Openings on cancer cure I

The challenge of cancer cure remains closely linked to the mechanism underlying the cause of the neoplastic process that caused any particular cancer.  And the practice of Oncology  of today is clearly with limited vision not adapted to the challenge posed by most cancers.  This challenge is compounded by the inadequacy of insurance reimbursement which does not cover most gene testing, and the lack of knowledge of genes and their pathways.  This lack of knowledge of genes is actually in part due to political pressures that lead to mal-distribution of research funds to mostly ineffective institutions, institutions that compete for funds but with no clear vision...leading to disparate research!

Cancer cure has shown us that unless you know what mechanism is underlying one particular cancer, the treatment will be short lived or clearly ineffective.  Indeed the treatment may be harmful since it may induce new gene alterations that may worsen the clinical setting of the patient.  We also know that even when a cause is known, and the target defined, attacking cancer cell always induce a survival reflex, the cancer cell quickly develop or amplify new pathways to remain alive.  That secondary survival born new mechanism have yet to be significantly approached by modern Oncology.  Indeed, we are still focused on first
treatments.   Is it true that MTOR inhibitors should follow anti-VEGF?  These principle have been mentioned in the literature but not written in stone....In colon cancer, Emphasis have been made on secondary anti-VGEF since these have been known to amplify after use of primary anti-VGEF...

Some Cellular activity in neoplasms

"The researchers also found that the human genome is peppered with more than 1,200 large regions that are consistently devoid of DNA methylation throughout development. It turns out that many of the genes considered master regulators of development are located in these regions, which the researchers call DNA methylation valleys (DMVs). Further, the team found that the DMVs are abnormally methylated in colon cancer cells. While it has long been known that aberrant DNA methylation plays an important role in various cancers, these results suggest that changes to the cell's DNA methylation machinery itself may be a major step in the evolution of tumors."
From "Ludwig Institute for Cancer Research"

Although this statement states the importance of Methylation of genes in Colon Cancer, none of the histone deacetylators or epigenetic acting medication such as medications such as etoposide are not actively used in Colon cancer. It is also fair to assume that current medications used must have an impact of the cells in this disease despite the fact that we don't deliberately follow relevant biomarker to quantify these effects.  Indeed doing so could lead us to sharpen our use of medicines...
Despite their complexity, epigenetic phenomena are critical in immune defense, cell orientation determination, and here in neoplastic transformation.   Differentiation is somewhat relatively shut down and contribute to cellular return to multiplication involved in cancer.  Some suspect this is due to methylation of differention and gene stopping division (CDKs and ROS modulators to say the least).  New cell orientation is further re-enforced by cellular committment to new mission by 14-3-3 and the consensus NOTCH gene.  Other epigenic facts will precipitate this through Cytokine like factor, the rise in importance of Cyclin B1 should be noted here for lung cancer.

Another way of orienting cellular processes
is the creation or production of transcription factors...indeed the production of certain TF may lead to a shutdown of other line of protein affecting the cell  as well as production of some cell effectors re-orienting the cell....

Change in micro-environment may create new set of circumstances that  favor one cellular orientation or production vs another and could be used as a means of pushing the cell toward a direction Vs another....(Clathrin or no Clathrin) " it performs critical roles in shaping rounded vesicles in the cytoplasm for intracellular trafficking. Clathrin-coated vesicles (CCV) selectively sort cargo at the cell membrane, trans-Golgi network, and endosomal compartments for multiple membrane traffic pathways." wikipedia

formation of these essential structure would be impossible without Clathrin....

For Neuropathy

1.Duloxetine
2.Nortryptilin
3.Neurontin
4.Baclofen, Ketamin gel!
from the literature!

Gene interference!

There is now strong evidence that YWHAG gene abnormality are strong initiator of cancer (biomarker)
that PAK-1 disruption could dissociate Rho from G proteins and slow down Metastasis!

