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Wednesday, January 23, 2013
WATCH OUT FOR HYPERTRIGLYCERDEMIA AND PANCREATITIS IN THE EVEROLIMUS TAKING PATIENT AND PROMPTLY INSTITUTE FENOFIBRATE AND REDUCE THE DOSAGE TO SEE IF THIS IS CONTROLLED.
OTHER SIDE EFFECT STOMATITIS, FATIGUE, RASH DIARRHEA AND UPPER RESPIRATORY INFECTIONS. ANEMIA AND HYPERGLYCEMIA HAVE BEEN REPORTED.
OTHER SIDE EFFECT STOMATITIS, FATIGUE, RASH DIARRHEA AND UPPER RESPIRATORY INFECTIONS. ANEMIA AND HYPERGLYCEMIA HAVE BEEN REPORTED.
NOMENCLATURE OF GENES INVOLVED IN CELL PROLIFERATION (PART III)
1. MELK, PK 38
---------Thanks to Jean-Pierre Tassan who published this:
"
1. MELK, PK 38
---------Thanks to Jean-Pierre Tassan who published this:
"
| Note | MELK (Maternal Embryonic Leucine zipper Kinase) belongs to the CAMK serine/threonine protein kinase superfamily. Melk is a protein serine/threonine kinase that is maximally active during mitosis. It is involved in diverse functions such as cell cycle, cytokinesis, mRNA splicing and apoptosis. | |||||
| Description | The full-length protein is 651 amino acids with an estimated molecular weight of approximately 74,5 kDa. | |||||
| Expression | MELK is expressed in cells of various tissue origins. MELK is highly expressed in oocytes, spermatogonia and embryos, which is indicative of a role in the germ-cell development. MELK is highly expressed in a large panel of cancers MELK expression is dependant on cell transformation (Gray et al., 2005). Its expression is strongly dependant on cell-cycle: MELK is undetectable in cells which have exited cell cycle (Badouel et al., 2010). | |||||
| Localisation | Cytoplasm, nucleus and cell cortex. | |||||
| Function | The exact function of MELK is currently unknown, however MELK was shown to be involved in cell cycle progression via the protein phosphatase CDC25B phosphorylation (Blot et al., 2002), in cytokinesis (Le Page et al., 2011), in apoptosis via its interaction with the Bcl-2 family of proapoptotic genes (Lin et al., 2007) and apoptosis signal-regulating kinase (ASK1) (Jung et al., 2008) and in inhibition of mRNA splicing during mitosis via its association with NIPP1 (Vulsteke et al., 2004). MELK function is required for mammary tumorigenesis in vivo (Hebbard et al., 2010). | |||||
| Homology | MELK belongs to the
Kin1/PAR-1/MARK family of protein kinases found from yeast to human.
These kinases are involved in cell polarity, dynamics of microtubules
and intracellular signalisation. ================================== This kinase is the real deal, Choi S suggested it may confer resistance to 5_FU and Radiation in colorectal cancer. It is located at 9p13 In Breast Cancer, it is bad news (prognosis) because it blocks Apoptosis through Bcl-GL (Fau is an associate). =========================================================== 2. CM2 or Minichromosomal Maintenance Complex, location 3q21 regulated by CDC2 and 7 of which we spoke about as needed for cell division this one initiate genome replication, marking proliferation |
FERTILITY PRESERVATION IN YOUNG ONCOLOGY PATIENTS.
We at CRBCM appreciate the article in a recent JNCNN publication :" Optimizing fertility preservation practices for adolescent and young adult cancer patients" by Rebecca Johnson and Leah Kroon.
The article suggest that there 70, 000 young people with cancer (age 15-39) who undergo chemotherapy with significant risk of loss of fertility. And offering them fertility preservation is crucial and obligated step in their management. With the advancement in cancer treatment, over 70 to 80% survive after cancer and have to live with long term psychological distress from infertility.
54% of Oncologists reportedly do not discuss this risk.
80% of Male patients and 48% of female patients recall having discussed the issue with their Oncologist
which is a shame!
Barriers to the issue:
1. Availability of the service
2. Integration of the practice of referring the patient into the routine of the Oncology office
3. knowing that sperm collection can occur while patient is still inpatient
4. Fear of delay to therapy, particularly in female where Ovarian stimulation requires 2 weeks delay/lag of time
We look at this as an integral part of a Survivorship Center.
We at CRBCM appreciate the article in a recent JNCNN publication :" Optimizing fertility preservation practices for adolescent and young adult cancer patients" by Rebecca Johnson and Leah Kroon.
The article suggest that there 70, 000 young people with cancer (age 15-39) who undergo chemotherapy with significant risk of loss of fertility. And offering them fertility preservation is crucial and obligated step in their management. With the advancement in cancer treatment, over 70 to 80% survive after cancer and have to live with long term psychological distress from infertility.
54% of Oncologists reportedly do not discuss this risk.
80% of Male patients and 48% of female patients recall having discussed the issue with their Oncologist
which is a shame!
Barriers to the issue:
1. Availability of the service
2. Integration of the practice of referring the patient into the routine of the Oncology office
3. knowing that sperm collection can occur while patient is still inpatient
4. Fear of delay to therapy, particularly in female where Ovarian stimulation requires 2 weeks delay/lag of time
We look at this as an integral part of a Survivorship Center.
Tuesday, January 22, 2013
The issue of clinical research and participation in clinical trials
Hello
again. I'm John Marshall for Medscape. I want to tackle the beginning
of what will be a very important issue for 2013 and beyond, the issue of
clinical research and participation in clinical trials.
Go back to 2012. If I said, "99%," you would know what I am talking about. If I told you the number "47%," you would know what I am talking about, particularly here in Washington, DC. These are prominent numbers. But if I told you the number "97%," would you know what I am talking about?
That is the number of patients in the United States with cancer who receive the so-called standard of care, meaning that 3% of patients go on clinical trials and 97% receive standard of care -- lemmings that are following the one before them, doing what we did years ago. There is no advancement, no progress. We know the shortcomings of these treatments, but for whatever reason, there is an element of safety and security or a complicated environment where patients are not demanding clinical trials and they are not being offered clinical trials.
So, this year, as part of our Ruesch Center for the Cure of Gastrointestinal Cancers Annual Symposium: Fighting a Smarter War Against Cancer, we tried to tackle this. We tried to bring everybody together in a meeting about a month ago, to get all the key stakeholders -- from the US Food and Drug Administration (FDA), the Cancer Therapy Evaluation Program (CTEP), and industry to patient representatives, patients, and academic folks -- together and ask why we aren't doing a better job with clinical trials. We had a fascinating day in discovery on this and I think some answers may have emerged.
Let's first look at what the priorities are for the different stakeholders. Let's start with the FDA. Their priority is safety and efficacy. That is what they are charged to do. The priority of the payers, the ones funding all the clinical treatment as well as paying for clinical research, is to control costs. Their job is to control cost in an ever more expensive world. Sponsors, pharmaceutical companies, and CTEP want access to high volumes of patients and high-quality data. They want a crisp, pure world in which they can test their drugs to get things moving forward. In community oncology, where most cancer care is delivered, I think you would argue that their stake -- their priority -- is going to be high-quality, highly efficient care. That is success in the community. In academic oncology, we are judged by how many patients go on clinical trials. What percentage of patients can we put on a clinical trial? We do a little bit better in a comprehensive cancer center (10%-20%), but it's nowhere where it needs to be.
As for patients, nobody ever asks them what their motivation is and why they would want to do this. So, at this meeting, we asked them, and it was pretty clear that they don't see what's in it for them to go on one of these clinical trials. They are very put off by the whole placebo thing, even though they don't have a good understanding of what is out there. They have these visions of what this means. They don't see how they are a part of it, how they are helping to drive the answer. We have done a terrible job of educating our public. I think we have done a terrible job of designing clinical trials that have significant value to them. We do these great big clinical trials that result in very small improvements in outcome, which, honestly, are a big waste of time.
We had Deborah Schrag give a wonderful talk on her study in rectal cancer, which challenges the need for radiation in rectal cancer.[1,2] Here is a big study that no one is going to fund -- maybe the federal government, depending on how steeply we go off the cliff -- that is trying to remove a therapy that may be unnecessary in the treatment of colorectal cancers, namely radiation. She spoke about how difficult that study was to put into play. This is a very interesting study that would make things easier for patients, but it took more than a year for the study to get up and running.
There are so many barriers out there. One of the things that really emerged for me was that we need to start over and think about this in a different way. We have some good leads. Take the I-SPY2 clinical trial in breast cancer.[3] This is a great new model for us, a parent protocol where molecular profiling is done and treatment assignment is based on an individual's molecular profile based on our best understanding of the molecular biology.
