have you heard from the state

State Health Commissioner

To

Today at 12:39 PM

Nationwide Increase in Measles Cases

 

According to the Centers for Disease Control and Prevention (CDC), the United States is having more reported cases of measles this year than usual. Many healthcare providers in the United States have never seen a patient with measles and may not recognize the signs and symptoms. Healthcare providers need to be more alert than ever to the possibility of measles.

Health care providers should consider measles in patients who

·         present with febrile rash illness and clinically compatible measles symptoms [cough, coryza (or runny nose) or conjunctivitis (pink eye)],

·         recently traveled internationally or were exposed to someone who recently travelled

·         have not been vaccinated against measles

Healthcare providers should also consider measles when evaluating patients for other febrile rash illnesses, including Dengue and Kawasaki’s Disease. 

basic research 2

Secondary malignancy

When a receptor is permanently blocked Or destroyed
When a gene is over stimulated
When bypass activation exist and may involve an important pathways
Addition of immunomodulator to an alkylating agent. Seems of concern

Pomalidomide
Dinaciclib
ARRY 520

For CLL
FCR remains standar of care
And bendamustne rituxan an alternative
And ibrutinib for bulky diseases

 Secondary tumor produced by a known gene alteration
Should be treated by blocking a gene within the same pathway either upstream or down stream.  Instead of using standard of care for that tumor.

In pancreatic cancers most of the intervention
Have not confronted  the NF kB

Review the NOTCH pathway

Spark level associate Ted with good prognosis in pancreatic cancer
Spar level

still a question today 2 years into this?

Basic research idea

Pattern of transcription genes cancer cell Vs normal cell using microarray technology as a way to identify critical specific acquired change by cancer cell

Alteration of pattern of receptors on cancer cell
Are some receptors more specific to cancer cell

Persistence of life in red cell in the absence of nuclear material, what gives?

Why mismatch repair failure fails to trigger P53 activation in cancer cell
Is there deregulation of P53
Is there a transcription factor inhibiting P53

Inducing quiescence in cancer cells
 triggering senility in cancer cell
inducing differentiation which reverse blastic aptitudes in cancer cell?

questions in liver cirrhosis

A 65 year old African American man came for consultation
he is known to have  Hepatitis C since 1982 when he first  noted jaundice
He met with my predecessor and 2 GI DRs who have advised him current therapy with Interferon and ribaverin, his alpha fetoprotein is 4.  But his Viral load 4 million. His Viral genotype undetermined
and whether such determination matters is a question, since H is "old school" and decline therapy be cause he feels fine! And grant it the Viral load has no defined prognosis value per certain authors.He will only be convinced to treatment if there is evidence of early cirrhosis.  That's where Liver imaging CT sonogram or MRI comes  in.
But is there a way of determining that Cirrhosis is on its way
can genes for fibrosis be detected in time to force the hands of such patients?
literature search brings the importance  of Fibronectin,fibrinogen,laminin Tenascin, TGF-Beta1, Metalloproteiases, TIMP1, Plasminogen-PAI-1, and even CTFRs

Interest in the Quiagen article cited below, is this the way of the future!?
Can we compare this gene abnormality-expression to MRIs of the liver for direction.
what are the biomarkers to use?



From Quiagen (for discussion only)
"Pro-Fibrotic: Acta2 (a-SMA), Agt, Ccl11 (Eotaxin), Ccl12, Ccl3 (MIP-1a), Ctgf, Grem1, Il13, Il13ra2, Snai1
(Snail).

Anti-Fibrotic: Bmp7, Hgf, Ifng, Il10, Il13ra2.
Extracellular Matrix & Cell Adhesion:
ECM Components: COL1A2, COL3A1.
Remodeling Enzymes: Lox, Mmp1a (Collagenase 1), Mmp13, Mmp14, Mmp2 (Gelatinase A), Mmp3, Mmp8, Mmp9
(Gelatinase B), Plat (tPA), Plau (uPA), Plg, Serpina1a (a1-antitrypsin), Serpine1 (PAI-1), Serpinh1, Timp1, Timp2,
Timp3, Timp4.
Cellular Adhesion: Itga1, Itga2, Itga3, Itgav, Itgb1, Itgb3, Itgb5, Itgb6, Itgb8

Inflammatory Cytokines & Chemokines:Ccl11 (Eotaxin), Ccl12, Ccl3 (MIP-1a), Ccr2, Cxcr4, Ifng, Il10, Il13,
Il13ra2, Il1a, Il1b, Tnf.
Growth Factors: Agt, Ctgf, Edn1, Egf, Hgf, Pdgfa, Pdgfb, Vegfa.

Signal Transduction:
TGFß Superfamily: Bmp7, Cav1, Dcn, Eng (EVI-1), Grem1, Inhbe, Ltbp1, Smad2, Smad3, Smad4, Smad6, Smad7,
Tgfb1, Tgfb2, Tgfb3, Tgfbr1 (ALK5), Tgfbr2, Tgif1, Thbs1, Thbs2.
Transcription Factors: Cebpb, Jun, Myc, Nfkb1, Sp1, Stat1, Stat6.