That patient with mood disorder could be candidate to Breast cancer through interaction DISC1-DYNLL1-BRAC1...
That involvement of RUNX2 represent an escalation since this gene can induce Malformation
and again 14-3-3 could mark a dangerous escalation given the auto-exacerbation potential at this gene
and that this amplification should be a biomarker for use of BRAF inhibitor also (to be tested)

The list may go on but these are worth mentioning!

pondering on this case

A 57 year old male presented in December 2013 to a general clinic complaining of abdominal and diarrhea that was intermittently bloody, the patient maintains he did not have insurance and did not undergo an abdominal cat scan.   By march 2014, he has lost weight and went to Juarez Mexico to be evaluated, There, an abdominal cat scan was also not completed.   Finally 2 weeks ago, he was admitted with leg swelling and shortness of breath, the rectal bleed continued....This time not only he was found with bilateral Deep vein thrombosis (DVT),  a Pulmonary Embolus, A CT revealed a a 7 cm liver Metastatic lesion, the mass in the distal transvers Colon had a "controlled" perforation and an abces like formation was observed through the wall of the Colon at the Ulcerated bleeding mass.  The bleeding was important, in 2 weeks of the evaluation, he received 8 units of PRBC, and anticoagulation could not be performed.  An IVC filter was placed.
A surgical consult was reportedly obtained and somehow decision not to proceed with palliative resection was not immediately made, and the patient was referred to CRBCM for an oncologic opinion and need assessment for Neo-adjuvant chemotherapy.

While an eager Oncologist would certainly Obtain an MRI of the brain, preparing for use of Avastin, place a port catheter for a Folfox infusion, One needs to set back and look at certain aspects of this case.
Treating with chemotherapy
1.May open wide the perforation in light of a shrinking tumor, leading to a frank peritonitis
2.The mass is bleeding, an indication for palliative surgery
3.The "Abces" could also spark a significant abdominal infection/peritonitis when marrow suppression is induced by chemotherapy.
4.The anticoagulation that is contre-indicated by the bleeding mass, could be further exacerbated by chemotherapy which on its own has been linked to DVT.  The thing is removal of this colon lesion would allow easy anticoagulation and diminishing post-phlebitic consequences!
5.We will not dwell on consequential Microangiopathy which will come into play when liver lesion resection will be due!
6.To make this matter interesting genetically, the CEA was below 4 and drastically  so!  0.7 as a matter of fact.
7. And the KRAS not requested by early observers!

This case has touched so many aspect of problems encountered in the management of Colon Cancer that capture our attention....

By the way, we have recommended the palliative removal  of the culprit Colon lesion, the patient does not have insurance and the surgeons are not very eager to proceed...such is life in the real world and there is nothing you and I can do other than advocating for our patients!   Quite frankly, chemotherapy drug makers have been responding to us so far in helping patients but obtaining a service from specialty physicians has been the hardest to achieve!  No one wants to help for free especially institutions which receives millions in public funds!

Our (CRBCM and Greater East Cancer center) work continues though...will see it through...because our fight is just!

Alpha Anti-trypsin, interesting questions

A tour de force of nature going awry, or a simple application of cellular principles that raises questions?
Is it a liver disease or a lung disease or both...What are the biomarkers of disease progression, are the disease anti-secretion proteins or molecules of relevancy to  say breast cancer ?what is the role of Cytokines (IL-1&6)? are they evaluation more reliable than PFTs., importance of the CYP1, CYP2

Careful what you read or should you have a second look into cytokines? YKL-40

There are certain genes that cause concern and are deemed prognosis. That is their presence clearly induces a bad prognosis because they cause either cancer irreversibility (ie. excessive presence of Cyclin B1), cancer resistance (MDR gene) or resistance to therapy (YKL-40 induce resistance to gamma irradiation).However
Certain Cytokines have duplicite or ambiguous roles that is, depending on the scenario or the writer, have a defined role to suit the circumstances in which they are studied.
The YKL-40, like the Metalloproteases and certain prominent cytokines and , have been used to conveniently by many authors to be reported as biomarkers, or prognostic factors.  A recent article suggest they are prognosis in Bladder Cancer.   But it seems that they can be elevated  not only in certain cancers but in inflammatory diseases.  In fact a certain cellular state of Hydroxylation may increase this Biomarker, but also stimulation of a common pathway with no prognosis impact (AKT).  In this case, reversing the gene may not have a meaningful therapeutic role.  
Given its role in Vascular remodeling, this gene  (YKL-40) seems important in the Vasculitis and coronary events!? (bladder inflammation)  or is-it?