I think that every single major disease, maybe every disease,
needs exactly this type of parent protocol. In order to do this, we are
going to need better and quicker pathology. We need to change a few laws
around molecular profiling -- the timing, who pays for it, and all of
those things. I think it will require a more centralized pharmacy,
because if everybody is going to participate in this, all of us can't
keep all of these drugs on the shelf. We would need some sort of
centralized management for access to investigational drugs throughout
the community, not just at comprehensive cancer centers but throughout
our medical community. I think the opportunity here is ripe, because
many of our healthcare systems are merging and coming together. One of
the things that we can do as not just academic ivory towers but
corporations is begin to provide the community with this type of
centralized tissue analysis, pharmacy support, and clinical research
support. Then, a patient, no matter where he comes into the system, can
get that tumor analysis. He can get access to what we think is the best
new therapy -- not just improving things a little bit, but trying to
make major leaps forward.
I don't think we are too far away from where we need to be. We have the conceptual protocols in breast cancer and some new ones in lung cancer. I think we need to develop them in colon cancer, pancreas cancer, gastric cancer, and hepatocellular cancer in the gastrointestinal world, and then split the cancers into their individual types and treat patients according to our best guess at the moment, tagging it with drug development and moving forward. It will be biomarker co-development. We will increase our accrual rate from the puny 3% up to 25%, ask good questions, answer them quickly, and then move on.
I think the future is bright for us in clinical research and cancer medicine. It will take some cooperation, but I think that together with our patient partners, we can drive this forward. Looking forward to a bright 2013, I'm John Marshall for Medscape.
Go back to 2012. If I said, "99%," you would know what I am talking about. If I told you the number "47%," you would know what I am talking about, particularly here in Washington, DC. These are prominent numbers. But if I told you the number "97%," would you know what I am talking about?
That is the number of patients in the United States with cancer who receive the so-called standard of care, meaning that 3% of patients go on clinical trials and 97% receive standard of care -- lemmings that are following the one before them, doing what we did years ago. There is no advancement, no progress. We know the shortcomings of these treatments, but for whatever reason, there is an element of safety and security or a complicated environment where patients are not demanding clinical trials and they are not being offered clinical trials.
So, this year, as part of our Ruesch Center for the Cure of Gastrointestinal Cancers Annual Symposium: Fighting a Smarter War Against Cancer, we tried to tackle this. We tried to bring everybody together in a meeting about a month ago, to get all the key stakeholders -- from the US Food and Drug Administration (FDA), the Cancer Therapy Evaluation Program (CTEP), and industry to patient representatives, patients, and academic folks -- together and ask why we aren't doing a better job with clinical trials. We had a fascinating day in discovery on this and I think some answers may have emerged.
Let's first look at what the priorities are for the different stakeholders. Let's start with the FDA. Their priority is safety and efficacy. That is what they are charged to do. The priority of the payers, the ones funding all the clinical treatment as well as paying for clinical research, is to control costs. Their job is to control cost in an ever more expensive world. Sponsors, pharmaceutical companies, and CTEP want access to high volumes of patients and high-quality data. They want a crisp, pure world in which they can test their drugs to get things moving forward. In community oncology, where most cancer care is delivered, I think you would argue that their stake -- their priority -- is going to be high-quality, highly efficient care. That is success in the community. In academic oncology, we are judged by how many patients go on clinical trials. What percentage of patients can we put on a clinical trial? We do a little bit better in a comprehensive cancer center (10%-20%), but it's nowhere where it needs to be.
As for patients, nobody ever asks them what their motivation is and why they would want to do this. So, at this meeting, we asked them, and it was pretty clear that they don't see what's in it for them to go on one of these clinical trials. They are very put off by the whole placebo thing, even though they don't have a good understanding of what is out there. They have these visions of what this means. They don't see how they are a part of it, how they are helping to drive the answer. We have done a terrible job of educating our public. I think we have done a terrible job of designing clinical trials that have significant value to them. We do these great big clinical trials that result in very small improvements in outcome, which, honestly, are a big waste of time.
We had Deborah Schrag give a wonderful talk on her study in rectal cancer, which challenges the need for radiation in rectal cancer.[1,2] Here is a big study that no one is going to fund -- maybe the federal government, depending on how steeply we go off the cliff -- that is trying to remove a therapy that may be unnecessary in the treatment of colorectal cancers, namely radiation. She spoke about how difficult that study was to put into play. This is a very interesting study that would make things easier for patients, but it took more than a year for the study to get up and running.
There are so many barriers out there. One of the things that really emerged for me was that we need to start over and think about this in a different way. We have some good leads. Take the I-SPY2 clinical trial in breast cancer.[3] This is a great new model for us, a parent protocol where molecular profiling is done and treatment assignment is based on an individual's molecular profile based on our best understanding of the molecular biology.
I don't think we are too far away from where we need to be. We have the conceptual protocols in breast cancer and some new ones in lung cancer. I think we need to develop them in colon cancer, pancreas cancer, gastric cancer, and hepatocellular cancer in the gastrointestinal world, and then split the cancers into their individual types and treat patients according to our best guess at the moment, tagging it with drug development and moving forward. It will be biomarker co-development. We will increase our accrual rate from the puny 3% up to 25%, ask good questions, answer them quickly, and then move on.
I think the future is bright for us in clinical research and cancer medicine. It will take some cooperation, but I think that together with our patient partners, we can drive this forward. Looking forward to a bright 2013, I'm John Marshall for Medscape.
Latest in Hematology-Oncology
Medscape Oncology © 2013
WebMD, LLC
Cite this article: Why Are Only 3% of US Cancer Patients in Clinical Trials? Medscape. Jan 17, 2013.
Most Popular Articles
According to ONCOLOGIST/HEMATOLOGISTS
ARSENIC TRIOXIDE COULD SIGNIFICANTLY EXPAND ITS ROLE IN CANCER TREATMENT. AND VITAMIN C AND MICROHYDRIN COULD COME AT THE RESCUE.
Cancer cure is through death of cancer cell. To date, the main way of death for cancer cellis
through Caspase activation cascade. In most cells, we know the main
way the activation of Caspase occurs. That is Cytochrome C is naturally
anchored at the membrane inside the Mitochondria. The Anchor is in fact
a chemical bonding or attachment through electrons like molecules do
attach to each other. We believe there, Cytochrome C is attached to a
Cardiolipin which is part of lipid of the membrane. Just imagine
another molecule showing up with free electron, the free electron could
attract and pull the one involved in the attachment and break free the
Cytochrome C. Cytochrome C electron no longer attached comes out and
activate the Caspase (mostly Caspase 9 which eventually activates
members of its family) and there start the Caspase work to coagulate DNA
and genes start breaking leading to cancer cell death. One of molecule
that produces such disturbing free electrons, is Arsenic Trioxide.
This delivery of free electrons by arsenic trioxide is not limited to
the mitochondria. It occurs through the cytosol (liquid milieu of the
cell) disrupting many cellular pathways, delivering global intracellular
disruption. ( for those savvy people, do remember that the " breaking"
of the anchor could be induced from outside the Mitochondrial membrane
through the AKT or Bax effect--this is where Bcl-2 negative effect is
the strongest ) arsenic trioxide
This global disruption has been established to treat Acute Promyelocytic Leukemia (APL) (by the way, Chinese researchers lead the way on this one). Frankly speaking, this "Global disruption"can be used in any cancer. The problem is that it can occur in any cell, including our normal cells. Giving caution to the amount you use because of a narrow safety index.
Vitamin C and Microhydryn have also free electron, that is why they can cool down free radicals and therefore are called Anti-Oxydants . The free electrons of these compounds seem to add to those of Arsenic Trioxide to Increase toxicity to the cancer cell. It is worth mentioning that, at the DNA level, these free electron break the strand, triggering our first law (activation of P53 and stoppage of cell cycle).
3 main problems
1. Good and bad pathways are stopped, mitigating the effects of global destruction.
2. (non selectivity) Good and bad cells are killed. This effect is worse in patients with poor reserve of free electron clearing molecules (Gluthation based, Superoxide based and others). (CAUTION TO EVERYONE)
3. Arsenic is hard to get rid of, and chronic exposure signs will result.
But frankly speaking, you can use this to kill any Cancer. Research will continue at CRBCM no matter what!