Epithelial-to-Mesenchymal Transition: Akt1, Bmp7, Col1a2, Col3a1, Itgav, Itgb1, Mmp2 (Gelatinase A),
Mmp3, Mmp9, Serpine1 (PAI-1), Smad2, Snai1 (Snail), Tgfb1, Tgfb2, Tgfb3, Timp1.

Others: Bcl2, Fasl (TNFSF6)."

*New study attracting CRBCM attention:
Glembatumumab Vedotin in Metastatic Triple Negative Breast Cancer
(but comparison with Xeloda raises question, is this best in this disease?)

*Ramucirumab, and anti VEGF receptor 2, a noel antiangiogenic with role in Gastric cancer!
8mg/kg IV Q2weeks,  with or without taxanes....

CPRIT meeting again

The Cancer Prevention and Research Institute of Texas  (CPRIT) oversight committee is meeting again
 May 21 2014?
Observers are asking....


1.what will be new
2.who is going to get grant beside universities
3.what the public will hear new
4.is there new strategy that may come out other than giving grants to various university applicants
5.can we read an orientation or trend in these grants....is the new oversight steering research toward a specific goal
6.is it reaching other cities of Texas
7.is El Paso involved
8. 4-5 years into this, are we better off!
9. is the organization listening to us, consumers and research community (other than the huge university who created this!)
10.how should it demonstrate that influence peddling has subsided

Cancer cure is at stake, too much is at stake to keep away!

Mighty puzzling lung cancer!

In the United states along, over 225,000 people will be diagnosed with lung cancers
and 160,000 people diagnosed with this disease, will die from it.  And it is known that 84 percent of people diagnosed of this disease, will die from it.  Indeed, patients diagnosed with stage IA, the earliest stage, have a 5 year survival of only 50% despite our current advances in therapy. Making lung cancer one of the deadliest cancer of all cancers.

Comparative data on survival Breast Vs lung cancer
----------------------------------------------------

 BREAST CANCER 5 YEAR SURVIVAL BY STAGE                            LUNG CANCER 5 YEAR SURVIVAL PUBLISHED

FROM NCI SEER'S DATA BASE                                                             IN 3RD EDITION OF ASCO-SEP PG 157

STAGE 0              100%                                                                                         STAGE IA      50%

STAGE I         100%                                                                STAGE IB  47%
STGAE II         93%                                                                STAGE IIA  36%
STAGE III        72%                                                                 STAGE IIB  26%
STAGE IV        22%                                                                 STAGE IIIA  19%
                                                                                                  STAGE IIIB  7%
                                                                                                   STAGE IV   2%

==========================================================

These figures point to not only which cancer is deadliest, but also how critical it is to detect the disease early in an effort to improve survival.  As most patients with lung cancers present with advanced disease and chances of survival  is relative to stage of disease, It has been a constant effort of researchers to diagnosed lung cancer early.
To date, lung cancer prevention has been attempted by chest X-ray, sputum cytology, and finally the Lung Cancer Action project (ELCAP) and the National Lung Screening Trial (NLST) have tested successfully low dose Cat Scan (CT) in patients 55 to 74, with 30 year pack or more history, to not only detect lung cancer earlier but also to show survival benefit.

Today, attempts to screen and detect lung cancer has expanded to cellular detection of minimal presence of lung cancer cells in the blood.   These efforts are preliminary, and it is unclear at what stage this phenomena could be detected.

The CRBCM with support from the University of Texas in El Paso (UTEP) Biologic  cancer research Department has launched an investigation of to detect early variation in genes that could signal lung cancer development in high risk patients as defined above.

These efforts have been supported by MDHONORS, an London institution, which provided limited funding (the CRBCM has committed its own funding so far) but also by the University of Virginia Tissue Bank  (LCBRN) which provided initial tissue (tissue and sera) specimen.   

The CRBCM insists on thanking these non biased, non political organizations who truly help the progress of science without greed or political gain.  Thank you!

CRBCM,international!

A nice complex of our readers!

And thank you!

 on 5/13/14

Entry	Pageviews
Sweden	15
United States	12
Poland	5
Canada	1
China	1
Germany	1
Malaysia	1
Netherlands	1
Slovenia	1

WHAT METASTASIS TEACHES US

One can imagine what happens in the process of Metastasis as followed.   A cell with malignant transformation has acquired genetic structures that will allow it to detach from the main tumor tumor and throw itself in an unfamiliar environment, and swim in a lymphatic liquid or blood until it will find an appropriate location, and seed the place whether the local cell like it or not.   To accomplish these functions, the Metastatic cell comes prepared!  And the preparation comes with genetic Mutations, activation and depression that could be detectable by a careful non biased observer.   Each step that is outlined above and that the metastatic cell is undergoing though this process, will be affected by the natural type of the cell involved in the Metastasis.   ie, if the cell is a T lymphocyte, tissue invasion in the seeding process will use many catalytic enzymes that will breakdown the skin and other tissue environments (laminin, and other supportive molecule).  This will result in the observation of what we describe as Leukemia Cutis!   The point is that after seeding has occurred, local survival must be ensured, and it is so ensured by paracrine selective secretion of growth hormone (Mostly TGF-B as demonstrated by many types of cancers)

