Freedom of Information worked one more time!

The revelation that Dabigatran (Pradaxa) level should be monitored to reduce bleeding risk
has shaken the medical community.   greed has once again obfuscated the truth.  The makers of the drug
have hidden the solemn truth, you got to keep a level per Crystal Phend: "Boehringer Ingelheim determined that keeping plasma levels within the optimal 40-to-200 ng/mL range could cut bleeding risk by up to 20% compared with unadjusted use and by 40% compared with well-controlled warfarin (Coumadin) without sacrificing effectiveness in cutting risk of ischemic stroke in atrial fibrillation."

This is just disappointing that once again, greed may have won over patient safety!  Someone please come to me with proof to the contrary before I protest vigorously!

Miscellaneous updates

1.Watch out now with patient being readmitted for a new cycle of chemotherapy may be counted as a readmission...the EHR has been diagnosed to make this mistake!
2.Is it true that the only people who like CERNER are the hospital administrators because of its instant billing feature!
3.Is it true that the Practice of "Time out" for last checks reduces Medical errors?

In Breast cancer:
===========
1.Salsa Trial:  10 years for Tamoxifen in adjuvant setting
2.ABCSG:  Obesity may portend poor outcome in patients receiving Aromatase Inhibitors in Breast cancer treatment.

3.POEMS:   Chemotherapy alone  Vs Chemotherapy + Goserelin (the combination of chemo+Goserelin showed better fertility protection)
4. The combination of Dual Trastuzumab and Lapatinib failed to increase survival

Oncologists are awaiting resulst of Pertuzumab + Trastuzumab!for a final conclusion on these issues!

5.In breast cancers that are small and Her-2 positive, T<2cm  weekly Taxol+Herceptin gives >=95% survival, just do this don't wait for a non coming  trial!   Please treat because the Mortality may be as high as 20-25%------give Herceptin as described

PDL-1 Inhibitors, the WOW of the moment!

Beside starting the neoplastic process which involves rapid uncontrolled multiplication through installing transcription factors and related machinery to multiply genetic cancer materials and set the stage to metastasis, science has unveiled a critical point that favor the unedited expression of solid Neoplasms:   the PDL1 or CD274.
Indeed during the neoplastic transformation, the cell undergoes several molecular transformations that changes drastically molecular membranes sufficiently to trigger autoimmunity our natural protector against cancer development.   It is therefore painstakingly that all successful cancers will take control of this Cluster of differentiation 274 to escape or block autoimmunity.
The importance of PDL1 is critical when you look at the downstream pathway of this molecule:
1.  It has control on the IL-2 production, the same IL-2 which in high dose CURES renal cancer!
By stopping or mitigating IL-2, this PDL-1 removes this outcome for cancers....
2. It impacts BCL-2, the gene that allow cells to escape sensitivity to many chemotherapy by ultimately blocking caspases'stimulation mainly at Mitochondrial level.
3. It decrease stimulation of the NF-kB and the AP-1 subsequently, basically reducing abnormal noises that could trigger the immune response to wake-up!

With the Ibrutinib receptor for hematologic Malignancies, PDL-1 is at this time the most prominent find in solid tumor to date.  And soon, no chemotherapy may be given without it in solid tumor.  It is the Velcade of the Multiple Myeloma.

check your sources, Are we in the belly of the beast!

When you study Arterosclerosis
when you study Breast cancer
Molecular movement inside the cell is important
then you come across this:
"
On binding a ligand the protein and ligand are internalized. This internalization is independent of macropinocytosis and occurs by an actin dependent mechanism requiring the activation Src-family kinases, JNK and Rho-family GTPases.^[29] Unlike macropinocytosis this process is not affected by inhibitors of phosphatidylinositol 3-kinase or Na⁺/H⁺ exchange.
CD36 ligands have also been shown to promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer.^[30]
Recently, CD36 was linked to store-operated calcium flux, phospholipase A₂ activation, and production of prostaglandin E₂<sup>[31]"  wikipedia

this is about CD36


and you start thinking, am I in the belly of the Beast.


Research has shown!


                                                                         PERK
                                                                              !
                                                                              !
                                                                 Phosphorylate
                                                                              !
                                                                              !
                                       PABP(interaction)---elf4 (ternary complex) which activates IRES   (HnRNPC1)

                                                     CD36-------Glucose
                                                                   !
                                                                   !
                                                             Reinitiation of protein translation


then there is a GNC4
a general initiation factor
A general translation factor
ATF4
work to do!</sup>

What is this finding worth in Breast cancer

Now we are learning that immunology could be prognostic in Breast cancer
pathologic finding of tumor infiltration by lymphocytes could announce susceptibility to
chemotherapy drugs...always ask now pathologist to describe lymphocyte infiltration of Breast cancer tissue!
Susman reported:
"For every 10% increase in stromal tumor-infiltrating lymphocytes found in the breast cancer tissue, there is a corresponding 16% increase in the chance that a woman will achieve a pathological complete response to therapy (P=0.038), said Sherene Loi, MD, PhD, head of the Translational Breast Cancer Genomics Lab at the Peter MacCallum Cancer Centre in Melbourne, Australia."
Already Oncologists who neglected their Immunology are confronted by reality, we are entering immunology at a fast pace, read up!ASCO is cool with this!

