mobility and perfect for survival and adaptation.  A cell trained to escape mechanism of local and distant defense, and full of survival and adaptation skills!  The ESCAPE include eluding local attacks by change in receptors, glycocalyx and level of pump and MDR gene expression,   but also distant (escape Anoikis) cell rejection.

Cancer is a formidable opponent with so many opportunities for target intervention if you know where to touch or block the flow of things for the cure.  The timing of change of the flow of forces/trends provides as much opportunity as a check point.  One may want to target these events.

CURE IS POSSIBLE WHEN YOU LOOK AT THIS WAY OF THINKING!

WITH EVERY LAW COMES A SET OF SPECIFIC GENES, ENZYMES, REGULATORS, PATHWAYS AND POTENTIAL DRIVERS, WE WILL HUNT THEM, STUDY THEM AND DEVELOP TARGET THERAPY OVER THE NEXT FEW YEARS, FEEL FREE TO DO THE SAME, THE RACE IS ON!!!!!

EXPERIMENT SUPPORTING THE 4TH LAW.

TAKE YOUR SHOES OFF RIGHT NOW, WEAR THEM BACK BACKWARD OR SIMPLY PUT, WEAR THE RIGHT SHOE ON THE LEFT FOOT, AND PUT THE LEFT SHOE ON THE RIGHT FOOT AND SIT FOR A WHILE.  THE BODY HAS ALL THE SUDDEN A NEW SITUATION, THE ABNORMAL SENSATION WILL START AND GROW ON YOU AND WILL NOT LET YOU FORGET IT UNTIL YOU EITHER CORRECT THE ISSUE , DECIDE TO STAY AND ADAPT.  SUFFICE IS TO SAY THE BAD SENSATION AND ULTIMATELY DISCOMFORT WILL AMPLIFY AND GROW ON YOU.

ANY NEW STIMULATION WILL GROW AND AMPLIFY. AT CELLULAR LEVEL, GENE TRANSCRIPTION AND NUCLEAR EVENTS LEAD THE WAY.   ANY NEW TREND ADOPTED BY THE CELL IN RESPONSE TO SOME EVENT, WILL NEED AMPLIFICATION AND SUSTENANCE TO BE A DRIVER EVENT...

It is because of the 4th law that a coffee will not taste the same at the time it was cooked versus 8 hours later!   Things will keep happening in that cup whether you like it or not!  That is nature!

COROLLARY POTENTIAL RESULTING FROM THE 3RD LAW
As DIFFERENTIATION wanes and is finally shut down by a complete silencing of differentiation genes, PROLIFERATION gene expression is amplified  through transcription gene and and promoter silencing for differentiation, and promoter stimulation for the proliferation trends and forces.  the FORCE AMPLIFICATION AND IMPLEMENTATION LAW enter into effect (4TH LAW OF NATURE)
Any general elected trend of forces need to be amplified, protected, and fully implemented. The implementation should however follow the 5th law, the most important law in the life of the cell, LIFE PRESERVATION.   THIS LAW WILL LEAD TO THE 6TH LAW. LAW OF ADOPTION, ADAPTATION AND CONFORMITY OR SURVIVAL LAW.

PROLIFERATION HAS A TRUE COROLLARY EVENT.  Indeed during proliferation, the cell show it can return to its young form which means potential of return to totipotential cell.  And in some instances, with proliferation comes totipotentiality which is observed in Teratomas.  This happens when a set of genes were not fully silenced due to heterogeneity or mutation of genes and defective silencing.  A second corollary to the 3rd law, is the return to mobility because  among the gene of proliferation, many will impact the Cytoskelton and protection against Anoikis.

Each law and Corollaries  will be discussed with genes involved as we move forward.