Going back and breaking down the process
1.cellular detachment: which will involve among othes genes the E-Cadherins
2.Movement of the cell, which will involve many processes, from genes involved in podocyte formation to protein movements inside the cell,
3.eluding autoimmune mechanisms to escape self destruction and recognition
4. adopting "mesodermal" conformation
5.swimming or displacing self along endothelial cells,
6.crossing vascular endothelium at site of seeding
7.Again avoiding detection from other cells (by providing overwhelming credentials!)
and winning the preferential nutrition game!
although most of the functions are concommitently acquired and accomplished (particularly through "embryonal" transformation or stem cell state or capability adoption), most functions are newly acquired through the neoplastic transformation (new CBF or gene binding ie BCR-Abl).

Suffice is to stress that to do these processes, the cell has to be sure it does not trigger Apoptosis and condemn itself to dying!   So unless RAS /MEK/ERK is a driver pathway, many times it has to be shut down may be through the p66shc!   This damn p66shc has been shown to help the neoplastic cell survive Anoikis.
wiki:"programmed cell death which is induced by anchorage-dependent cells detaching from the surrounding extracellular matrix (ECM)".   The point is that the cell will make sure it has plenty of Bcl-XL,   Cyclin B1,NPM1 to move forward into the Metastatic state (of course p53, Rho are involved)
CRBCM, let's go to work

NOTES FROM SAN DIEGO -PANCREATIC CANCERS

*NO NEWS IN PANCREATIC CANCERS

It is increasingly evident that 4 options are offered in Pancreatic cancers
1-Folforinox, the best regimen offered in the young and great performance
with real improvement in Response rates and survival benefit
2.But in elderly and patients with poorer performance status, Abraxane 125mg/m2 + Gemzar1000mg/m2 weekly x3 Q4weeks offers the best alternative.

with survival data
(compared Gemzar alone)
----------------------------
    1 year  35 %  Vs    25%
   2years 10%   Vs   6%
   3years   4 %  Vs   0

(take these data with caution)
with Abraxane combination better tolerated than Folforinox
3. Gemzar +Tarceva still an option
4. Gemzar alone, basically no longer an option given the tolerability of Abraxane -Gemzar and its superiority!  unless you are desperate!

CAUTION IN THE FUTURE THEY MAY BE GENETIC BIOMARKERS TO HELP DETERMINE WHAT OF THE 2 (FOLFORINOX vS ABRAXANE-GEMZAR)

WITH ABRAXANE -GEMZAR FOR TUMOR WITH (SPARC,RRMM,hEMT1)

WITH FOLFIRI (TOP1,ERCC1,THYMIDILATE SYNTHASE (TS))

(THESE ARE PERSONAL NOTES AND MAY BE MISTAKEN)

Biomarkers in Lung Cancer

For the first time, almost one year after the Harvard people talked about it, I hear in this setting talking about
testing in lung cancer at diagnosis although recommendations are in place
EGFR,ALK, and ROS1 are recognized at the meeting...they also mentioned BRAF,Her-2,MET,RET,KIT in passing.  The gobal presence in diverse lung cancers 35% for these markers.

ROS1 part on the Insulin panel?  This is question raising!

The success story here in San Diego is CERETINIB, 20 times as active as Crizotinib?  400-750mg/day
with a success rate in 56% percent in people who progressed on Crizotinib
and response rate noted on Brain Mets, with pictures to support the claim
but watch for Nausea and Diarrhea.  
and elevated transaminases (particularly bothersome for Crizotinib) and not as much a problem with CERETINIB.
should you try to use a Chemotherapy drug, suggestion is Premetrex would be a better choice in Alk positive patient.  Is this close to AdenoCA?

*HSP90 inhibitors, the chaperone!

*still in the ALK positive, do not forget ALECTINIB
which may cause Hypophosphatemia, and possible could be effective in Brain Mets!

TO BE CONTINUED

Question of the day (GIST and GiST again!)

Could Ibrutinib conquers resitance in GIST particularly those from NF1?
remember this is just a Mast Cell disease evem though Cajal is favored?
Is GIST a basically RAS driven disease?
is the Anti-MEK  strong Alternatives to MTOR inhibitor in GIST?
Can Nexavar add to GIST treatment in NF1 diseases?
frankly based on my experience now NF1 presence is a clear clue to target treatment in GIST, the skin lesion tell the Oncologist I am here!  don't beat the bush!   But Gleevec and Sutent is not the real answers when NF1 is present!

Hello SAN Diego California, Update in Oncology!

The CRBCM is here to get updated in Oncology for the year 2014
many new drugs, many changes have occurred
and we will have a chance to open a window on new changes in Oncology
The lovely town of San Diego town itself has changed
Even the steakhouse of L street has progressed
but our schedule is tight! let's go to work!