Of Note: Use of this information outside of the topic discussed herein, is not endorsed by the CRBCM
This global disruption has been established to treat Acute Promyelocytic Leukemia (APL) (by the way, Chinese researchers lead the way on this one). Frankly speaking, this "Global disruption"can be used in any cancer. The problem is that it can occur in any cell, including our normal cells. Giving caution to the amount you use because of a narrow safety index.
Vitamin C and Microhydryn have also free electron, that is why they can cool down free radicals and therefore are called Anti-Oxydants . The free electrons of these compounds seem to add to those of Arsenic Trioxide to Increase toxicity to the cancer cell. It is worth mentioning that, at the DNA level, these free electron break the strand, triggering our first law (activation of P53 and stoppage of cell cycle).
3 main problems
1. Good and bad pathways are stopped, mitigating the effects of global destruction.
2. (non selectivity) Good and bad cells are killed. This effect is worse in patients with poor reserve of free electron clearing molecules (Gluthation based, Superoxide based and others). (CAUTION TO EVERYONE)
3. Arsenic is hard to get rid of, and chronic exposure signs will result.
But frankly speaking, you can use this to kill any Cancer. Research will continue at CRBCM no matter what!
Of Note: Use of this information outside of the topic discussed herein, is not endorsed by the CRBCM
NOMENCLATURE OF GENES DISCUSSED IN THE 3RD LAW (CONTINUED)
5. E2F1 VERY IMPORTANT GENE
ITS PROTEIN PROMOTES CD2AP TO AFFECT T CELL FUNCTION AND FUNCTION OF PODOCYTES, DISTURBANCE THEREFORE WILL AFFECT THE KIDNEY IN THE HOST.
IT IS REPRESSED BY THE RETINOBLASTOMA PROTEIN AND LEAD TO SENESCENECE
WHEN INVOLVED IN THE CDK1 PATHWAYS IT IS ALSO REPRESSED. IT IS A VERSATILE GENE OF WHICH PROTEIN IMPORTANT IN CELL CYCLE HAS FUNCTION VARYING WITH ITS POSITION. IT IS KNOWN TO BE AT THE ESTROGEN RECEPTOR.
YOU CANNOT TARGET THIS GENE AND COME UP EMPTY. HMGA GENE INCREASES THIS E2F1. IT HAS INTERACTION WITH SENESCENT CHROMATIN.
6. GEMININ
Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle. (WIKIPEDIA)
ITS PROTEIN PROMOTES CD2AP TO AFFECT T CELL FUNCTION AND FUNCTION OF PODOCYTES, DISTURBANCE THEREFORE WILL AFFECT THE KIDNEY IN THE HOST.
IT IS REPRESSED BY THE RETINOBLASTOMA PROTEIN AND LEAD TO SENESCENECE
WHEN INVOLVED IN THE CDK1 PATHWAYS IT IS ALSO REPRESSED. IT IS A VERSATILE GENE OF WHICH PROTEIN IMPORTANT IN CELL CYCLE HAS FUNCTION VARYING WITH ITS POSITION. IT IS KNOWN TO BE AT THE ESTROGEN RECEPTOR.
YOU CANNOT TARGET THIS GENE AND COME UP EMPTY. HMGA GENE INCREASES THIS E2F1. IT HAS INTERACTION WITH SENESCENT CHROMATIN.
6. GEMININ
In Mitosis
During mitosis or M phase, geminin stabilizes the replication factor Cdt1 by protecting it from ubiquitination and therefore subsequent proteolysis, thereby potentially promoting DNA replication during the following cell cycle. Although inhibition of geminin by RNAi leads to destabilization of Cdt1 protein and impairment of DNA replication during the following cell cycle in many cancer cell lines, no such cell cycle defect is seen in primary and immortalized cell lines (although Cdt1 levels are still reduced in these cells).[5]Geminin therefore is an important player in ensuring that one and only one round of replication occurs during each cell cycle. (WIKIPEDIA)
CONTINUE EDUCATION WITH NMCR
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==========================================================
EDUCATION CONTINUA
The CRBCM will be in Chicago to participate in the debate
and update itself in Oncology.
We thank Xcenda for allowing the cancer center to participate,
information is what we need as scientists!
January 22, 2013
Harnessing the Power of HDAC Inhibitors in Ovarian Cancer
Apicidin is a fungal metabolite with antiparasitic activity, and this histone deacetylase (HDAC) inhibitor has shown antiproliferative activity against various cancer cell lines. Korean researchers focused on the molecular mechanisms of apicidin in human ovarian cancer SKOV-3 cells and found that the agent has the potential to hinder cancer cell migration and invasion. They describe the mechanism of action by which apicidin reduced HDAC4 in this particular cancer.
RESULT: Histone
deacetylase inhibitor, apicidin, inhibits human ovarian cancer cell
migration via class II histone deacetylase 4 silencing
Cancer Letters (PubMed) | Dec 28, 2012 (Free abstract. Full text $31.50)
Cancer Letters (PubMed) | Dec 28, 2012 (Free abstract. Full text $31.50)
Platinum-based chemo leads to modest survival benefits in metastatic ovarian cancer so pairing it with other agents may offer a therapeutic boost. To that end, investigators in New York successfully married the experimental HDAC inhibitor panobinostat with doxorubicin and carboplatin. They explain why this triplet of agents proved to be “synergistic” in ovarian cancer cell lines, including SKOV-3.
RESULT: The
histone deacetylase inhibitor panobinostat demonstrates marked synergy
with conventional chemotherapeutic agents in human ovarian cancer cell
lines
Investigational New Drugs (PubMed) | Dec 02, 2011 (Free abstract. Full text $39.50)
Investigational New Drugs (PubMed) | Dec 02, 2011 (Free abstract. Full text $39.50)
==================================
for further reading, go to the source or write us!
FACTORS BEING MONITORED IN THE WELLNESS PROGRAM (part II)
1. AGE
Because with age comes all the trouble. Age is a relative thing. At what age do we start monitoring things?
And 40 years of age appears the most thought of in Western Societies. Mammograms are started and 45 years is a risk factor for men who then ae being monitor for cholesterol. The natural or true age is linked to genetic and environmental factors. Age is linked to the length of Telomeres and to Senescence. Telomeres are these youth protector molecules which keep being clipped and shortened at each cell cycle until the DNA is exposed to Endonucleases (if you get my drift!). Sometime we can fool it and make it a variable by exercising, and then it plays catch-up with you later. Some time, it is not so much of a variable, it is just there to be lived with...Suffice is to say, when you are young you feel invincible, protected. Being old, well, you have a "Risk factor" . Cancer does not like to be old, and works hard to preserve or elongate its Telomeres. This is an area of Target therapy.
2. Cholesterol, we spoke about yesterday-see WELLNESS PART I
3. WEIGHT MANAGEMENT WE WILL SPEAK ABOUT NEXT
4. BLOOD PRESSURE, Hb A1C FOR DIABETIC
5. THYROID FUNCTION (THYROID STIMULATING HORMONE LEVEL)
6. BNP
Brain natriuretic peptide - Wikipedia, the free encyclopedia
Basic natriuretic peptide (BNP), now known as B-type natriuretic peptide (also BNP) or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the ...
7.RENAL FUNCTION AND CREATININE
8. HEMOGLOBIN LEVEL
9. C-REACTIVE PROTEIN STATUS (AND ANTI NUCLEAR ANTIBODY STATUS)
10. FEV 1 (OR WHETHER YOU FEEL TIRED AND SHORT OF BREATH)
11. OXYGEN SATURATION OR SLEEP APNEA PRESENCE
12. ALBUMIN LEVEL (LOWER THAN 3.5g)
13. MENTAL STATUS / ANXIETY
14. PROTEINURIA
15. ADHESION TO PREVENTION AND IMMUNIZATION
(FLU-SHOT, PNEUMONIA AND NOW SHINGLE SHOT, ANNUAL OPHTHALMO VISIT,MAMMOGRAM,COLONOSCOPY,BONE DENSITY MONITOR, SMOKING CESSATION AND AVOIDANCE OF ALCOHOLI SM)
THESE 15 FACTORS SUM UP YOUR HEALTH. THIS IS THE REPORT CARD YOU SHOULD GET FROM YOUR DOCTOR WITH EVERY VISIT!
WE WILL DISCUSS THEM AS WE GO ALONG
Because with age comes all the trouble. Age is a relative thing. At what age do we start monitoring things?