Progress in Cancer

Despite the rise of Ramucirumab released by the FDA in 4/2014,
"- Eli Lilly and Company (NYSE: LLY) announced today that the U.S. Food and Drug Administration (FDA) has approved CYRAMZA™ (ramucirumab) as a single-agent treatment for patients with advanced or metastatic gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. With this approval, CYRAMZA becomes the first FDA-approved treatment for patients in this setting." press release by Lilly,
There are 2 major progress events noted in Oncology,
1. is the rise of PD1 /PDL1 inhibitor for solid tumors
2. the rise of Ibrutinib in Hematologic diseases

With the the Inhibitor of PD1/PDL1, science has found the best way to harness immunity against tumor, and doing so in most cases without significant side effects.  Indeed, these therapeutic interventions have proven to be for most patient achievable and well tolerated.  What the PD1 Inhibitors have been able to achieve is what we intended by Using IL-2 or Interferon (non specific global action of all old therapeutic interventions)  versus a new sophisticated well targeted therapy with Activated Lymphocytes.  Cancer cells try to escape surveillance by our immune system, and we are trying to say NO.  And ladies and gentlemen, this time it worked, and working in most recalcitrant cancers!  The Melanomas of the days will no longer escape our reach, and now respond in unprecedented number and for unprecedented length of time...this period is worth living!  Literally, These drugs can be tried in almost every solid tumors with some legitimate relative success, and quite frankly within days, we might end up with groups of solid tumor described of those PD-1 inhibitor sensitive, and those which are not!  And what is great, the addition of Modalities involving the immune system, seems additive in global effect.  So nothing stop you but the price, adding Ipilimumab to the Anti-PDL1 and the effect follows!   And of course clinicians follow ....

The success of Ibrutinib is just as incredible but hits one principle that we knew long time ago, and that is cells of the hematologic lineage, particurlarly white cells, stop differentiation and this simple fact protect them from natural maturation and simply dying of Apoptosis that awaits all mature cell.  Indeed in the treatment using this modality, there is a sharp Lymphocytosis that scientist has attributed to delocalization a normal step into maturation toward Apoptosis!  The drug has done what we intend to achieve  when we say Cure,  asking a cell to choose the natural way or pathway  to death.  Because we can't bomb every cell but asking to follow its fate is the only way to the cure!

Help us with the Cytokines

If you really want to know how to lose weight, help us with investment into the cytokines
that is where nature has hidden with loss measures
but before we tell you which the right way is to have clear biomarkers of toxicity
because they affect the CREB genes
and many other receptors
they are overexpressed in specific Autoimmune disease
and could induce IBD and therefore neoplasms particularly of the Gallbladder
monitoring must be implemented prior to release!

Tomorrow is even better!

By developing new techniques to measure protein elasticity as part of progress in nanobiotechnology,
the French are pushing the envelop that will soon define Medicine of the future.  The prospect of finally projecting a molecule and studying its elasticity brings our knowledge in the belly of the beast even closer.
Already the prospect that we could first interrogate Core Binding Proteins, and than know to change their elasticity and movements, and more likely unveiling new attachment sites to molecule of our choosing, open prospects of new medical interventions like never before!
If you could image AP-1 or the GAG-MYD-ETS molecule as if examining the international space station, I am sure you will find even more interesting location where you could stack things that may affect its global functions in way that cannot be suspected...this is a critical way to impact disease that are today impenetrable such as the MDS and the leukemia...we will follow these efforts carefully...tomorrow is brighter in Medicine as we see it from here...

focus on ETS gene

1.Could a combination of Thyroid and retinoic acid be effective in MDS under expressing ETS gene
Rascle et al :
" We show here that Myb-Ets inhibits both RAR and c-ErbA activities on specific hormone response elements in transient-expression assays. Moreover, Myb-Ets abrogates the inactivation of transcription factor AP-1 by RAR and T3R, another feature shared with v-ErbA. Myb-Ets also antagonizes the biological response of erythrocytic progenitor cells to retinoic acid and T3."