Somebody just needed to tell me! GIST, not everything is in the BAG (or known!) if you get my drift...!

THE CLINICAL CASE :
==================
A 50 year old Hispanic woman with history of Neurofibromatosis came to me in March  2014, she had an episode of hematemesis .  She was found to have a large mass in the body of the stomach.  The mass was a GIST (gastrointestinal stromal tumor).  She reportedly was seen by a surgeon who in consult with the internist and before Oncology was involved decided a neoadjuvant approached.  The patient was on Gleevec before my consultation.   The patient had skin lesions of Neurofibromatosis and could not raise her arms because of extensive shoulder arthritis.  We decided to continue her her Gleevec at 400 mg daily.
Now 3 months later, her ANA is positive 1:1280,  and her mass in the stomach has grown from 11 cm to 15 cm, marking a resistance disease.   A surgeon will see her today for an eventual resection of  "resistance disease" and Sutent has been initiated!

SHOULD WE HAVE SUSPECTED THIS?  HERE IS THE LITERATURE!
==========================================================


Yang et al:"Further, genetic or pharmacologic attenuation of c-kit signaling in Nf1+/- hematopoietic cells diminishes neurofibroma initiation and progression. Finally, these studies implicate mast cells as critical mediators of tumor initiation."

Ingram et al:"Neurofibromin, the protein encoded by NF1, functions as a tumor suppressor protein by negatively regulating Ras activity in mammalian cells."
-----------
 "FROM THE INTERNATIONAL GIST SUPPORT GROUP!

Pathology and Prognostic Findings

The GISTs in NF1 patients are usually multiple and usually found on the small intestine, though a few have been found on the stomach. Areas of hyperplasia of ICCs between GISTs in NF1 may be precursor lesions (Andersson et al, 2005). NF1 GISTs do generally stain positive for KIT protein (CD117), like most other GISTs. Compared to sporadic GISTs, NF1 GISTs are more likely to show S-100 reactivity (a marker of neural differentiation), entrapped myenteric nerves within the tumor, and skeinoid fibers within the tumor (Takazawa et al, 2005).
Yamamoto et al (2008) found that all GISTs from five NF1 patients did stain positive for PKC theta.
Although they may fall into any GIST risk category, NF1 GISTs usually show low cell proliferation (growth) indicators such as mitotic count or Ki-67 index (Andersson et al, 2005; Miettinen et al, 2006). NF1 GISTs rarely metastasize (Levy et al, 2004). Andersson et al (2005) reported follow-up for 9 NF1 patients who had surgery for GIST; none of the patients died of GIST, and 6 of 9 were well up to 32 years later. Miettinen et al (2006) described follow-up for 35 NF1 GIST patients, of whom only 5 died of metastatic disease.  Mussi et al (2008) reported follow-up for 28 NF1 GIST patients, of whom 7 (25%) developed metastases.  In both of the preceding two series of NF1 GIST patients, none of those with multiple GISTs developed metastatic disease."

"
There are no reports yet of the use of mTOR inhibitors or MAPK inhibitors on NF1 GIST cells or in NF1 patients with GIST.  Johannssen et al (2008) found that MPNST cell lines from NF1 do show growth arrest (but not cell death) when exposed to rapamycin (an mTOR inhibitor).  The rationale for use of mTOR and MAPK inhibitors in NF1 is clear.

Response of NF1 GIST to Imatinib and Sunitinib

There are only a few published papers about response of NF1 GISTs to tyrosine kinase inhibitor drugs:

• Lee et al (2006) reported a case of NF1 GIST that did respond to imatinib (Gleevec). 
• Kalender et al (2007) reported  a patient with initial response to imatinib (Gleevec) who subsequently became resistant and experienced progression.  However, the metastatic lesions in liver and omentum did decrease in size during the first four cycles of sunitinib (Sutent).  Results of longer follow-up were not provided in the paper.
• Mussi et al (2008) described imatinib treatment results for eight NF1 patients.  Four patients who received adjuvant imatinib after complete resection did not experience recurrence.  Four additional patients with metastases received imatinib, and three of them demonstrated primary resistance (rapid progression), while one patient with a PDGFRA mutation had stable disease temporarily."

========================================================

THIS IS NOT YOU STANDARD GIST
MAY BE AN MTOR INHIBITOR WORKING DOWNSTREAM SHOULD BE MORE EFFECTIVE
OR MAY BE SOMETHING UPSTREAM
IT IS A MAST CELL ISSUE
AND MAY BE THAT'S WHY THE SKIN LESION HAPPENS IN NF1 PATIENTS
COULD AN ANTI-MEK OR IBRUTINIB DO A BETTER JOB?
OR JUST DIRECTLY AN ANTI-RAS?

WE WILL ARGUE FOR MTOR INHIBITOR SINCE THIS IS NOT A GIST WITH STANDARD DRIVE OR INTENTIONS?  YOU TELL ME!  WILL UPDATE THIS CASE AS IT UNFOLDS!