And 40 years of age appears the most thought of in Western Societies. Mammograms are started and 45 years is a risk factor for men who then ae being monitor for cholesterol. The natural or true age is linked to genetic and environmental factors. Age is linked to the length of Telomeres and to Senescence. Telomeres are these youth protector molecules which keep being clipped and shortened at each cell cycle until the DNA is exposed to Endonucleases (if you get my drift!). Sometime we can fool it and make it a variable by exercising, and then it plays catch-up with you later. Some time, it is not so much of a variable, it is just there to be lived with...Suffice is to say, when you are young you feel invincible, protected. Being old, well, you have a "Risk factor" . Cancer does not like to be old, and works hard to preserve or elongate its Telomeres. This is an area of Target therapy.
2. Cholesterol, we spoke about yesterday-see WELLNESS PART I
3. WEIGHT MANAGEMENT WE WILL SPEAK ABOUT NEXT
4. BLOOD PRESSURE, Hb A1C FOR DIABETIC
5. THYROID FUNCTION (THYROID STIMULATING HORMONE LEVEL)
6. BNP
Brain natriuretic peptide - Wikipedia, the free encyclopedia
Basic natriuretic peptide (BNP), now known as B-type natriuretic peptide (also BNP) or GC-B, is a 32 amino acid polypeptide secreted by the ventricles of the ...7.RENAL FUNCTION AND CREATININE
8. HEMOGLOBIN LEVEL
9. C-REACTIVE PROTEIN STATUS (AND ANTI NUCLEAR ANTIBODY STATUS)
10. FEV 1 (OR WHETHER YOU FEEL TIRED AND SHORT OF BREATH)
11. OXYGEN SATURATION OR SLEEP APNEA PRESENCE
12. ALBUMIN LEVEL (LOWER THAN 3.5g)
13. MENTAL STATUS / ANXIETY
14. PROTEINURIA
15. ADHESION TO PREVENTION AND IMMUNIZATION
(FLU-SHOT, PNEUMONIA AND NOW SHINGLE SHOT, ANNUAL OPHTHALMO VISIT,MAMMOGRAM,COLONOSCOPY,BONE DENSITY MONITOR, SMOKING CESSATION AND AVOIDANCE OF ALCOHOLI SM)
THESE 15 FACTORS SUM UP YOUR HEALTH. THIS IS THE REPORT CARD YOU SHOULD GET FROM YOUR DOCTOR WITH EVERY VISIT!
WE WILL DISCUSS THEM AS WE GO ALONG
CPRIT Foundation and the CPRIT Grant review and approval process
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.
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DetailsMonday, January 21, 2013
WELLNESS PROGRAM (PART 1).
As we set out to prevent Breast Cancer, we need to establish a wellness program for our clinic that would be
part of a comprehensive intervention aimed at decreasing cancer risk but also overall mortality risk for our patients. Estrogenic relative imbalance with noted increase of peripheral estrogenic molecule is suggested in obese patient. This fact is a known Breast cancer risk. And cholesterol management goes along obesity management. This discussion will focus on Cholesterol blood level management.
* LDL=Total Cholesterol - HDL cholesterol - (triglyceride/5)
* new LDL direct measurement can also be achieved directly without need for fasting.
----------------------------------------------------------------------
LDL" Bad cholesterol"
* normal is below 130mg/dL
* above this, lifestyle/diet intervention needed
any time you start intervening, reduce the baseline by 30-40%
To assume almost zero risk for cardiovascular disease reach 40mg/dL or below, but this is may be not a reasonable goal.
-----------------------------------------------------------------------------
In patient with history of Coronary heart disease, peripheral Vascular disease or diabetes, bring cholesterol to less than 100 mg/dL absolutely or better yet 70mg/dL for high risk patients.
-----------------------------------------------------------------------------------
In general the 5 year risk decrease by 1% for every 2mg/dL decrease in LDL
Medication to decrease LDL, pravastatin, Simvastatin, Ezetimibe, Niacin,
watch liver function test, CPK, C reactive protein, check ANA (associated autoimmune disease) and TSH
Definitely no Fish oil that increases LDL (unless the patient is already on medication decreasing LDL and you aimed at decreasing Triglyceride and aiming at anti-inflmmatory effect).
==========================================================
TRIGLYCERIDES
Normal below 150 mg/dL
150- to 200 mg/dL, is consider Borderline
200 to 499 consider high and needing intervention
more than 500mg is considered critical with impending pancreatitis and Chylomicronemia Syndrome and warrant immediate intervention
Intervention here means
1.Smoking Cessation
2.weight loss program
3. Exercising
4. Reduce Cholesterol intake to less than <200mg/day
5. Reduce saturated fat to less than 7% of total calories daily
6. Increase daily fiber to greater than 10g/day
7. consider increased phyto-Stanols and sterols (greater than 2 g/day)
8. start Nicotic Acid or Gemfibrozil or Fenofibrate, Poglitazone, or Roziglitazone (for Diabetic)
remember Colesevelam increases Triglyceride
for Pioglitazone and Roziglitazone, watch for fluid retention and Congestive Heart Failure!
------------------------------REMEMBER, ACHIEVABLE GOAL IS 30-40% REDUCTION-----
NEXT WEIGHT LOSS!
As we set out to prevent Breast Cancer, we need to establish a wellness program for our clinic that would be
part of a comprehensive intervention aimed at decreasing cancer risk but also overall mortality risk for our patients. Estrogenic relative imbalance with noted increase of peripheral estrogenic molecule is suggested in obese patient. This fact is a known Breast cancer risk. And cholesterol management goes along obesity management. This discussion will focus on Cholesterol blood level management.
* LDL=Total Cholesterol - HDL cholesterol - (triglyceride/5)
* new LDL direct measurement can also be achieved directly without need for fasting.
----------------------------------------------------------------------
LDL" Bad cholesterol"
* normal is below 130mg/dL
* above this, lifestyle/diet intervention needed
any time you start intervening, reduce the baseline by 30-40%
To assume almost zero risk for cardiovascular disease reach 40mg/dL or below, but this is may be not a reasonable goal.
-----------------------------------------------------------------------------
In patient with history of Coronary heart disease, peripheral Vascular disease or diabetes, bring cholesterol to less than 100 mg/dL absolutely or better yet 70mg/dL for high risk patients.
-----------------------------------------------------------------------------------
In general the 5 year risk decrease by 1% for every 2mg/dL decrease in LDL
Medication to decrease LDL, pravastatin, Simvastatin, Ezetimibe, Niacin,
watch liver function test, CPK, C reactive protein, check ANA (associated autoimmune disease) and TSH
Definitely no Fish oil that increases LDL (unless the patient is already on medication decreasing LDL and you aimed at decreasing Triglyceride and aiming at anti-inflmmatory effect).
==========================================================
TRIGLYCERIDES
Normal below 150 mg/dL
150- to 200 mg/dL, is consider Borderline
200 to 499 consider high and needing intervention
more than 500mg is considered critical with impending pancreatitis and Chylomicronemia Syndrome and warrant immediate intervention
Intervention here means
1.Smoking Cessation
2.weight loss program
3. Exercising
4. Reduce Cholesterol intake to less than <200mg/day
5. Reduce saturated fat to less than 7% of total calories daily
6. Increase daily fiber to greater than 10g/day
7. consider increased phyto-Stanols and sterols (greater than 2 g/day)
8. start Nicotic Acid or Gemfibrozil or Fenofibrate, Poglitazone, or Roziglitazone (for Diabetic)
remember Colesevelam increases Triglyceride
for Pioglitazone and Roziglitazone, watch for fluid retention and Congestive Heart Failure!
------------------------------REMEMBER, ACHIEVABLE GOAL IS 30-40% REDUCTION-----
NEXT WEIGHT LOSS!
Sunday, January 20, 2013
Mutiple Myeloma management notes from training!
-------------------------------------------------------------
At relapse, if our patient had a good response and a long
duration of remission (> 12 months), we favor re-introduction of the
initial regimen. If the patient has suboptimal response or a short
remission duration, we would change the class of drug used (eg, if
initially treated with an immunomodulatory agent [thalidomide,
lenalidomide], we would switch to proteasome inhibitor [bortezomib,
carfilzomib]. If initially treated with a proteasome inhibitor, we would
switch to an immunomodulatory agent). In this particular case, we would
need to factor in that the patient now has renal failure and a new bone
lesion. We generally re-introduce bisphosphonates quarterly at relapse
in patients with new bone lesions. However, since this patient has renal
failure, we would wait for renal improvement and favor pamidronate over
zoledronic acid with a reduced dose of 30 mg (from 90 mg).1
Also due to the renal status of this patient, full-dose lenalidomide
should not be used. I would favor switching to bortezomib because it can
be used at full dose. However, dose-adjusted lenalidomide is also an
option.2 A second ASCT may also be considered, especially if the initial remission was extremely long (eg, > 4 years).