2. E26 amplified in P.Vera?
3.What is the effect of Jakafi on the ETS gene expression.
4.Blocking GAG-ETS interaction could prove a major intervention in Myeloproliferative disorders and viral multipliction


It all looks like that this ETS is a way of directing the cell to a more vigourous multiplication particularly in the neoplastic process and Viral Multiplication through amplification and interactions with regulatory GENES.  (don't ask me now where is the miRNA).  This gene is so effective in its work, human cell adopted it.
and the shameless HIV comes in and uses it through the ENV-POL-GAG as mentioned!

Watched a Video on Vitamin D on Medscape

I am puzzled by a Video on Medscape on Vitamin D.  I did hope I will learn more about Vitamin D
I came out just as confused...and indeed more puzzled by this question than ever.  Now I wonder what is the background of the man...The most sobering is that he did not have an answer for us and in fact added to the controversy.  Whenever this happens, it points to not only we need to know more, but that the analysis on itself was superflous...The notion that Vitamin D help for cellular growth and kinetic was the most insightful, the rest was globally speculative at best.
Several aspects where not discussed and goes to fundamental questions we struggle with:
Vitamin D has a known membrane receptor and one needs to define
genes downstream this Receptor
what other receptors are modulated by Vitamin D particularly when used at high dose as it is now fashonable
why is it that Vitamin D deficiency is associated with Autoimmune disease
what is the effect of Vitamin D on genes at epigenetic Zone
What are the Cytokines involved in various states of Vitamin D presence
Can high exposure of Vitamin D affect Methylation of genes or Acetylation of Histones
Can that Acetylation or Methylation be permanent as to realy induce Neoplastic performance
At which doses these permanent genetic changes are actually induced
and what are the risks of chronic versus intermittent exposure to Vitamin
at which doses there could be a problem
and what gene (heterozygosity) predispositions the carrier to genetic insults
is there relation with the lipid receptors and genes
Is there relation with the Insulin Receptors and genes
Is there relation with genes at the epigenetic Zone,
ONLY STUDIES AT THESE LEVELS, ANSWERING AT LEAST HALF OF THESE QUESTIONS, DESERVE VIDEO BEING SELECTED FOR CONSUMPTION IN A MEDICAL MEDIA...

• 

Events at the Zone!

Certainly we know that a number of diseases could be prevented by stopping a number of mechanisms at the epigenetic level, we know that certain genes are very active at this levels such the Dnmt1, but also
HAT, HDAC, Histone H3 lys9 methyltranferase.   These genes could lead us to make certain conclusions on the state of the epigenetic zone.   Globally we understand that Hypomethylation is good for you because it is a state of non silenced genes, and for tumor repressors, it means a state of activity suppressing neoplastic transformation...And of course hypermethylation will silence these genes and lead to inactivity of tumor suppressor genes and most likely to overstimulation of cancer inducing genes.   This of course explains the effectiveness of drug such as Vidaza (in MDS).  At the zone, there is Methylation or Hypomethylation but this to occur Histone activity  has to occur to allow it to happen for those genes that are covered...

Many steps remain to be clarified
but it is now established that Dnmt1-3: maintenance of Methyl transferase and therefore favors methylation.  That aging is associated with increased detectable methylation.  Length of the Telomeres may be associated with activity at this epigenetic level, and that Methylation of important genes may leed to dementia (see RTT syndrome and schizophrenia) and methylation of important genes such has the Reelin gene
with impact on DAB1, GSK3B, NUDEL, TBR1 and of course Tau and CDK5.(PER WIKIPEDIA) (and there comes the trouble of PTSD)
There is a global increase in Cytokines particularly IL4 which :"IL-4 also has been shown to drive mitogenesis, dedifferentiation, and metastasis in rhabdomyosarcoma.<sup>[10]" wikipedia

And there comes the consequences....

Genes to watch summarized by our friends at wikipidea

"</sup>
SUV39H1 has been shown to interact with HDAC9,^[3] HDAC1,^[4] Histone deacetylase 2,^[4] Retinoblastoma protein,^[5][6] CBX5,^[3][7][8] HDAC3,^[4] DNMT3A,^[9] MBD1,^[7] RUNX1,^[10] SBF1^[11] and CBX1.<sup>[1]"

AND IF SP1 IS NOT MENTIONED IT IS A MISTAKE!

AND EVERYTHING IS CLEAR NOW!</sup>

Belinostat enters the Battle!