Critical genes under review

*Membrane action
*Early in the pathway
 *ability to recruit the caspases
*Through its action by GTF2i  (TFII)
it activates c-Fos promoter, this may play into response to therapy (Via TFII)
*SMARCB1, overall control of cellular growth (SWI/SNF)
*POLR2A
*XPB
*MED26
*TATAs
*CRK(L)

These are of interest at CRBCM

Vicious circle of life!

An 89 year old man was brought to my clinic because he had painful feet, he had to be carried.
Just 2 days ago he was well walking to a local Spanish market, because of the season, people buy local brews...He saw one that could give him "strength and anti-Oxidants".  He bought it rapidly and ended up with brisk diarrhea that completely dehydrated him.  Well with dehydration came renal failure and elevation of Uric Acid which precipitated a gout attack.  He had such pain, he could not walk the poor man...he had to be " handily transported" to our clinic....Poor man did not know that 2 days earlier, in that market, he was changing his life...what we don't know sometimes takes us places!

Here, we are still looking for the genes that brought this about! CRBCM.....

Lung Cancer detection Going back to Basic!

Our study on lung cancer detection got boosted by UTEP individual efforts, indeed the availability of some Antibodies to certain genes allowed the crew led by DR Chai to screen sera of lung cancer patients for these molecules.  This extra efforts allowed us to identify Cyclin B1, NPM1, and 8 other antibodies at various quantities.   Suffice is to add that Cyclin B1 was found more frequently in 26 % of patients.  We have discussed NPM1 briefly in other blog.  But the confirmation of the presence of Cyclin B1 again point to the point that a number of molecular transformations will be occurring once the neoplastic process is underway early in the cascade of cellular events.

One of the first event after the neoplasm is engaged, most likely cigarette induced MDM2 driven changes, is that mitosis should be the general orientation of the now proliferating malignant cell.  And Cyclin B1 does this by committing the cell to cancerous proliferation.   With Cyclin B1 increased, the cancerous cell is squarely turned to changes favoring division and proliferation.  Protection of the Nucleus for chromosomes is broken down to allow spindle formation, this is achieved through Cyclin B1.  Clearly under Cyclin B1 cellular division goes wild and natural stops of this process by the APC gene is removed by the shutting down of the Mitosis exit door!

Other gene interacting with Cyclin B1 will engage P53, p38/JNK, MAPK and even the stress related HSP genes.  Through CRK, the Reeling and DABK1 is not far behind!
Another observation was a Koc gene amplification.  This is another finding pointing to cancer underway.  Here again certain RNA need to be shut down to  and our friend Koc will do that!   This is an attempt to stream line the activities.

STILL TRYING TO FURTHER PROBE THE LUNG CANCER DATA AT CRBCM

LETTER TO OUR INVESTIGATORS

would you please send us the list of the names of the 10 antibodies that
Dr. Choi has also measured in the lung cancer project?

Also, please let us know when you will have the raw data available as we would like to look at it
and, for example, check if there is a correlation between the expression of MDM2 and the duration and intensity of smoking (years/packs per year) in the lung cancer patients.

We are looking forward to doing further analysis of the data collected and then apply for more funding to run the study with a larger number of samples.

With our thanks and very best regards,

CRBCM!

How about "Embryonal" and "Blastic appearance" inside information

*According to Perez Moreno et al....E2A works in the depression of E-cadherin
a phenomena which intervene in the metastasis of cancer...is fair to conclude the Blocking E2A could decrease metastatic potential of cancers?
*Depression of E-Cadherin may also play a role in Epithelial mesengial transformation or transition, a phenomena that seems to occur early in the neoplastic transformation, could blocking E2A be used in cancer prevention?
*does the embryonal or blastic appearance is linked to the over expression of the HOXb1 and family
or is it linked to the overexpression of PBX1

Memorable  possible intricacy
 ================================================
 (TCF3)               !-  HOXb1------E-Cadherin
*E2A---PBX1---!-  MEIS-1-----MLL+PAF----TET1---c-MYB
      !                     !-  HOXs
      !
CBP/p300----TWIST-1
==================================================
what about SRG3?  what do we know?"SRG3 (Smarcc1) is a core subunit of the SWI/SNF complex. In the absence of SRG3, embryonic development ceases during peri-implantation stages," ncbi! could intervene in differentiation arrest?
=================================================
The MEK must be somewhere, and Rho gene!
ARE THESE POTENTIAL TARGETS?

THE HOXS ARE STANDING OUT!
 

notes

IN ALL
*Cells are devoided of granules
*presence of CD19, CD22
*leukemia Cutis
----
some of the prognosis factors
elevated LDH
high white count
evidence of CNS involvement?
pro-B cell ALL
*t(4,11), t(8,14), >5 cytogenic abnormalities
 t(1,19),t(9,22)

Good prognosis: del-9 and hyperploidy (50-60 Xsomes
=========================================

Notes on Myeloma, lesson learned (II)

*If del 17 present -give RVD (revlimid, velcade, Decadron)
*After first transplant, your options are:
1.Tandem Therapy  Vs  Revlimid
2.Maintenance therapy with Revlimid +/- Velcade based on Cytogenetics
whatever drug you choose give until progression of disease.