=============================================================
SECOND OPINION
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
==================================================================
tougher case
==================================================
During treatment, Mrs Anderson developed peripheral
neuropathy. There are a number of ways to reduce the risk of
treatment-induced peripheral neuropathy. The randomized French trial
found that subcutaneous bortezomib is not inferior to IV bortezomib and
significantly reduced the risk of peripheral neuropathy.5 Efficacy with carfilzomib monotherapy is comparable to that of bortezomib but the risk of PN is greatly reduced.3,6
Regimens containing melphalan or cyclophosphamide may be active and
would not contribute to PN. Thalidomide can cause treatment-induced
neuropathy and would not be an option to reduce the risk of neuropathy.
-------------------------------------------------------------
Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota
At diagnosis, if patient had no high-risk molecular
markers and excellent renal function. In this setting, at Mayo, we
prefer to start with lenalidomide and dexamethasone because it has high
remission rates, is oral, well tolerated, and unlikely to induce
peripheral neuropathy. When using lenalidomide in patients
with no personal history of VTE, we favor prophylaxis with aspirin at
325 mg daily. We would use IV bisphosphonates monthly for 12 months and
quarterly for 1 additional year. In patients with low-risk disease, we consider
risks and benefits of maintenance therapy. If maintenance therapy is
chosen, consider limiting the duration to 12-24 months.
=============================================================
SECOND OPINION
+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++
Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California
Mr Johnson's presentation was fairly typical and
consistent with standard risk myeloma. At UCSF, we would consider this
young (< 60 years), standard risk patient to be an excellent
candidate for autologous transplantation at presentation. Therefore, we
would avoid melphalan containing therapy and limit upfront lenalidomide
therapy to 4-6 cycles thus allowing ample marrow reserve for stem cell
collection. Lenalidomide/dexamethasone, bortezomib/dexamethasone, and/or
lenalidomide with bortezomib would all be considered excellent upfront
therapy options. Appropriate supportive care measures would be oral
calcium and vitamin D and IV bisphosphonates. Patients receiving
proteasome inhibition should receive anti-viral prophylaxis to prevent
zoster reactivation and patients receiving immunomodulatory agents
should receive venous thromboembolism (VTE) prophylaxis. Patients at
increased risk for VTE should receive therapeutic warfarin, while
low-risk patients, such as this one, can receive aspirin (325 mg) daily.
In patients treated with autologous transplantation, we favor
lenalidomide maintenance based on the CALGB 100104 and French randomized
post-transplantation maintenance trials.1,2 The median time
to progression in the CALGB study was almost double for the lenalidomide
arm (46 months) versus the placebo arm (27 months). The optimal
duration of maintenance therapy remains unclear but we attempt to
continue maintenance in this setting for at least 1 year and often for
2-3 years depending on tolerability and count suppression.
At relapse, Mr Johnson has developed significant renal
insufficiency and this prevents the use of full-dose lenalidomide, as
lenalidomide clearance is primarily renal. Since Mr Johnson's remission
lasted 24 months, one could choose to use either dose-reduced
lenalidomide, or a bortezomib-containing regimen. There are a number of
reports describing improved renal function in patients receiving early
bortezomib administration and no increased toxicity. Consequently, we
would likely recommend a bortezomib-based regimen, like
cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in this case.
One should consider re-instituting bisphosphonate therapy once the renal
function improves (unless the renal insufficiency is due to
hypercalcemia for which bisphosphonates should be used right away). At
relapse, one always needs to consider toxicity from prior therapy. Since
the patient has a history of neuropathy, we would choose to administer
bortezomib at weekly intervals and by subcutaneous injection. If the
neuropathy increases, option would include switching to carfilzomib or
lenalidomide-based therapy.
- 1 McCarthy PL, et al. N Engl J Med. 2012;366(19):1770-1781.
- 2 Attal M, et al. N Engl J Med. 2012;366(19):1782-1791.
======================================================
follow-up
========================================
Once a patient has achieved remission following upfront therapy,
it is important to follow their myeloma for evidence of relapse. Early
recognition of disease relapse often can prevent morbid complications
including hypercalcemia, compression fractures, and renal failure. For
patients on maintenance therapy, we will follow their CBC including
neutrophil and platelet counts every 4-6 weeks and adjust dosing
accordingly. A history and physical exam and laboratories including
serum protein electrophoresis, quantitative immunoglobulins, serum
immunofixation electrophoresis, and serum free light chains can be
followed every 12 weeks. We will follow 24-hour urine tests (TP, UPEP,
UIFE) every 12 weeks if a patient has had disease that is only
assessable by urine tests (this is rare). We perform bone marrow
biopsies every 12-18 months unless the patient has truly nonsecretory
disease for which BMB exams are performed every 3-6 months. We rarely
performed routine skeletal surveys but prefer PET/CT or total body MRI
exams, every 12-18 months.
Elizabeth Bilotti, MSN, RN, APN
For patients who have achieved a CR post-transplant, we would follow
every 3 months or as clinically indicated for reported symptoms, with a
change in the frequency of assessments at the time signs of relapse
became present. Evaluation would include full laboratory assessment
(CBC, chemistry panel, quantitative immunoglobulins, SPEP, free light
chain analysis, serum immunofixation with 24-hour urine analysis as
appropriate ‒ UTP, UPEP, and urine immunofixation on a 24-hour
urine). Radiographic imaging and BM biopsy would be determined based
upon medical necessity and only used routinely in patients with
non-secretory disease.
=============================================================
Patients with the t(4;14) should receive bortezomib
containing induction therapy. Often we will include lenalidomide and
dexamethasone (thus RVD) as induction therapy in this setting. We would
recommend transplantation and consider bortezomib maintenance following
transplantation. The CALGB study has yet to evaluate lenalidomide
maintenance therapy in the subset of t(4,14) patients, thus lenalidomide
maintenance is also acceptable.
Martha Q. Lacy, MD
I agree, t(4;14) patients have high remission rates with
bortezomib. We would likely go with a bortezomib-based regimen and
advocate bortezomib maintenance.
Elizabeth Bilotti, MSN, RN, APN
As the patient opted not to receive maintenance therapy, I
would not recommend any changes in monitoring or assessments. However,
had this cytogenetic information been available at the time of
diagnosis, we would have likely recommended bortezomib as part of
induction therapy. At relapse, we would opt for a combination regimen,
with a bortezomib backbone, and, under the current renal circumstances,
would choose VCD (bortezomib, cyclophosphamide, and dexamethasone).
tougher case
==================================================
Martha Q. Lacy, MD
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota
This patient has intermediate/high-risk molecular markers consisting of the t(4;14), high beta-2 microglobulin,
and a short duration of response following ASCT. Patients with the
t(4;14) translocation have high response rates to bortezomib, so we
prefer starting with a bortezomib-based regimen. If no maintenance
therapy is given after the ASCT, remission duration is generally short.
In addition, we would prefer bortezomib-based maintenance therapy for
this patient. The choice to use bortezomib, 1 dose every other week, as
maintenance is based on the HOVON-65/GMMG-HD4 trial that showed patients receiving bortezomib maintenance had improved PFS and OS.1 Since
the remission was a fairly short duration (< 12 months), we at Mayo
favor switching class to an immunomodulatory agent-based regimen. A
second ASCT generally would not be performed if the first remission was
less than 12 months.
This patient is now dual refractory, and historical outcomes
for this patient type are poor. Data by Kumar and colleagues found that
in 286 multiple myeloma patients refractory to bortezomib and relapsing following, refractory
to, or ineligible to receive lenalidomide or thalidomide, the median OS
was 9 months and median event-free survival was only 5 months.2 Recently, carfilzomib
was approved for patients who have failed at least 2 prior therapies
including bortezomib and an immunomodulatory agent. In a phase II trial
of heavily pre-treated myeloma, carfilzomib monotherapy resulted in 20%
overall response rate with a 7.4-month median duration of response in
214 bortezomib and lenalidomide refractory/intolerant patients. In
addition to carfilzomib, a clinical trial would also be a reasonable
approach for this patient.3 Agents in late stage trials
include combination therapy and the immunomodulatory agent,
pomalidomide, which produced a 26-29% response rate in patients
refractory to both bortezomib and lenalidomide.4 Alkylating agents may also be considered for this dual refractory patient.
Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California
Mrs Anderson initially presented with high-risk disease based on high beta-2 microglubulin,
complex cytogenetics, and FISH (+) for t(4,14). She was appropriately
treated with a bortezomib-containing regimen and went on to receive an
ASCT. Unfortunately, she relapsed within 1 year of transplant, which
suggests very aggressive disease and poor OS. She was treated
appropriately with salvage RVD but only enjoyed remission for
approximately 5 months. At this point, one could consider using
carfilzomib since the patient has received 2 prior regimens including
both an immunomodulatory agent and proteasome inhibitor. Data recently
published in Blood suggests an anticipated response rate of 23.7% and median duration of response of approximately 8 months.1
A clinical trial would also be an excellent option for this patient.
Aggressive chemotherapy including alkylator-based therapy like hyperCAD
or PACE could also be considered in a robust patient.Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California
When is a second transplant indicated?
Thomas G. Martin III, MD
Patients who clearly benefit from second autologous stem cell
transplant (ASCT) are those who enjoy a remission duration longer than
24 months. Patients achieving a remission duration less than 12 months
should not be considered for second transplant. Patients who achieved
remission following ASCT between 12 and 24 months fall in the grey zone
and should be considered for second transplant on a case by case
basis. Obviously, patients should have good performance status and be
in remission (chemoresponsive) at the time of second transplant.
Elizabeth Bilotti, MSN, RN, APN
At this time, the indication for a second transplant, outside
of a novel conditioning regimen on protocol, would not be
recommended. The patient got less than 12 months remission out of the
first transplant, presumably when the disease would be more sensitive.
Martha Q. Lacy, MD
If you chose a clinical trial for this patient, what agents would you focus on?
Thomas G. Martin III, MD
The 2 most promising drugs on the horizon are carfilzomib and
pomalidomide. I would focus on clinical trials that include one or both
of these 2 agents. Impressive preliminary results were presented by Dr
Richardson at ASCO 2012 utilizing a novel naked anti-CD38 monoclonal
antibody.1 To date monoclonal antibody therapy for myeloma
has had limited success but these agents may be more potent when
combined with immunomodulatory agents.2 A number
of phase II and III trials are now underway evaluating the potency of
these new monoclonal antibodies. Additional studies combining proteasome
inhibitors to mTOR, AKT, and HDAC inhibitors are underway and may
demonstrate positive results.
Elizabeth Bilotti, MSN, RN, APN
In evaluating clinical trials we would focus on
pomalidomide, a combination regimen that includes carfilzomib,
monoclonal antibodies, and AKT inhibitors.1
Katherine Sanvidge Shah, PharmD, BCOP
Our team would likely focus on novel agents with potential
mechanisms differing from those she has seen previously such as the
monoclonal antibody, elotuzumab (in combination with agents such as
lenalidomide and dexamethasone). We would avoid agents known to cause or
worsen PN as this patient has experienced grade 2 PN previously. Also,
though now FDA-approved for the treatment of myeloma, I would also
consider phase II or III carfilzomib combination trials (± lenalidomide,
pomalidomide, dexamethasone, etc) trials as most patients do not
experience new onset or worsening of their PN. One could also consider
AKT or HDAC investigational agents.
| CERTIFICATE OF | |
| CONTINUING EDUCATION | |
| AMA PRA Category 1 Credit(s)™ | |
| Educational Concepts Group, LLC verifies that | |
| Mutombo Kankonde, MD | |
| has participated in the enduring material titled | |
| Optimizing Care for Patients with Relapsed/Refractory Multiple Myeloma | |
| on 20-Jan-13 and is awarded 1 AMA PRA Category 1 Credit(s)™ |
|
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NOMENCLATURE OF GENES INVOLVED IN THE 3RD LAW.
1.BIRC5 A CELL CYCLE GENE MAKING A PROTEIN REGULATOR OF CELL CYCLE AND APOPTOSIS MODULATION, SURVIVIN, IN BREAST CANCER IT IS A VALIDATED BAD PROGNOSIS INDICATOR.
2. BUB1
BUDDING UNINHIBITED BENZIMIDAZOLES 1
A SERINE THREONINE PROTEIN KINASE IMPORTANT A CHECK POINT.
LISTEN TO THIS, MUTATION OF BUB1 CAUSES ANEUPLOIDY, CHROMOSOME INSTABILITY AND PREMATURE SENESCENCE
DOES THIS SOUND LIKE A TARGET, I BET YOU!
3. CCNB1
WIKEPEDIA SUGGESTS:
"
Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34(cdc2) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript, that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.[2]
Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly."
IF YOU DON'T SEE A TARGET HERE, CLOSE YOUR EYES!
CYCLIN B1 BEING AT THE "SWITCH" IS THE LATCH OF THE EXIT DOOR TOWARD CELL PROLIFERATION. PRESENCE OF CYCLIN B1 COULD SIGNAL MALIGNANT PROLIFERATION.
4.CDC, CELL DIVISION CYCLE------MCM2 (TO BE CONTINUED)
1.BIRC5 A CELL CYCLE GENE MAKING A PROTEIN REGULATOR OF CELL CYCLE AND APOPTOSIS MODULATION, SURVIVIN, IN BREAST CANCER IT IS A VALIDATED BAD PROGNOSIS INDICATOR.
2. BUB1
BUDDING UNINHIBITED BENZIMIDAZOLES 1
A SERINE THREONINE PROTEIN KINASE IMPORTANT A CHECK POINT.
LISTEN TO THIS, MUTATION OF BUB1 CAUSES ANEUPLOIDY, CHROMOSOME INSTABILITY AND PREMATURE SENESCENCE
DOES THIS SOUND LIKE A TARGET, I BET YOU!
3. CCNB1
WIKEPEDIA SUGGESTS:
"
Cyclin B1 is a regulatory protein involved in mitosis. The gene product complexes with p34(cdc2) to form the maturation-promoting factor (MPF). Two alternative transcripts have been found, a constitutively expressed transcript and a cell cycle-regulated transcript, that is expressed predominantly during G2/M phase of the cell cycle. The different transcripts result from the use of alternate transcription initiation sites.[2]
Cyclin B1 contributes to the switch-like all or none behavior of the cell in deciding to commit to mitosis. Its activation is well regulated, and positive feedback loops ensure that once the cyclin B1-Cdk1 complex is activated it is not deactivated. Cyclin B1-Cdk1 is involved in the early events of mitosis such as chromosome condensation, nuclear envelope breakdown, and spindle pole assembly."
IF YOU DON'T SEE A TARGET HERE, CLOSE YOUR EYES!
CYCLIN B1 BEING AT THE "SWITCH" IS THE LATCH OF THE EXIT DOOR TOWARD CELL PROLIFERATION. PRESENCE OF CYCLIN B1 COULD SIGNAL MALIGNANT PROLIFERATION.
4.CDC, CELL DIVISION CYCLE------MCM2 (TO BE CONTINUED)
Monitoring Circulating Tumor Cells with the Cellsearch® System Can Predict Prognosis in Metastatic Breast Cancer
New Study Reinforces Important Role of Integrating Therapeutic Monitoring Tools Raritan, NJ (July 13, 2009) – Measuring the change in circulating tumor cell (CTC) count can accurately predict the prognosis and survival in patients with metastatic breast cancer (MBC), according to a newly published report in the July 10 issue of the Journal of Clinical Oncology. The retrospective study compared how well CTCs and a more sensitive than conventional modality, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), predicted survival in MBC patients on standard therapies. The comparison showed that both technologies significantly correlate to overall MBC patient survival (p<0.001 for CTCs and p=0.001 for FDG-PET/CT). However, a CTC count of five or more could better predict the prognosis and survival in MBC patients.The CellSearch® System is the first 510(k) diagnostic test used to automate the capture and detection of CTCs, tumor cells that have detached from solid tumors and entered the patient’s blood.
“Measuring CTCs in metastatic breast cancer patients provides oncologists with an additional tool to help us better monitor patient outcomes,” said one of the lead authors, Dr. Massimo Cristofanilli*, associate professor in the Department of Breast Medical Oncology at The University of Texas M. D. Anderson Cancer Center. “The CellSearch® CTC test provides an early indication about patients’ disease progression and overall survival.”
CTCs and FDG-PET/CT are two of the most promising new tools for therapeutic monitoring in patients with MBC. The number of CTCs identified in patients with MBC is related to patient prognosis; a high number of CTCs at any time during treatment is associated with poor prognosis.
“Veridex is committed to providing oncologists with high-value in vitro diagnostic solutions, such as the CellSearch® CTC test, to help them make informed patient care decisions,” said Ken Berlin, general manager of Veridex. “This study demonstrates the utility of integrating the CellSearch® CTC test in therapeutic monitoring of patients with metastatic disease.”