Is is a modulator of chemical reactions?  let's pause and reflect!

don't finger CRBCM, we are trying!

I was literally stopped to be questioned about statements on my blog!
it is a blog
the statements although based on facts
are inted to shock or tease the readers mind
and query !
they are not scientifically already established
their main objective is to capture the readers' mind
and fashon it a way to tease and prompt an internal reaction
you are not to cure nanism or dwarfism with Dasatinib even in DDR2 positive affected individual
but don't close your mind to the idea
DDR2 checks is not part of standard check covered by insurance, but let's keep on fighting to make it so!
Indeed many known abnormal genes or known Mutations are not currently tested despite their proven importance in clinic.  ROS-1 for example is well known for its importance in lung cancers, but not customarily requested.  The NCCN is slow to come up with these recommendations in order to stay conservative...In a world which cries for more therapeutic answers.  A world in which we know that all cancers are not equal!
There are of course link that we know or suspect to be important but can't prove a thing...not because data are missing but because money is not in research.  We suspect for example that some G-proteins are important in the severity of certain Diabetic vasculitis and Neuropathy, but we wait for funds to test the hypothesis in clinical settings...
Where are our congressman?
Where are funding institutions?
Where are the politicians?

progress at CRBCM!

The CRBCM is continuing to advance...
we are completing our mission in Louisville Kentucky, with expansion into Indiana, from Madison to Seymour IN. (and of course scottsburg).  mission going well.
Our son graduated from Sallisbury, MD
and of course the biggest new is the first payment to CRBCM for its EHR or Electronic record by Medicare...the expansion in on!
we are returning to El Paso to prepare or finalize our CPRIT participation.

what that's means in termes of gene abnormality for humira

The drug increases chances of getting lymphoma
viral infection (hepatitis)
TB
CNS complications
allergies
immune reactions
worsening of these immune diseases
is it a LYN, receptor, or other problem, a quick review is in order
(to be continued)

The case of Urothelial Cancer

Greater east cancer center was referred a case of a 42 year old man with history of previous admission for Peptic Ulcer disease who had reported to the hospital for indigestion, fatigue, 20 lbs weight loss and abdominal epigastric pains.
The patient underwent an EGD which suggested a non raised ulcer. Biopsy at the Stomach revealed an undifferentiated cancer.   A subsequent Colonoscopy revealed the same lesion in the Sigmoid and rectal areas with signet ring characteristics but clearly the same lesion.  Given the suspicion of a Urothelial cancer with plasmacytoid differentiation based on immunochemistry and flow, presence of CD138, it was decided to perform a Cystoscopy which indeed revealed a positive biopsy by the same malignancy.  There was evidence of a significant penetration of the Detrusor.  There was extensive retroperitoneal node invasion with clear evidence of obstructive Uropathy.  Aside for a port placement, bilateral nephrostomies were placed.
It was decided this was a stage IV disease.
Of interest, the patient had history of recurrent folliculitis or abcesses on the skin or infected cysts removed.
(the question is the gene (s) involved may be linked to this abnormality)

The case  brings to genetic studies many questions that remain unanswered in the current state of treatment
1.Should we just proceed with Gemzar-Cisplatin (the Bladder regimen theory in Urothelial cancer treatment)
2 does Carboplatin has a role in the Metastatic setting (the creatinine was 6.0 on admission)
issue of dialysis was raised. But does reduced Cisplatin on a 5 day regimen better in this setting or is-it better to give Oxaliplatin.
3.The literature suggest response to gastric regimen such as EOX (Epirubicin, Oxaliplatin, and Xeloda-propsed by NIH)
frankly the idea of protracted exposure to Xeloda was attractive.
4. The peculiar nature of this disease raise the issue of whether BEP would be a better regimen and not MVAC, and a secondary role of Ifosfamide, Etoposide?
5.Is this cancer related to testicular cancer given the eventual secretion of Beta-HCG (germ cell cancers)
6.The production of CA 19-9, and the response to GI chemotherapy regimens raised many related questions
on whether genetic basis in this disease process mimic the pancreatic cancer process. role of protein 14-3-3,
and related cascade that uses the chaperon HSP-90.  Role of anti-MEK?
and that Cytoplasmic concentration of CDC25 could be a relevant bio-marker,
and activities of the SCHOC-2 and RAF-1 are relevant in this disease,
or Cyclin B1 for that matter (AS DEMONSTRATED IN OUR LUNG CANCER STUDY)!  COULD PREMETREX BE TRIED IN THIS DISEASE?  (REMEMBER THE MVAC -HAS METHOTREXATE!)