*In younger patients 3 drug therapy is better
-to increase efficacy, which turn out to be better,
-Maintenance therapy is standard
for high risk patients, think RVD
*for all transplant candidate
Give "triple therapy" for induction
but again for high risk Myeloma, think RVD

*some argue that Myeloma is a curable disease, indeed when you look at survival curb, a plateau exists...meaning aggressive treatment when feasible should be offered to our patients!

*Some start questioning that adding alkylating agent (Cytoxan) to the mix in myeloma may be pouring  flame to the Mutations already present, CRBCM agrees! But may be important when del 17 present!

*Obtaining MRD appears important to reduce proportion of non responders to treatment.
and VTD appears beter than TD.  the proportion of VGPR  62  Vs 20
*and VTD anihilate the risk of t(4,14) translocation, choose this combination in people with this translocation

*Velcade should no longer be given Intravenously, always give Sub-cutaneously to decrease significantly Neuropathy!

*carfilzomid has definitely entered the frey, combination therapy CRD being offered, see results in the literature!

*One may consider deferring transplant in patient who are reluctant to proceed:(up to 25% of patients who qualify for transplant actually delay therapy believe it or not!)
3 criteria
A-Standard 3 medications used, and no complicated Cytogenetics in play
B-good response to therapy (high VGPR)
C-Good tolerance of treatment!

*CR 1X 10 (power 8)
but can consider by Molecular or flow 1x10(power4)

*Maintenance therapy is definitely standard since it has shown longer progression free and overall survival (HOVON65/GMMG-HD4)  Use of Velcade IV vs SC discussed earlier

*Ixazomid best for maintenance therapy since PO, and once a week dose considered, with decreased Neuropathy!

*for maintenance therapy, particularly in bad Cytogenetics, add Velcade to Rev. (please try to avoid Decadron in this setting if possible for side effects!)

*Major development
Velcade is safe in renal failure
and guess what is added to the list Carfilzomib, also safe!
renal failure bad for Pomalidomide!!! do not use!!!

*Most if not all Oncologists will treat laboratory signs of progression of disease
ptions would include
1.RVD
2.Resume Velcade
3.Carfilzomib
4.Pomidomide
5.DOXORUBICIN (+/- Melphalan?)

(All info to be used cautiously after check of literature)
Note I still to come!
CRBCM, tracking the news!lesson learned in LAS VEGAS!CRBCM does not fabricate and does not own this information....but this may help someone somewhere!

Natural laws at play in CLL-Theory

In all the pathology, there is no disease that makes so much sense than Chronic Lymphocytic Leukemia disease I will beg to venture.  Our understanding of this disease has grown so rapidly that what is left to discover is probably not as much as one may think.  What is needed today is a reorganization of what we know and minute details particularly at the Nuclear levels.  The disease affects about 15000 people, and kills about a third of our people who happen to have gone in a wrong path because of a genetic failure particularly in our way of managing infections and cellular death.   And along these paths, there are laws that need to be followed, and any failure of following these laws leads to these dangerous disease called CLL.
The first observation to remember following this theory is that there is no clear environmental disaster that can induce CLL directly unless people exposed have a genetic failure in their cellular death control!  CLL is the only type of leukemia not noted after the Chernobyl Nuclear Reactor incident and there no correlation with CLL with other chemicals or Benzene exposures!
Infections however have a demonstrated activity in CLL occurrence.   Scientists will tell you tha disturbances of the NF-KB, NFAT and STATs are commonly found in this disease.   With the Infections, one can quickly conclude that Cytokines and growth factors are and must be involved and they are  (ie. disturbance at IL4).  (Adenopathies'swelling is a result of cytokine activity!)   These are common occurrences, why is it that CLL is not why spread?

1.For CLL to occur, you got to have disturbance in the law against cellular death.

The first evidence for this is the fact that mainly and or only disturbance in DAPK 1 (Death receptor) has been clearly and convincingly demonstrated to be found in familial CLL.  There is a law of nature that says, "to fight infection, the cell must close the door to programmed death, But Apoptosis must happen when certain circumstances are met".  In CLL, This last portion of the law must not be met!  The B cell involved, most likely a memory cell, has gotten rid of genes that fulfill this last portion of the law!  They forget the notion of death.  It is not by mistake that sometime up to 98% of CLL cells have deletion of 13q14 which removes the regulator of Bcl-2  (miR16).  And it is not by mistake that there is an expansion of of Bcl-2, bak ,  Mcl-1 and XIAP reported in the literature.  (and try to find bax or caspases, they are profoundly "suppressively" disturbed)  All are a consequence of relatively total suppression of Apoptosis.  Now wonder why the cells of CLL are mature non dying cells!

2.The law of desensitization.