Study Design
A retrospective study was performed on 115 patients with MBC who had the CellSearch test performed as part of their initial staging process at M.D. Anderson over a three-year period. CTC count and FDG-PET/CT imaging were performed at baseline in 102 evaluable patients before starting a new therapy and then again at the midpoint of their therapies (9 - 12 weeks). Patients outcomes were categorized according to midtherapy CTC counts as favorable (< five CTCs/7.5 mL blood) or unfavorable (≥ five CTCs/7.5 mL blood). Based on FDG-PET/CT, patients were considered responders if metabolic activity of target lesions decreased more than 25% compared to baseline, and if there was no change or a decrease in size. Patients were considered nonresponders if the FDG uptake was similar or higher and/or if target lesions had increased in size. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival.
Study Findings
A total of 115 patients with metastatic breast cancer were considered for the study and 102 were evaluable for efficacy. The median overall survival time was 14 months (range, 1 to > 41 months). In univariate analysis, both midtherapy CTC counts and FDG-PET/CT response predicated overall patient survival (p<.001 and p=.001, respectively). The overall concordance between the CTC counts at midtherapy and FDG-PET/CT was 67% for response/nonresponse and 74% for progression/nonprogression. In the discordant category, detection of five or more CTCs during therapeutic monitoring accurately predicted prognosis in MBC beyond metabolic response. FDG-PET/CT was able to predict outcome in discordant instances of patients with less than five CTCs at midtherapy. Midtherapy CTC levels remained significant in a multivariate analysis (p=.004). These results suggest a higher and independent predictive value of CTCs compared with FDG-PET/CT among patients with a CTC count of five or more. In addition, there was a strong correlation between complete response and the absence of significant levels of CTCs (median CTC level zero).
* Dr. Cristofanilli is a principal investigator for a CellSearch® validation study and received honoraria from Veridex, LLC.
About CellSearch®
The CellSearch® test works by using antibodies that are joined to microscopic iron particles, called ferrofluid. These antibody/ferrofluid combinations attach very specifically to CTCs. Powerful magnets then draw the CTCs out of the blood sample and they are then stained with additional bio-molecules and chemicals so that they can be positively identified as CTCs.
CellSearch® test results should be used in conjunction with all clinical information derived from diagnostic tests (e.g., imaging, laboratory tests), physical examination and complete medical history in accordance with appropriate patient management procedures. For further information on intended use, warnings and limitations, please refer to the CellSearch® CTC Test Instructions for Use, or visit www.veridex.com.
About Veridex, LLC
Veridex, LLC, a Johnson & Johnson company, is an organization dedicated to providing physicians with high-value in vitro diagnostic oncology products. Veridex's products may significantly benefit patients through earlier disease detection and may enable personalized strategies to help improve patient management and outcomes. For more information, visit www.veridex.com.
# # #
from Johnson and Johnson site!
IN METASTATIC DISEASE THAT IS ADVANCED, ONE OF THE GENE MENTIONED IS THE NME1/NM23A
This gene (Non Metastatic Cell 1) is expressed at 17q21.3 and produces protein NM23A.Contrary to its name, it is noted to be expressed in advanced Metastatic disease and as such could have prognosis indication.
Remember, there is that notion that if a Molecule found in Metastatic state is present in the early stage of a cancer, it is predictive of more advanced cancer, higher recurrence rate and higher mortality risk.
Remember, there is that notion that if a Molecule found in Metastatic state is present in the early stage of a cancer, it is predictive of more advanced cancer, higher recurrence rate and higher mortality risk.
CPRIT BACK IN THE NEWS!
IN AN INTERVIEW JUST FEW DAYS AGO WITH THE HOUSTON CHRONICLE,
Governor Perry was wrongfully condemned and attacked by the newspaper when he stated: "CPRIT' job is not just to fight cancer, but to create economic avenues from which wealth can be created". At CRBCM we believe that any investment does that. And investment in health does create wealth no matter how you want to sugar coated it. They are Cities across the country which would be empty without health enterprise money. Fighting cancer is a noble thing but fighting cancer and changing lives by creating opportunities is even better. You can't advance this noble cause without putting brains to work. When you pay brains to work you create opportunities and wealth whether you like it or not. The wrong way to invest however is to become biased, distributing the wealth to Universities exclusively and their cronies at each CPRIT fund allocation sessions. And all this based on assumptions that Universities are the only media of scientific research. We argue that CPRIT can create scientific research in new locations as long as qualified people can be hired to do the work. Universities have funds from their vast pool of donors. They should be the number one beneficiaries we agree, but not the only one. Also the distribution of wealth should not exclude some cities, Biotech companies benefiting from grant should not locate only to Houston, Dallas or Austin. That's the argument El Paso, the fourth city (population wise) in this State, is making! So yes CPRIT should improve its policy. New requirements need to be put in place to allow a fairness in this system! And a bigger pool of beneficiaries is called for to expand the pool of ingenuity in the race for cancer cure
=============================================================
Referenced Article
IN AN INTERVIEW JUST FEW DAYS AGO WITH THE HOUSTON CHRONICLE,
Governor Perry was wrongfully condemned and attacked by the newspaper when he stated: "CPRIT' job is not just to fight cancer, but to create economic avenues from which wealth can be created". At CRBCM we believe that any investment does that. And investment in health does create wealth no matter how you want to sugar coated it. They are Cities across the country which would be empty without health enterprise money. Fighting cancer is a noble thing but fighting cancer and changing lives by creating opportunities is even better. You can't advance this noble cause without putting brains to work. When you pay brains to work you create opportunities and wealth whether you like it or not. The wrong way to invest however is to become biased, distributing the wealth to Universities exclusively and their cronies at each CPRIT fund allocation sessions. And all this based on assumptions that Universities are the only media of scientific research. We argue that CPRIT can create scientific research in new locations as long as qualified people can be hired to do the work. Universities have funds from their vast pool of donors. They should be the number one beneficiaries we agree, but not the only one. Also the distribution of wealth should not exclude some cities, Biotech companies benefiting from grant should not locate only to Houston, Dallas or Austin. That's the argument El Paso, the fourth city (population wise) in this State, is making! So yes CPRIT should improve its policy. New requirements need to be put in place to allow a fairness in this system! And a bigger pool of beneficiaries is called for to expand the pool of ingenuity in the race for cancer cure
=============================================================
Referenced Article
Mission creep
CPRIT is supposed to help find treatments for cancer, not 'create wealth.'
Saturday, January 19, 2013
FOLLOWING UP ON THE 3RD LAW. (SWING OF THE PENDULUM)
WITH CELL DIFFERENTIATION AT ONE EXTREME, AND CELL PROLIFERATION AT THE OTHER SIDE. During Malignant transformation, the pendulum swings from de-differentiation to proliferation. Pushing the EXIT-door open. At the molecular level, there is an increased expression of genes involved in promoter regulation (TTK, E2F1), but also a gene is involved with the resumption of mitotic phases BUB1, MCM2,CDC. Microfilament formation and Histone related molecules also reappear ((NUSAP1,ZWINT,CENPA), but also CEP55, CKAP). Activity at the promoter region is proven by overexpression of EZH. Relevent cyclins involved are proven by activation of CDKN2 . Over-expression of any combination of these genes marks the first sign of a Cancerous trend in a differentiated cell.
Of all these, E2F1 and NUSAP-1 seem to be the focus of target therapy as interactions with HMGA are suggested in the literature!
Of all these, E2F1 and NUSAP-1 seem to be the focus of target therapy as interactions with HMGA are suggested in the literature!
THIRD LAW OF NATURE, NO PROLIFERATION AND CONCURRENT DIFFERENTIATION. HOW THIS LAW CAN BE USED FOR CANCER CURE
While the first and second law refer to the well being of the nucleus for protection of the cell division and its integrity, the 3rd law pertain to cell differentiation. Basically the first law say that if DNA is altered, cell need to be stopped to allow correction. And the powerful P53 Activation has been put in place for that. Significant alteration of DNA will send powerful signal to P53, cause itS activation, and lead to cell cycle arrest. This is where the power of Cisplatin based combinations reside. And sure enough, this the basis of the notion that strong repair system will weaken this type of drug. The all notion of Microsatellite Instability and its role in cancer is based on this law.
The 2nd law, is significant destruction of the scaffold of Mitosis, the Microtuble and all actinic or actinic like molecules which makes mitosis impossible should lead to cell destruction no matter what. The intergrity of this system of Microtubule and filament not only control the critical phases of Mitosis (Metaphase, Anaphase), it control the integrity of membrane but also the cytoskeleton and cell mobility. It is the nervous system of the cell and the control of various anchors. Organelles of the cell are not just free flowing in general, they are anchored to the Reticulum membrane most of the time (unless destined to Autophagia for cell preservation) and important Molecules involved in Apoptosis such as Cytochrome are attached to Mitochondrial membranes. Suffice is to say that major alteration to these line of proteins will bypass major Cytosol based protection including the Bcl-2. This is the strenghth base of Taxol and Ixabepilone. It is the explanation for neuropathy and cardiac toxicity of Adriamycin. It is partially the explanation of Q-T prolongation etc.