With the release of Belinostat, the FDA has made a big step forward, and once again points to the
importance of Oncology medications in the Histone deacetylators or drugs affecting primarily the epigenetic phenomena.   The challenge with these drugs is not only how to quantify the level of de-acetylation or methylation in the epigenetic zone, but measure some of the genes known to be located in the area and how they are affected. How DNMT1/DMAP1 react to these drugs (quantification needed...)  (not to confuse with DMT1, another total ball game altogether!)
De-acetylators have demonstrated activity in Leukemias, but this one was also tested in unknown primaries and lung cancers.  A question also remains, are these  important in NF-kB driven diseases or HSP90 overexpressions (Gastric cancers?).   Belinostat has been approved in Peripheral T cell lymphoma. (see also Vorinostat, released for Cutaneous T cell lymphoma).

Gastric cancer treatment moving along!

Week's Best Articles: Oncology

And they went ahead and did it. combining Rilotumumab with standard ECX in gastric cancer in patients who are MET positive " dose de-escalation study to identify a safe dose of rilotumumab (initial dose 15 mg/kg intravenously on day 1) plus ECX (epirubicin 50 mg/m2 intravenously on day 1, cisplatin 60 mg/m2 intravenously on day 1, capecitabine 625 mg/m2 twice a day orally on days 1—21, respectively), administered every 3 weeks."  MDLINKS the NIH reported: " rilotumumab  A fully human IgG2 monoclonal antibody directed against the human hepatocyte growth factor (HGF) with potential antineoplastic activity. Rilotumumab binds to and neutralizes HGF, preventing the binding of HGF to its receptor c-Met and so c-Met activation; inhibition of c-Met-mediated signal transduction may result in the induction of apoptosis in cells expressing c-Met. c-Met (HGF receptor or HGFR), a receptor tyrosine kinase overexpressed or mutated in a variety of epithelial cancer cell types, plays a key role in cancer cell growth, survival, angiogenesis, invasion, and metastasis." ================ This will mark progress in Gastric cancer next will see Ramucirumab (VEGF) combined to this same combination in the same disease... and may be we will see progress in Gastric Cancer after all

A burst of Target therapies

In certain diseases such as Melanoma, standard chemotherapy had failed miserably, yes indeed Cisplatin and the Adriamycin of the world had failed to give us a result and combining them did not help either.  For a while there, non specific immuno-modulation with interferon had been the standard approach but those days are gone also.   Today it is the PD-1...and already Ipilimumab that enjoyed the center case in Metastatic Melanoma is moved a bit by the storm of Pembrolizumab and the Nivolumab.   Clinician wonder now what to give first to a newly diagnosed patient, and whether clinical setting such as the location of the primary lesion should guide the drug selection.   For the BRAF of the world, Vemurafenib/Zelboraf have had their time, but this drug effect is short lived given the relatively quick return of the lesion, and the need to remove surgically the eventual squamous (kerato-acantomatous )lesion that may result of their use.   Like the Ibrutinib foe CLL, Pembrolizumab is now king in Melanoma.  (and Nivolumab is moving already to lung cancers).  The land is shifting, it is exciting to keep up.  But frankly, is it right to treat liver infested by Melanoma from the skin, versus Melanoma from the Uveal origin when we know that one has the GNAQ gene.   Yesterday I met a lady who had recurrent Melanoma in the Nostril...a PET is awaited. should I be able to offer directly Pembrolizumab arguing that the drug is said to be very easy on patients? (should my case turned to be Metastatic of course).  Can the first treatment be a combination with Ipilimumab?  Or is it too expensive...what cost can we afford?

In the Ovarian setting, anti-PARP are trying to enter the maintenance setting in Platinum sensitive disease, and BRCA status is pointing to responsive patients...should we use BRCA to make a case for Maintenance disease control with Olaparib.   The FDA is waiting for result of a larger study...not the "19" study they say!!!!  But May be this story is yet to be written...

On the Her-2 front, 2 is not better than 1 or is it?

and I could go on all night long....we live an exciting time in Oncology!

with news like this coming along:  " Top Stories

Ibrutinib Stands Center Stage in CLL" (medscape)

THE BEST IS YET TO COME! ONE THRUTH BUT MANY HIDDEN LAYERS (THE CELL).

Dig this by REN et al! and you will understand that the anti-VEGF is still JUST the begining of the membrane story: "The small Ras-related GTP binding and hydrolyzing protein Ran has been implicated in a variety of processes, including cell cycle progression, DNA synthesis, RNA processing, and nuclear-cytosolic trafficking of both RNA and proteins. Like other small GTPases, Ran appears to function as a switch: Ran-GTP and Ran-GDP levels are regulated both by guanine nucleotide exchange factors and GTPase activating proteins, and Ran-GTP and Ran-GDP interact differentially with one or more effectors."

