RECURRENT LIPOSARCOMA

The other day we were in a conference discussing a case of Liposarcoma.  The man was in his 50ies and had been referred to the University surgeon for an extensive abdominal Liposarcoma that needed further resection. The disease had been resected at least twice by the community surgeon before, it had returned with significant peritoneal and pelvic infiltration.  Interval between resections had been in years, but now it was in months.  Clearly, the disease has packed further gene abnormalities now that it is evidently metastatic.  Let me take this back, because despite the widespread invasion in the abdomen, there was no tissue invasion.  There were no clear liver, lung or brain invasion.  This disease was killing a man before our eyes because of clear infiltration of abdominal tissues.
Because of the interval between surgeries, the Oncologist argued that this is a low grade tumor and may not be handled with standard chemotherapy and I strongly believe he was right.  My case with Angiosarcoma did not budge with Gemzar, Taxol followed by MAID,  I am trying AVASTIN ALONE now!
But returning to the case, the hospital and the surgery department are now breathing on the neck of the surgeon because they do not see the point of putting the patient through very expensive surgeries followed by  costly ICU stays every few months. I guess there are potential liabilities linked to the exercise. Particularly because the surgeries were done when this patient was with evident big progression of disease, but asymptomatic still.   Oncologist and Surgeon alike argued we should not wait for symptoms, because it could be inoperable by then, and an aggressive surgery plan is helpful in these local diseases.
With standard chemotherapy out the only thing left is Target therapy as an effective option.  We did not get help from the pathology department since no genetic abnormality testing is done (this is not Mayo or Harvard.  DR KRIS who speaks of gene panels in lung cancer does not live here).  And Votrient, the only  FDA approved drug is indicated in those who failed chemotherapy.  Basically, you have to put this man on chemotherapy that you know will harm him unnecessarily in order to get to Votrient (Pazopanib), an anti-VEGFR(s), Anti-c-KIT, anti-PDGFR a/Beta.  with 3-4 months advantage over placebo.
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FDA NEWS RELEASE

For Immediate Release: April 26, 2012
Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov
Consumer Inquiries: 888-INFO-FDA
FDA approves Votrient for advanced soft tissue sarcoma
The U.S. Food and Drug Administration today approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.
Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.
A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.
“Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas.”
The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.
The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.
Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.
Votrient was granted an orphan drug status designation for this indication. An orphan designation is given to a drug intended to treat a disease affecting fewer than 200,000 patients in the United States. Votrient was first approved in October 2009 for the treatment of advanced kidney cancer.

Votrient is marketed by GlaxoSmithKline of Research Triangle Park, N.C.
For more information:
FDA: Office of Hematology and Oncology Products
FDA: Approved Drugs: Questions and Answers
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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For the sake of argument

1. In this man we know it is a Liposarcoma

therefore the primary deficiency is in the handling of lipid.  Insulin Receptor, may be?  IGFR, IGFBP, PPR1. CCR11
(GOT TO RUN TO CONFERENCE WITH XCENDA IN CHICAGO---TO BE CONTINUED!)

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INTERESTING DEBATES

1.NF1 Mutation is upstream from
BRAF
and MTOR
But NF-1 is Mutated in Melanoma
can infusion of protein resulting from NF-1 be used to strengthen effect of MTOR inhibitor and BRAF inhibitor by maintaining these pathways open!

2.  Discriminating Redundancy in cellular language
same gene base corresponding to same Amino Acid
same receptors at membrane being sensitive by different stimuli
but when it comes to the RAS, nature and intensity need to matter and this also a function of tissue involved!
some time however the nature of the stimulus is more important particularly inside the cell where ie HP90 seems to stimulate more the CoN to achieve PTEN suppression. And you know that CoM stimulation raise Bcl2 level...we will say more in our upcoming article of langaue of the cell as it pertains to pathways!

3. PTEN is repressed by low expression of gene or mislocalization (reported PNUTS 'role) at Nuclear level or both?

CHANGES ARE COMING TO YOU, LIKE IT OR NOT!

SOME PEOPLE REALLY BELIEVE THEY ARE THEY TOO BIG FOR CRITICISM, THEY FEEL OFFENDED WHEN YOU CONFRONT THEM WITH A TRUTH THEY CAN'T BELIEVE.
Everyday Big professors are reminded how important they are by our praises and regular consultations.  Professors grow on us because they have knowledge we believe to be the truth, and because often they are right rather than wrong.  But every time they are solicited, they practice a certain logic they have perfected to come to a logical conclusion.  They pass on this logical process to their students and friends and, as a result, a university culture is created and passed on!  Such a system, however, needs to be challenged once in a while to be made better.  It is made better when it accepts change, because accepting new plausible changes prepares us to wider sorts of challenges, it is the strength of diversity, it prepares us against challenges to come, challenges we will have to reckon with at one point or another. It is the strength of these United States. It is why this country is better prepared than other countries which is somewhat monolithic, culture wise!

When monolithic systems are confronted, when our professors are confronted and when they refuse to face the truthful difference, they reject it with anger and become defensive and somewhat violent (not necessarily physical violence) in their tone.
I was in a recent meeting where I suggested to an eminent oncologist that we look into potential new targeting therapy for a rare type of sarcoma.  An eminent man who I admire became irate or vexed at an unexpected level which surprised me.  It is the truth that everyone nowadays should be looking to target therapy for answers in cancer.  But his reaction was off the wall!   I can understand that evidence based medicine forces us to argue only what has been proven,  but in a university setting, the non-proven should challenge us to look for more, it should be where we start if the goal is to push the envelope further.  I don't know what was in the man's drink to be so offended by the truth we all face, the puzzle that is cancer. I don't know under what "University environment" political pressure he finds himself, so I give him a break, give him slack !  He was just defending his turf !