The 3rd law is more complex, cell differentiation should not go with full proliferation. Cell that are fully differentiated should not be multiplying like crazy. and for sure, we do not want hundred of livers, 3 brain or 99 lungs. Have wonder why Atypia goes along with cancer transformation. Well you have to lose differentiation to restart multiplying again! And the poorly differentiated, the worse the magnitude of cancer.
The story of differentiation goes like this:
All cells have the same genome. But based on their position, internal and external stimuli, they will go one way or the other to specialize in a certain function for tissue and organ specialty. The external stimuli could be a change of Oxygen content, Ph, or messages from your neighbor cells sending growth messages etc. Internal stimuli are cytokines, morphogens, growth factors and signaling molecules or intracellular particulates. These will stimulate Receptors or pathways (such as the NF-kB) and cause genetic and epigenetic consequences in the Nucleus. Expression of genes which the cell want and need to be specialized will be achieved through heavy duty transcription of genes. On the other hand, to control the uniqueness of the tissue, epigenetic closure of multiplying capability genes is first completed to seal the deal on the fate of the cell. Differentiation is like an EXIT door. you can enter, but don't try coming back. And once you enter, immediately you are taking care by the transcription machinery directing you to where you should be going and you lose multiplication ability. The door however is not fully irreversibly closed. In cancer the flow of force reverse and instead of moving forward, the door is reopen and the differentiation machinery is reversed or disabled (poor differentiation), the door is reopen, and the cell start to multiply again as part of the cancerous process. Studies of Estrogen effect Vs Progesterone has shed some light in this case. When one look at estrogen, it has more effect on the Exit door, constantly pushing that door toward Multiplication than Progesterone that has little effect of the door but with similar effect on the terminal differentiation. Making Estrogen more cancer inducing than progesterone. Yes taking Estrogen gives you the relief of symptoms but it is the push toward reversing the Exit door flow (toward proliferation transcription) that is the problem!
Is expression of H3K or FG2 the markers of Exit door tinkering, we are working hard to determine this.
AS ONE LOOK AT THIS FLOW TOWARD DIFFERENTIATION, A SLEW OF THERAPEUTIC TARGETS EMERGE, THE ARRAY GOES FROM :
1. NEIGHBOR MESSAGES
2. ENVIRONMENT CHANGES
3. BLOCKING RECEPTOR UPSTREAM THE NF-kB AND COMPARABLE PATHWAYS
4. BLOCKING THE PATHWAYS
5. SEALING THE DOOR
6. METHYLATION OF GENES, AND PARALYZING OR MODULATING ENZYMES INVOLVED IN EPIGENETIC CHANGES (PCAF, p300 MAY BE)
7. BLOCKING TRANSCRIPTION MACHINERY, EXPRESSION OR GENES DIRECTLY.
CERTAINLY, SIGNS OF RESUMPTION IN ACTIVITY OF GENES MEANT FOR PROLIFERATION IS AN EARLY SIGN OF CANCEROUS TRANSFORMATION, AND The BEST WAY TO DETERMINE THAT A DRUG IS CANCER PRODUCING.
AS A MATTER OF FACT, THIS IS HOW PAMIDRONATE AND OTHER BIPHOSPHONATE ACT TO CONTROL CANCER, BY INCREASING DIFFERENTIATION AND RELIEVING PRESSURE ON THE EXIT DOOR.
WELL DIFFERENTIATED TUMORS WILL HAVE A BETTER PROGNOSIS BECAUSE THEIR GENERAL FLOW OF FORCE IS STILL TOWARD DIFFERENTIATION AND NOT THROUGH THE PROLIFERATION DOOR .
WE ARE WORKING HARD AT CRBCM!
The 2nd law, is significant destruction of the scaffold of Mitosis, the Microtuble and all actinic or actinic like molecules which makes mitosis impossible should lead to cell destruction no matter what. The intergrity of this system of Microtubule and filament not only control the critical phases of Mitosis (Metaphase, Anaphase), it control the integrity of membrane but also the cytoskeleton and cell mobility. It is the nervous system of the cell and the control of various anchors. Organelles of the cell are not just free flowing in general, they are anchored to the Reticulum membrane most of the time (unless destined to Autophagia for cell preservation) and important Molecules involved in Apoptosis such as Cytochrome are attached to Mitochondrial membranes. Suffice is to say that major alteration to these line of proteins will bypass major Cytosol based protection including the Bcl-2. This is the strenghth base of Taxol and Ixabepilone. It is the explanation for neuropathy and cardiac toxicity of Adriamycin. It is partially the explanation of Q-T prolongation etc.
The 3rd law is more complex, cell differentiation should not go with full proliferation. Cell that are fully differentiated should not be multiplying like crazy. and for sure, we do not want hundred of livers, 3 brain or 99 lungs. Have wonder why Atypia goes along with cancer transformation. Well you have to lose differentiation to restart multiplying again! And the poorly differentiated, the worse the magnitude of cancer.
The story of differentiation goes like this:
All cells have the same genome. But based on their position, internal and external stimuli, they will go one way or the other to specialize in a certain function for tissue and organ specialty. The external stimuli could be a change of Oxygen content, Ph, or messages from your neighbor cells sending growth messages etc. Internal stimuli are cytokines, morphogens, growth factors and signaling molecules or intracellular particulates. These will stimulate Receptors or pathways (such as the NF-kB) and cause genetic and epigenetic consequences in the Nucleus. Expression of genes which the cell want and need to be specialized will be achieved through heavy duty transcription of genes. On the other hand, to control the uniqueness of the tissue, epigenetic closure of multiplying capability genes is first completed to seal the deal on the fate of the cell. Differentiation is like an EXIT door. you can enter, but don't try coming back. And once you enter, immediately you are taking care by the transcription machinery directing you to where you should be going and you lose multiplication ability. The door however is not fully irreversibly closed. In cancer the flow of force reverse and instead of moving forward, the door is reopen and the differentiation machinery is reversed or disabled (poor differentiation), the door is reopen, and the cell start to multiply again as part of the cancerous process. Studies of Estrogen effect Vs Progesterone has shed some light in this case. When one look at estrogen, it has more effect on the Exit door, constantly pushing that door toward Multiplication than Progesterone that has little effect of the door but with similar effect on the terminal differentiation. Making Estrogen more cancer inducing than progesterone. Yes taking Estrogen gives you the relief of symptoms but it is the push toward reversing the Exit door flow (toward proliferation transcription) that is the problem!
Is expression of H3K or FG2 the markers of Exit door tinkering, we are working hard to determine this.
AS ONE LOOK AT THIS FLOW TOWARD DIFFERENTIATION, A SLEW OF THERAPEUTIC TARGETS EMERGE, THE ARRAY GOES FROM :
1. NEIGHBOR MESSAGES
2. ENVIRONMENT CHANGES
3. BLOCKING RECEPTOR UPSTREAM THE NF-kB AND COMPARABLE PATHWAYS
4. BLOCKING THE PATHWAYS
5. SEALING THE DOOR
6. METHYLATION OF GENES, AND PARALYZING OR MODULATING ENZYMES INVOLVED IN EPIGENETIC CHANGES (PCAF, p300 MAY BE)
7. BLOCKING TRANSCRIPTION MACHINERY, EXPRESSION OR GENES DIRECTLY.
CERTAINLY, SIGNS OF RESUMPTION IN ACTIVITY OF GENES MEANT FOR PROLIFERATION IS AN EARLY SIGN OF CANCEROUS TRANSFORMATION, AND The BEST WAY TO DETERMINE THAT A DRUG IS CANCER PRODUCING.
AS A MATTER OF FACT, THIS IS HOW PAMIDRONATE AND OTHER BIPHOSPHONATE ACT TO CONTROL CANCER, BY INCREASING DIFFERENTIATION AND RELIEVING PRESSURE ON THE EXIT DOOR.
WELL DIFFERENTIATED TUMORS WILL HAVE A BETTER PROGNOSIS BECAUSE THEIR GENERAL FLOW OF FORCE IS STILL TOWARD DIFFERENTIATION AND NOT THROUGH THE PROLIFERATION DOOR .
WE ARE WORKING HARD AT CRBCM!
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