When an antigen, or any stimulant persists at a receptor, natural laws will kick in to engage desensitization. Nor desensitization has been normally described as decrease in receptors.  The reality is just a it more complex.  As a matter of facts, decreasing receptors which are proteins assumes decreasing gene or gene expression  but the reality can be more severe!  Gene could be mutated or silenced, or fully deleted.  Sometimes the full arm containing the gene could be lost.  There are many deletions in CLL and silencing of promoters (ID4, SFRP family and even DAPK) is notoriously common.  Desensitization can start at receptors, G proteins to miRs and Chromosome arms removal!  This happens for proteins involve in regulations of cytokines, regulators of many involved genes, and hell, even Glycogene regulation is deranged in the process!  The law of desensitization is violated big time here!  In presence of chronic stimulation, even The IgVh region is Mutated! (a strong prognosis in CLL)

Abruptly you find yourself facing the inadequacy of current Biomarkers for CLL.  But things are coming your way with a vengeance and soon!   The CRBCM is following...!

Some genes of interest

1.MTNR1B : A MELATONIN GENE
" insulin levels also exhibit a nocturnal drop, which has previously been suggested to be controlled, at least in part, by melatonin. This regulation can be explained by the proposed inhibitory action of melatonin on insulin release." Mulder et al.

This gene has been linked to gestational Diabetes and some have used it to secgregate patient with propensity to Diabetes Mellitus type 2.

2.HHEX
" HHEX serves to repress VEGFA, another protein which is important in endothelial cell development."wikipedia...Can it play a role in angiosarcoma?
PAZ et al " Hhex is a critical regulator of hematopoietic development and is necessary for the maturation and proliferation of the earliest definitive hematopoietic progenitors."
 HHEX interacts with SOX13
" SOX13 is known to repress Wnt/TCF signaling by interacting with TCF1. We show that Hhex is able to block the SOX13-dependent repression of Wnt/TCF activity by displacing SOX13 from the SOX13·TCF1 complex."Marfil et al

"Otx2, and Lim1 appear to promote hhex transcription through homeobox sites in a Wnt-responsive element located between −0.65 to −0.55 Kb of the hhex promoter. (2) Siamois/Twin also induce the expression of the BMP-antagonists Chordin and Noggin, " RANKIN et al

for CRBCM, role in pancreatic cancer, liver cancer and thyroid cancer needs further clarification

3.Cytokynes (EPC)-JAKs---STAT 3,5----Bcl-xL ----CYTOCHROMEC---CASPASE9-  (WIKIMEDIA)
is this the mechanism of PTSD.?

Prevention and monitoring following cellular zones

As predominant abnormalities of genes are more described as they are specific to each cancer, most likely location of genes in the cell could further characterize gene location for further development of prevention intervention.
These interventions may include:
-gene modification (morphologic, post translational modifications, and otherwise...)
-gene activation that induce overexpression
-gene suppression which induce deactivation (PTEN)
-gene silencing (through methylation and other complementary molecules)
-etc...
Whether you approach the gene targeted for intervention by standard approach or nanotechnology, it is important to predict where you are more likely to find this gene.  Is the gene more likely in the extracellular matrix (Metalloprotease) or in the Nucleus or rether in the epigenic zone.  Where is the gene that is more likely to be other mutated, over expressed or suppressed.

Most of the times, given the light speed of interactions and travel down the pathways, where to intervene may not be relevant, but increasing the odds force scientist to locate intervention points.  ie, Patient with lobular cancer with history of Familial Gastric cancers are known to have E-Cadherin abnormality, focusing prevention efforts on the membrane, will go a long way than focusing studies on Telomeres...

To be continued.....

OUR OLD EXPERIENCE HELPS ! LAS VEGAS ROCKS!

Yes as a drug gains more indications, the past experience makes it easier for Oncologist practitioner to re-use drugs they have been used to!
For Hepatocellular Carcinoma, the drug on the mind of all oncologists is NEXAVAR, yeah, we have been accustomed to managing its rashes and Diarrhea, and watch its marrow suppression.  A combination of weekly visits and then monthly for our patients to start with!
Well it is the same dance once again in Metastatic thyroid cancer, the kind of Metastatic progressing and resistant to Iodine based treatments!   NFX1 OR SHOULD WE SAY
 NBCI-gene "Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth.'
Jing Du et al:"Correlation analysis revealed that there was a positive relationship between the level of HPV16 E7 and the expression of p65. The correlation between E7 and p53 was also significant, although to a lesser degree"
IT'S NOT JUST P65, BUT P300, P25
AND THE NOTCH1 IS NOT FAR ! MEANING VEGF-A-DELTA,JAGGED1,AND A SLEW OF
MIR (s) AND SF3Bs, NOT TO MENTION TENACIN AND CADHERINS!

LAS VEGAS WILL STAY ON OUR MINDS FOR A WHILE, RESPECT SILTUXIMAB FOR THIS!

*How in the world can you succeed this!  But Siltuximab did, BE INDICATED IN A RARE FORM OF A RARE PRESENTATION OF A RARE DISEASE...
EVEN WIKIPEDIA DEFINE :
"Multicentric Castleman disease (MCD) involves growths at multiple sites.^[8] About 50% is caused by KSHV, also called HHV-8, a gamma herpesvirus that is also the cause of Kaposi's sarcoma and primary effusion lymphoma, while the remainder of MCD are of unknown cause. The form of MCD most closely associated with KSHV is the plasmacytic form of Castleman disease while another pathologic form, the hyaline-vascular form, is generally negative for this virus."