THE BEST IS YET TO COME IN TARGET THERAPY!  SO MANY LAYERS, AND SO MANY AREAS TO DIG FOR CELLULAR LAWS AND THE TRUTH !!!

treatment in Gastric Cancer and G-E Junction

Although Ramucirumab a " fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF in angiogenesis.<sup>[4]" wikipedia,   

Has been approved by the FDA, oncologist still have a tough time as to when integrate this drug in their cascade of treatment to offer to their patients with these conditions.  And this despite the clear failure of the many standard therapy offered first.   The average one year survival being given by Gastric cancer current treatment is globally poor since most of the patients affected in our experience are relatively young.  And current result of Cisplatin or Oxaliplatin -5-FU based therapy remain repeated endlessly without progess.   In france, there is more use of Taxane based treatment, particularly in metastatic cancers.  The clear role of this drug, Ramucirumab is currently undefined as it may move from 2nd line (as released by the FDA) and as more clinical trials are moving forward, and also and mainly as oncologists are moving away from standard therapy to target therapy.

In this disease, we are still missing the mark.  And results of current treatments impose this glooming conclusion.
The basic understanding is still predominantly that the disease grows from  a chronic irritation by gastric acid onto an unprepared squamous epithelium of the Esophagus.   This basic idea prompted scientist who eventually won the Noble Process proving that the presence of H.Pylori could induce a neoplastic syndrome.  By Chronic Irritation basic genetic understanding would suggest an onslaught on the NF-kB and an intense activity of the epigenetic area where the c-MYC,
RUNX and c-FOS reside.   Constant infection or Acid induced irritation means also that some receptors will be desensitized to the point of shutting down of downstream genes which will end up methylated or suppressed or even mutated while some transcription factors (and subsequent miRNA ) will be over expressed.  We know this disease to be highly metastatic to the lymph nodes, liver and peritoneum.  We know that seeding through the peritoneum with local invasion to the Ovary (Krukenberg) and local invasion to the rest of the GI track (and the dread occlusion of the GI track).  But none is of these data has been completely explored fully.   And the story of agents acting of the epigenetic zone has not been fully elucidated or tackled!

Even the anti VEGEF, anti EGFR, and anti Her-2 can only act whenever their action reach the epigenetic area....our efforts in this disease can only be significant until the level of c-FOS, the CREB, the cytokines, and effect on Mitochondrial processes are clarified and neatly addressed.   How molecular transfer is affected and how we use this information for therapeutic purposes could make the new difference in this disease.  The mere fact that the there is a transformation to Barret disease, gives tremendous opportunity to stop the disease or at least to bend these events preventively (what is the MEK doing?).

For the time being, the success of the EOX and other combinations continue to make us believe there is a truth in these statements, and our focus should still be from the blast to a targeted therapy in these cancers...
The CRBCM is still at work...from Warsaw Indiana.</sup>

Genes proposed for Molecular testing by Jennel Hodge at al!

ABL  AKT1   ALK   APC   ATM   BRAF    CDH1
CDKN2A  CSF1R    CTNNB1   EGFR    ERB2    ERB4   EZH2
FBXW7    FGFR1   FGFR2   FGFR3   FLT3    GNAC    GNAS
HNF1A    HRAS    IDH1   IDH2    JAK2       JAK3     KDR
KIT      KRAS    MET     MLH1    MPL    NPM1     NRAS
PTPN1   RET   NOTCH1    PDGFRA    PIK3CA   PTEN   PTPN11
RB1   SMAD4   SMARCB1   SMO   SRC  STK11    TP53   VHL
==========================
FOR PERSONALIZED MEDICINE

CLEARLY AN INCOMPLETE LIST
AS IT DOES NOT INCLUDE

MOST CYCLINS AND TGFs, THE P14-3-3, THE CRUX THAT COMMITS TO NEOPLASTIC TRANSFORMATION, THE STRUCTURE FULL OF AUTOPHOSPHORYLATION (THAT NEEDS TO BE SHUT DOWN), AND THE INITIATORS MDM-2

AND CURIOUSLY, THEY MISS THE 10 OTHER THE SAME PUBLICATION DISCLOSED BY DONG-JOO CHEON...!