Medscape Medical News

AMD–Aspirin Link: Latest Hint Not the Last Word

Linda Roach

Jan 22, 2013

 

Editors' Recommendations

• AMD and Retinal Disease News & Perspectives

Drug & Reference Information

• Genetics of Age-Related Macular Degeneration
• Wet Macular Degeneration Injection
• Pathology of Reactive Gastropathy

Australian researchers analyzing data from a large, population-based eye study reported this week finding a statistically significant association between 15 years of regular aspirin use and the development of neovascular age-related macular degeneration (AMD).
Compared with others in the Blue Mountains Eye Study, participants who reported using aspirin at least once a week were twice as likely as nonusers to develop neovascular AMD in the subsequent 15 years, according to the report published online January 21 by JAMA Internal Medicine (formerly Archives of Neurology).
The odds ratio for developing wet AMD was 2.46 among the aspirin users (95% confidence interval [CI], 1.25 - 4.83), after adjustment for several possible confounding variables (age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index). There was no such association for geographic atrophy, Gerald Liew, PhD, from the Centre for Vision Research, Department of Ophthalmology, University of Sydney, and the Centre for Eye Research Australia, University of Melbourne, Melbourne, Australia, and colleagues report.
The report marked the third large study in the last year to suggest an association between aspirin use and neovascular AMD. Most recently, similar figures were reported for an analysis of data from the Beaver Dam Eye Study.
Frightened to Death?
Continuing publicity about the studies has heightened concerns that elderly people might be frightened literally to their deaths if they stop taking the aspirin they need to prevent heart attack or stroke, said Emily Y. Chew, MD, PhD, deputy director of the Division of Epidemiology and Clinical Applications at the National Eye Institute, Bethesda, Maryland.
"It's a public health issue, because it's clear that the protective effect from aspirin is high. People are going to die because of not taking aspirin for their heart disease. My patients are scared to death right now," Dr. Chew said to Medscape Medical News.
Even if aspirin use were confirmed as an AMD risk factor using more robust study data, Dr. Chew said, it already is apparent that the risk would be quite small in absolute terms, at about 1% for aspirin users, and 0.5% for nonusers.
" 'Doubling' the risk sounds terrible," she said. "But the real risk for late-stage AMD in these people who took aspirin [in the Beaver Dam Study] is 1%, vs half a percent for those who didn't, which is not clinically meaningful."
Dr. Chew noted that her preliminary look at data from a carefully controlled clinical trial that she leads found no extra risk for AMD in aspirin users. On the contrary, aspirin users in the second Age-Related Eye Diseases Study (AREDS2), in which Dr. Chew is principal investigator, had a lower risk for neovascular AMD than control patients, with an odds ratio of 0.61 (95% CI, 0.49 - 0.75; P < .0001), she found in this early analysis, which has been presented at meetings but not yet submitted for publication.
A senior coauthor of the current study acknowledged that the published evidence for an aspirin–AMD link remains inconclusive.
"Our study only generates a hypothesis of a possible side effect of aspirin use, but this needs to be confirmed by future studies. However, any single study adds to the evidence that we have so far," said Jie Jin Wang, PhD, also from the Centre for Vision Research, Department of Ophthalmology, University of Sydney, and the Centre for Eye Research Australia, University of Melbourne, in an interview with Medscape Medical News.
In a commentary that accompanied the Australian study, 2 cardiologists, Sanjay Kaul, MD, and George A. Diamond, MD, from the Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, urged clinicians to be move cautiously in response as further research continues.
"From a purely science-of-medicine perspective, the strength of evidence is not sufficiently robust to be clinically directive," they write. "However, from an art-of-medicine perspective, based on the limited amount of available evidence, there are some courses of action available to the thoughtful clinician."
They suggest a middle course, individualized to the patient's needs:

• Secondary prevention: Maintain the status quo, because there is strong evidence that its benefits outweigh the risks.
• Primary prevention: Carefully weigh potential risks and benefits. In patients who, under current guidelines, are eligible for treatment because of their 10-year risk of myocardial infarction or stroke, "the presence or absence of strong risk factors for neovascular AMD might tilt treatment decisions in one direction or the other."
• Other uses of aspirin: Be cautious in recommending long-term aspirin to other patients, such as those requiring pain control.

The study was supported by the National Health & Medical Research Council Australia. The authors and commentators have disclosed no relevant financial relationships.
JAMA Intern Med. Published online January 21, 2013. Article full text, Commentary full text