But one thing for sure, let's be more receptive to change, because it will come, and impose on us whether we like it or not!  You can resist it for a while, but one of these days even your own son or a dear friend will wake you up to it!

CABOZANTINIB

	COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET, and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.

COMETRIQ was approved based on a pivotal trial in metastatic MTC patients (N=330) who were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry.

• Significantly prolonged progression-free survival (PFS) vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) — Median PFS was 11.2 months with COMETRIQ vs 4.0 months with placebo • Objective response rate (ORR) was 27% with COMETRIQ vs 0% with placebo (P<0.0001) — Median duration of tumor response was 14.7 months (95% CI: 11.1, 19.3) • Adverse reactions occurring in ≥25% of patients treated with COMETRIQ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.

Exelixis® Access Services comprehensive support program* For you and your patients — call 1-855-253-EASE (1-855-253-3273) 8:00 am to 11:00 pm ET, Monday to Friday

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IMPORTANT SAFETY INFORMATION

	BOXED WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.

ADDITIONAL IMPORTANT SAFETY INFORMATION Gastrointestinal (GI) perforations (3%) and GI fistulas (1%), all serious, were reported with COMETRIQ, including 1 (<1%) fatal GI fistula. Non-GI fistulas including tracheal/esophageal were reported (4%), including 2 (1%) fatal events. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.

Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher with COMETRIQ (3%) than with placebo (1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.

Increased incidence of thrombotic events (venous thromboembolism: 6% vs 3%; arterial thromboembolism: 2% vs 0%) was reported with COMETRIQ vs placebo, respectively. Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.

Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ ≥28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.

Increased incidence of treatment-emergent hypertension, stage 1 or 2 (modified JNC† criteria), was identified with COMETRIQ (61% vs 30% with placebo). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.

Osteonecrosis of the jaw (ONJ) occurred with COMETRIQ (1%). ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for ≥28 days prior to scheduled surgery, if possible.

Palmar-plantar erythrodysesthesia syndrome (PPES) occurred (50%) with COMETRIQ and was severe (Grade ≥3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.

Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome, compared with 0 patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.

Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.

COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.

COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.

The COMETRIQ dose was reduced in 79% of patients vs 9% for placebo.

†Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

For the full Prescribing Information, including Boxed Warning, please click here.

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		© 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080     02/13     [03-13-00043-B]

Challenge with diet and food supplements

It is nice to understand the potential activity or mechanism of action of food supplements and act on it. Example: "Vitamin C: MedlinePlus Medical Encyclopedia

www.nlm.nih.gov/medlineplus/ency/article/002404.htm

Function. Vitamin C is needed for the growth and repair of tissues in all parts of your body. It is used to: Form an important protein used to make skin, tendons, ..."

That knowledge empowers you and helps you take action.  You run to the store and buy a good supply of vitamin C and take it for now and the future.  What the information can not tell you is just as important.  How much Vitamin C you need to actually have the benefit described? How long you should be doing this?  Is your body just getting rid of the extra or all of it?  Based on your chromosome heterogeneity, was it safe for you to have done it?  Are you missing a critical enzyme to process the vitamin?
The NIH is finding out that things that are promised by food supplements, when put to the test and scientific scrutiny, do not deliver a clearly evident output.  "Taking an apple a day" (low methionine food item) will prolong your life.  While the scientific evidence as to how this is possible is established:  Does it really happen? No.  Why? Because what is left out is even more important.  How many apples  a day should you eat, what type of apple, what else should accompany this practice to make this goal achievable (low calory diet)? And so on and so forth. We all know that food supplements can impact some of the signal transduction pathways in our cells and, as a result, they could potentially impact our lives in some beneficial ways.  But is it safe to constantly be bothering our signal transduction pathways?  Do you believe it is right to do so constantly?  Who said this pathway needs to be switched on all the time?  What guarantees you that the body will not respond and shut it off anyway as it always reacts to action that we deliberately impose upon it!
Keeping a pathway on all the time may impact another pathway all the time, and if you just happen to have the wrong gene for this particular game, you may start on some road you should not be on!  So please, just because it may make sense, it does not yet mean that it is true and relevant for YOU! 

ACTIVITY AT THE CRBCM:

*WAITING FOR IRS TO FINALIZE ITS WORK INVOLVING THE CRBCM.  THIS WILL BE APPRECIATED, REALLY.
*WE HAVE SUBMITTED ON TIME 3 LETTERS OF INTENT (LOI) FOR RESEARCH WORK
FOR ONCE NOW WE HAVE A LOT OF SUPPORT FROM THE  NIH.
*REPORTING TO CHICAGO FOR UPDATE IN CANCER TREATMENT CONFERENCE, WILL GIVE YOU ALL KIND OF REPORTS FROM THIS CONFERENCE. THIS IS DATA MINING.
(CRBCM IS ON THE MOVE)
*WILL START FIELD WORK FOR 4 WEEKS.
*BY THE WAY, THE MD ANDERSON HAS AGREED TO SEE OUR PATIENT WITH METASTATIC PENILE CANCER.  THANKS!