AEBP1   VCAN  COL11A1  TIMP3   THBS2   COL5A1 COL6A2  THBS2 LOX POSTN (OF OVARIAN CANCER)

WHAT'S GOING ON?  LET'S REVIEW....PLEASE GO TO ORIGINAL ARTICLES

speculations

Could cytoxan-Oxaliplatin +/- antiandrogen    Vs Cytoxan -Oxaliplatin +/-Nexavar
makes a difference for Hepatoma

yes I know the French  had some success  with  GEMOX in Hepatoma
but is Cytoxan a better drug given the infectious origin of the Hepatoma
could stimulation of the CREB cycle prompts better fight against the viral load

As target therapy continue to advance, increasingly first line treatment will be a combination of these therapy
and cost will be increasingly the limiting factor:
After Paloma, is it right to propose Letrozole alone (Vs a combination with Palbociclib) particularly in Metastatic disease.  One may want to try Letrole alone and add Palbociclib when there is progression but do remember the study compare the combination to Letrozole alone upfront with a doubling of the progression free survival...Then come other aspects of the problem, What is the role of Fulvestrant or should we keep it after the failure of the combination...and then one will ask should you stop CDK4 inhibition while using Fulvestrant?  At least it is a good thing to have these choices for our patients!
It is important to mention that combination do not always work better:

Clemons:" Result suggest that the addition of vandetanib to fulvestrant did not improve biomarker response, PFS or OS in patients with bone metastases. Baseline bone turnover was prognostic for PFS and OS."  I should stress that Vandetanib is an anti-VEGF (different apple all together!)

When Her-2 is positive
Boix-Perales et al:
"The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer."
Here 18 months VS 12  PFS
and 80 V 69  OS

Now is it right in Metastatic Melanoma to give an Anti-BRAF knowing well it is a short lived (or add Ipilimimumab after 3 to 4 months? or of course a combination Ipilimumab-Nivolumab...what is the cost?  Is it worthwhile an English may ask?  But here comes the choices again...Target therapy, still creeping up in all of us...But clearly the way to go...

Keep it alive! 3 steps ahead...

No need to create a new Hospital
no need to create a new cancer center
but transform a wing of a old hospital in a cancer treatment wing
because it is not the shape and blings that makes a cancer center
but what the mission of the wing remains
and how good they accomplish the mission
the need is there, and progress could be achieved
and with each step we make, particularly with Target therapy,
more can be accomplished....
Our eyes have risen,  the challenge is being met,
and with every day new discovery,  the walk to cancer cure is becoming
increasingly possible...the fight is complex, but the devil is in the details,
because it is not enough to predict the behavior of a cell, because believe me it is going to react to
our attempts, but it is to think before it reacts, and plan ahead of it, 3 steps ahead...
It is easy said then done because of gene heterozygosity, and because of our inefficiency to control intersecting interactions with other genes or surrounding molecules....but let keep saying that within the walls of that new wing will be practiced only medicine of tomorrow!

Further speculation on lipid deposition

Before I start, let me be clear that the following is clear speculations
but it is a speculation based on preliminary facts thats seems to
results from our understanding of gene behaviors and major clinical events.
The fact is we build up cholesterol or lipid Atheromas in the blood vessels
and that simple factleads to major devastating events which at time terminates our
life in terms of stroke or cardiac attacks.
It is worth examining the the build up of Atheromas in a more detail fashon if we intend
to make a difference.
Our current understanding is that at one time in our life, during the normal development,
the build up of Atheroma starts.  We are talking about lipid deposition in our arteries.
for Artery to receive and capture  fat molecules, there must be structures and potentially cells that
must be ready to receive them, and receive them tightly in order to hold them for what appears to be years at
a time.  We suspect that the chemical structure of Laminin, fibronectin, or fibrin or one of these structures(other will add Pectin, Perlectan,Entactin)
that we commonly deem "cellular environment" appears to hold on to lipid matters somewhat tighly relatively.
However, the capillary "cellular environment" over the years, is constantly undergoing a shift under hormones,
cytokine and various stresses. This shift in composition, ultimately impacts the very nature
of the underlying molecules, and therefore lipid to parietal molecule interactions, jeopardizing the tight neat
relation at lipid-laminin or lipid-elastin interaction.  It is clear that cytokines may chance the very nature
of "cellular environment" and changing so very drastically as, at cellular level, mutations or gene line shutdown could
follow changes in cytokine or ambiant hormonal milieu.
The very example of Menopause and the rise of cardiovascular events in women is a perfect example of this phenomenon. The disapearance of Estrogen during
menopause affects drastically this interaction marking a rise in coronary events in women (what stabilize this event should be a lesson for all to learn)
And the disapearance dwindeling of Elastin content in the composition of blood vessel with advancing age
appears to be another evidence of these changes that go completely unnoticed but clearly affect our future life!
The structural composition of laminin has long attracted the observation of scientists, indeed this molecule has
many locations where binding to specific structures is made easy, we speak of chemical bonds. And certain Ateromas may feel
confortable sitting here and tightly!  The point of the matter is that at any given location,
the cellular environment makes it possible for Atheroma seeding.  The perfect example is the disease called Xanthelasma or tuberous Xanthomas, this is a mere
deposition of lipids in a part of our body where for all suspicions must haVE A SPECIAL CELLULAR ENVIRONMENT that provide seeding of lipids.  I bet you those eyelids
have special laminin or fibronectin composition.
And it is clearly foolish to believe that fat deposition does not have consequences.  This is the same foolishnes that
made our leaders debate for long time that obesity was not a disease state.  Fat deposition has profound consequences because it
other directly induce reaction or secondarily provoke secondary effects...and my suspicion if a new burse of cytokines that
will induce the "disease state".   Clearly, the resulting Arthropathy is evidence of such reaction.  All chholesterol disturbances are linked to Arthropathies
as a result.
An interesting question being explored currently is the role of pericytes.  There is no no single pericytes,
and locally, at site of cholesterol deposition, the pericyte composition may be not the same as other locations.  And the pericyte type predominant
in an area of Atheroma may not be the same as an area of absent lipid deposition.  Scientist are digging deeper at gene level, this is where the nature of integrins
and G-proteins may also vary.  This point links us to why diabetic patients particularly present various levels of Vasulitic process, some ending in Amputations
and various leg wounds, and some none...clearly Integrins (alpha, Beta family) and G-proteins have something to do that is worth examining...And then there is PDGFR-beta, NG2 and gets more complex )
CRBCM is clearly with you in this path to knowledge...