9.Cyclin B could serve an initial event.  Can Cyclin B level be followed by immuno?
10. Could cyclin B  and the HSP chaperon role play into the global elevation play into GI susceptibility to metastasize or to initiate in multiple level of GI tract
11 what is the role of STUB1 and Parkins?

IS CYCLIN B ------RAF1  THE MAIN CANCER ROUTE?

COULD THE SUSCEPTIBILITY TO TREATMENT THE SAME AS DISUSSED IN PANCREATIC CANCERS?  SEE NOTES FROM LAS VEGAS?   WHAT THE LINK WITH EMBRYONAL CANCERS OR SARCOMA---IS RAF 1/CDC25 STILL THE CULPRIT?

ROLE OF VELCADE IF UBIQUTYLATION IS INTO PLAY AS EXPECTED! It is plasmacytoid isn't it!

THE CRBCM WILL NOT HAVE THE MONEY TO ADVANCE THESE QUESTION GIVEN THE CURRENT NATURE OF LOCAL AFFAIRS!  YOU WHO CAN PLEASE CHALLENGE US! 

Case in point : Urothelial Cancer with plasmacytoid histology

>the tumor is bad news
1.It is Multicentric, Multifocal, and therefore metastatic at time of diagnosis
2.Its signet rings characteristic has deep meaning and may have had something to do with its tolerance by the body and metastatic or invasiveness. (and dyscohesive or non cohesive nature of cells at morphology of cell suggestive of Micro-environment corruption)
3.plasma cell characteristic "CD138"
4.secretion of Validated Biomarkers CA 19-9 and Beta-HCG
5.response to Platinun based regimen (Bladder---Gem-Cisp Vs GI origin---EOX)
6. Affect the young maximizing life loss
7.poor prognosis outlook
8.Wang et al. "The immunohistochemical profiles of the tumour cells were focal positive for E-cd, PCK, EMA, CAM5.2, CK7, CD138, AE1/AE3, and CK20, but negative for LCA, Vim, and S-100."
9.Nabbout et al:" After receiving 6 cycles of neoadjuvant chemotherapy (epirubicin, oxaliplatin, capecitabine), the lesions responded well and the patient underwent a complete gastrectomy with jejunoesophageal anastomosis."

The tumor current evaluation rarely include gene evaluation and therefore is inadequate.

by producing CA19-9 proximity to Pancreatic cancer is unquestionable

Genes with dangerous behaviors

1.Do remember that in the selection of genes to silence, find one that causes a Malformation  when mutated or deficient
i.e the BRAF gene can cause some of the cases of Leopard Syndrome
i.e always remember the story of Thalidomide and the reason it was banned, interacting with related genes paid off!

2.dangerous genes are those that can auto-activate or auto-inhibate, you know if some thing goes wrong, wild neoplasm can ensue!

3.now we learn that some gene like Casein can phosphorylate several other gene
watch out for the lighting of other genes!

4.Gene regulators of main pathways (ie...PTEN)

5.Genes at check points

6.Genes that are at terminal pathways, their lack terminates a function, but now derailing compensating mechanisms or bypass mechanisms can be neoplastic

7.genes that stop or derail differentiation

8.genes that are important in vital mitotic steps

9. the telomerases

10.genes that makes the cell move!

11. genes dominating the microenvironment and genes involved in protein transport within the cell (i.e the molecular chaperones) clathrin, Auxillin, HSP(s)

12. and in a class of its own, the Ubiquitins!   lung cancer seems to occur because of the direct effect on the Ubiquitins!   MDM2!  particularly the Adenocarcinomas!

13 belong to "a family of conserved regulatory molecules" ie 14-3-3....full of "conserved regions".  Once a cell decided to conserve it...it becomes a critical gene!

14. Gene that affect several members of the same genes (CABIN-1 affects  MEF(s))

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

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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.