BUT  SILTUXIMAB IS:

"On April 23, 2014, Siltuximab was FDA approved under the brand name of Sylvant^[11] for the treatment of patients with multicentric Castleman’s disease (MCD) who do not have human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8).<sup>[12][13]"WIKIPIDEA

WATCH THE 2  AND GO FIGURE!
BUT LET'S GRANT IT, IT IS STILL AN ANTI-INTERLEUKIN- 6, A FACT TO BE KEPT IN MIND AS WE LOOK INTO TBI AND PTSD!   CRBCM IS WORKING HARD!</sup>

LAS VEGAS conference III Mantle cell

We first saw the Death of CHOP/R-CHOP in this disease
Now we see the death of Modified HyperCVAD
Today we see the rise of Ibrutinib-Rituxan in the firt setting of disease treatment
than only come Idelalisib
and ABT-199
and may be HyperCVAD
and if you think of Bendamustine-Rituxan (after failure of Ibritinib), do not forget Maintenance therapy with Rituxan (rather than Interferon)

(as a note, in Europe R-CHOP/R-DHAP but is there a need?) (trying to be controversial here, am I successful?)  CRBCM, we take things in strides!

BUT IN THIS DISEASE, BENDAMUSTIN -RITUXAN MAY BE BETTER THE R-CHOP!
*WATCH THE MIPI

SEE
 "

The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)

Christian H. Geisler1"  GO TO ARTICLE

The Hematologic malignancy review has been completed in Las Vegas II....CLL

In CLL

*?review role of Thyrosine Kinase in CLL
*Prognosi factor remains the same (17p deletion, 11q dletion, ZAP70, etc.)
*CLL remains an uncurable disease
*FCR better than FC
*FCR better than Bendamustin -Rituxan despite more infection which does not impact mortality ultimately, and particularly in the young? (And who thought FCR lost its luster before Bendamustine-R ? watch for 17p deletion though and pick carefully!)
*17p deletion better treated in clinical trials
*Omecetaxine, an alternative approach to treatment
*Therapeutic choices
1.FCR
2.Benda-Rituxan
3.New anti CD20
4.Ibrutinib
5.Idelalisib
6.BCL-2 antibody
Obinutuzumab always used with Chlorambucil :"The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions." NEJM.

The Hematologic malignancy review has been completed in Las Vegas I....CML

In CML  (Information to be rechecked in the literature)
-Cytogenetic recovery becomes even more important as it guides
1. quality of response at 3,6,12 months and should be 10, 1 and 0.1% of the quantitative PCR
and failure to do so impact of patient survival
(MR less than 10% at 3 months, linked to 96% survival at 4 years whereas more than MMR>10% at 6 months is linked to 69% survival at 4years!)
2. direct impacting the survival
*Failure to meet that end point, particularly at 3 and 6 months, should prompt Cytogenetic Mutations reevaluation and based  on Mutation found pick the right TKI
*T3151---definitely Ponatinib or go to transplant (Allogeneic)
*Y253 and others---Dasatinib
*V299 and others---Nilotinib

*At 6 months, if Molecular response not met,
-check for adherence to treatment by the patient, and check for Mutations (ABL kinase domain point Mutation pattern assessment)

That now Major molecular response (MMR) could be expressed as , or MR 4.5

*Recognition that Frontline treatment is changing to 2nd generation TKI (Dasatinib, Nilotinib) but there is recognition that cardiovascular events are more frequent with these agents  ( and Pulmonary Hypertension-particularly with Bosutinib?)

*There is a recording of 4 year survival data (Dasison) MR4.

*Reduction in Ponatinib dosage from 45 to 30mg could reduce lvel of Arterial Thrombosis, and  hypertension rates ?without questionable effect on response rate.

Potential future collaboration lead at CRBCM!

"Thanks Peggy for your quick response,

As I mentioned to you last week, there was a potential collaboration with an oncologist in China. The story was that I met a clinical oncologist, Dr. Baofa Yu, who used be a research assistant professor at UCSD. When I was in Scripps Res. Institute in San Diego, I have known him quite well. He has returned to China about 10 years ago to establish private tumor hospitals using a therapeutic approach he developed to treat cancer patients (He has US and China Patents) . It was very successful. Currently, he has owned four tumor hospitals in China (in Beijing and other cities). He has interest in collaborating with an oncologist in US to use his novel approach to treat cancer patients. I have introduced our research collaboration to Dr. Yu on phone last week. He has great interest in collaborating with Dr. Kankonde. Dr. Yu may come to US for a visit in this coming July. Maybe we can meet here at El Paso. Dr Yu let me tell you that if it is possible, Dr. Yu would also like to invite you to China to visit his cancer hospitals in the near future."

The CRBCM will be honored to learn from DR Yu...

The future will be bright!And only the future will tell!