Down the road of many cancers, our understanding is still increasing....

It is increasingly puzzling that Gene suppression could be one of the most powerful way to induce cancer and most likely to affect cellular migration in a process well identified as Metastasis.  This fact is true Whether you discuss RB1, or PTEN or in some cases BRCA2 or WT1. (or the Cadherins for that matter) In squamous cancer of the head and neck, suppression of the FAT1 has been clearly documented in the neoplastic transformation. The question is what can possibly  cause this decrease of gene expression affecting tumor suppressor.   Mutation is one mechanism we can't rule out or avoid or sometime even address.  The example of Colon cancer expressing KRAS Mutation comes to mind.  Wild type KRAS reassures the observer that the EGFR system is still intact and medication affecting this system could work.  But what is exactly the intact EGFR system.  There is increase evidences these gene mutations could be induced by Methylation.   This facts warrants further exploration as "demethylation" of specific genes could have a therapeutic effect.   This speculation also re-emphasized the fact that combining Anti-EGFR with de-methylating agent could open certain doors therapeutically in some diseases.  Along this line, one may assume that certain gene loss we observe actually remove certain list of genes from the "relative danger" of methylation.  The fact is the level of Methylation in certain cancer (MDS,Leukemic processes) needs further clarification.
Please do not forget that certain Cytokines may in fact promote methylation of genes that were not meant to that fate!

Package insert:"

Vectibix is an epidermal growth factor

receptor (EGFR) antagonist indicated

for the treatment of wild-type

KRAS

(exon 2) metastatic colorectal cancer

(mCRC) as determined by an FDA-approved test for this use"

Medication Index

Abilify depression
Invokana,Canagliflozin is an SGLT2 inhibitor, DM
Patanol,watery eyes, allergic conjunctivitis
Topiramate: seizures, Migraine in adult patient
Farxiga 5mg  DM
Chlorhexidine, Gingivitis
Wechol, bile acid sequestrant
Lovaza, omega-3
acarbose, DM
Victoza,DM

Activities at CRBCM

*About to start Oncology work in warsaw Indiana for the first 2 weeks of July...
*Working with local University on CPRIT project
*Finalizing our lung cancer project funded by MDHonors
*waiting for Graduate student to finally analyze our survey on Cielo-Vista mall
* Waiting to hear about our study submitted at NIH_SBIR
*Continuing work with Talecris
*continuing taking new cases mostly from local referrals
*Finishing up on transition from local assumption of service from retiring physicians
*Covering local calls for Hospital 
*Looking into new research projects
Thank you and congratulation to our new staff!
CRBCM looking forward to more expansion...and opportunity.

Rare case of Femoro-Acetabular Impingement

A 41 year old Hispanic woman was referred to us for evaluation 10 days after an MVA.  She was hit on the driver side  (WHICH THE LEFT IN THE USA) but has developed Right femur pains. Apparently, under the shock to the left, her thigh hit to the RIGHT the structure separating the 2 front passengers. She also complained of Headaches without GI complaints.   her Brain MRI did not reveal a new lesion or a subdural Hematoma.   A plain Xray of the femur to make sure there was no fracture However revealed a surprising read:

" The right femoral head-neck junction appears somewhat flattened with a pistol-grip contour which may predispose the patient to a  cam-type femoroacetabular impingement. "

Given the Medico legal issue involved, a bilateral Hip MRI has been requested and an input from Ortho has been entered.

Question, if the Xray was obtained earlier, could Decadron help, will await Ortho imput, pt has been on NSAID....

Quality Measures for Diabetic patient

In Diabetic patients
1.HbA1c
2.Neurologic eval
3.Foot care
4.Weight Control (BMI)
5.Retinopathy Monitor
6.Renal preservation/Use of ACE inhibitor and related drugs/albuminuria Vs Proteinuria/Renal consultation
7.BP control if any
8.Leg edema / Venous stasis/leg ulcers
9.Coexistance of Arthropathy
10.Coexistance of CAD
11.Coexistance of Auto-immune disease
12.Coexistance of Thyroid dysfunction/other endocrine disorder (endocrinologist consult)
13.known genetic pattern of abnormality

Opinion on Melanoma treatment

*Having listen to the treatment on Melanoma
it appears to me the V600 or BRAF positive patient
have a short lived progression free because of a rapid development of secondary amplifications of gene that will force a resistance ...
and it may be that there is a secondary activation of lymphocyte during this treatment.   This secondary amplification of activation, prep the disease to use of anti-CTL4 or anti-PD1 or PDL1 (or a combination there of since this combination has greater efficacy)

Meaning in BRAF positive, the anti-BRAF could be used as an induction to have higher response rate but instead of waiting for a more likely recurrence rate, give within 2-3 months a combination of Ipilimumab and Nivolumab to obtain for sure long term progression free survival.  The only objection to this strategy right now is money....what insurance will cover this expensive strategy...But clearly it makes the logical sense!

what worry a local oncologist is of course the episode of Hypotension that may result for the combination of Ipilimumab to Nivolumab or anti-PD-1

My fear is because of expense, what makes sense will not be completed for a decade!
trial should start now please!

fort those with KIT, Sutent could serve as induction therapy prior to combination Ipilimumab-Nivolumab.

Now I wonder if this combination would be appropriate for my patient with NF1 + GIST which failed Gleevec....wonder if she can sign a consent for this!

=================================
will check this out
BRAF resistance 
due to reactivation of MAPK pathways through MEK amplification (is there a secondary overexpression of mesodermal expression?) should we measuring COT overexpression, or amplification of c-MET, IGF1R, or PDGFR, can use of ASPIRIN help, can Nexavar prolong the effect of Dabrafenib...? oh hell all thins thinking just drive you crazy....but that one should do in research!


=================================
few dosages to check!

Dabrafenib 150 mg PO BID
Nivolumab 1 mg/kg
Ipilimumab 3 mg/Kg
Trametinib 2mg PO QD
Vemurafenib 960mg in 4 tab Q12 h

===============================why the Kerato-Acantoma in anti-BRAF inhibitor, is the receptor in the same membrane fold?

post of the day

PALOMA-1 Trial Finds Palbociclib/Letrozole Doubles Progression-Free Survival in Metastatic Breast CancerMay 1, 2014, Volume 5, Issue 7

go to article! 

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in another question: what in hell is going on with achondroplasia with breast breast cancer?  2 cases in a year?  I need more gene testing...please.

And I knew a Cytokine bank is what we need in El Paso

Intralesional Cytokine Therapy in Cutaneous Melanoma: A Call for Clinical Trials

By E. George Elias, MD, PhD
November 1, 2013, Volume 4, Issue 17

"

In an exploratory study in patients with dermal and subdermal metastatic melanoma, we explored the use of intra lesional therapy with low-dose GM-CSF (500 µg once weekly). In case of failure to obtain a complete response in 4 to 6 weeks, IL-2 was substituted (18 million IU/wk).⁴ The results revealed that such intralesional therapy was well tolerated without major side effects.
Complete responses were obtained in patients with small lesions ranging in size from a few mm up to 1 cm regardless of whether these were primary, satellite, or in-transit metastases. However, none of the large sclerotic lesions responded to intralesional therapy with either cytokine. The complete responses were noted clinically and confirmed pathologically by rebiopsy of some of the injected sites at 6 to 8 weeks after cessation of the therapy, and showed absence of tumor cells and no mononuclear cell infiltrates."
============================================

How can we possibly go wrong????

From TBI
to Diabetes mellitus
to simply getting old
the key role  of Cytokine cannot be stressed enough
every time you experience muscle pains
or wake up with age related flaccid muscles, it is the the Cytokines...
every time with autoimmune disease you cannot put up weight, it is the Cytokine...
obesity would not be a disease without the Cytokines?
so when are we going to wake-up?  and truly fight cancer with the Cytokines?

and

Obesity Increases Breast Cancer Mortality in Premenopausal Women With Estrogen Receptor–Positive DiseaseJune 10, 2014, Volume 5, Issue 9

 

what else do you need to really join us and build this up!