a 49 year hispanic woman passed out while taking a shower, she was taken to the ER, further work-up revealed a 6.4 mass in the in her stomach which passed the physical wall of the and into the peritoneal wall. The mass turned up to be A GIST (Gastrointestinal stromal Tumor). An interesting finding by itself since it twist positively the prognosis and raise considerable interest for surgical Intervention.
The internet and the American cancer society suggest "
"Based on people treated between 1992 and
2000, the overall relative 5-year survival rate of people diagnosed with
a malignant GIST was estimated to be about 45%.
- If the tumor was confined to the organ where it started, the 5-year relative survival was 64%.
- If it had grown into nearby tissue when it was first diagnosed, the 5-year relative survival was around 30%.
- If it had spread to distant sites when it was first diagnosed, the 5-year relative survival was 13%. "
from the same sources
"
A few families have gastrointestinal stromal
tumors (GISTs) caused by a DNA mutation passed down from parent to
child. But most DNA mutations related to GISTs are not inherited. These
changes occur for no apparent reason, and are called acquired or sporadic.
The cancer cells of most patients with GIST have a change in an oncogene called c-kit. The c-kit
gene is found in all cells of the body. It directs the cell to make a
protein called KIT, which causes the cell to grow and divide. Usually
the c-kit gene is inactive. It is only active if there is a need for more interstitial cells of Cajal (ICCs). In most GISTs the c-kit
gene is mutated and is always active. This may explain why the cancer
forms. The cells are always growing and dividing. In some families that
have many members with GISTs, doctors have found inherited mutations of
the c-kit gene.
In about 5% to 10% of GISTs, the cancer cells have mutation in a different gene called PDGFRA,
which causes the cell to make too much of a different protein (also
called PDGFRA). This has the same effect on the cell as does KIT.
Most GISTs have changes in either the c-kit or the PDGFRA
gene, but not both. A small number of GISTs do not have changes in
either of these genes. Researchers are still trying to determine what
gene changes lead to these cancers."
Most of these stromal tumors stained positively for CD34 (
Miettinen et al 1995). The KIT protein is a transmembrane receptor for stem cell factor. The
intracytoplasmic portion of this receptor functions as a tyrosine
kinase. The availability of the immunohistochemical marker, CD117, to
the KIT protein, has revolutionized the diagnosis of GIST, by
identifying a treatment target. Approximately 95% of GISTs stain
positive for CD117, making it a very useful marker for diagnosis (
Miettinen and Lasota 2001). This has led to the development of the targeted therapy imatinib mesylate (STI-571; Glivec
®,
Novartis, Basel, Switzerland). This drug inhibits several tyrosine
kinase receptors with varying affinity, including KIT, the BCR-ABL
fusion protein, and the platelet derived growth factor receptor (PDGFR) (
Heinrich et al 2000,
De Giorgi and Verweij 2005). DIN et al
The surgeon have discussed the case and referred the case for Neoadjuvant Gleevec.
-------------------------------------------------------------------------------------------------------------------
"As imatinib targets the ATP (adenosine triphosphate) binding site of
the KIT receptor (encoded by exon 11), tumors with exon 11 mutations
treated with imatinib have a significantly better partial response rate,
event free and overall survival compared to exon 9 or no detectable
mutation. A partial response rate of up to 83% has been achieved,
showing how sensitive these tumors can be (
Heinrich et al 2003a;
Corless et al 2004;
Debiec-Rychter et al 2006)."DIN
(DO PATIENT NEEDS TO REDUCE ATP PRODUCING MOLECULES IN THIS DISEASE ?)
(HOW DOES CAJAL CELL ACTIVITY LINKED TO TUMOR PROGRESSION/PRODUCTION)
(IS IT CRITICAL TO KNOW WHICH GENE IS AFFECTED IN AN INDIVIDUAL PATIENT)
DON'T GET EXCITED WE KNOW THE ROLE OF EXON 11.
and like any good thing, Gleevec comes with a word of caution per DIN et al:
--------------------------------------------------------------------------------------------------------
" The main circulating metabolite is an N-demethylated piperazine
derivative which accounts for 16% of the AUC (area under the curve) for
imatinib. This, with imatinib accounts for most of the activity, but
there are a number of smaller metabolites. CYP3A4 is the major
cytochrome P450 involved in imatinib metabolism. Thus, drugs that are
co-administered may alter the pharmacokinetics. Erythromycin,
fluconazole, and rifampicin have shown inhibition of imatinib
metabolism. Imatinib increases exposure to simvastatin. Alprazolam,
caffeine, clindamycin, clonazepam, cortisol, ethinyl oestradiol, and
verapamil may cause toxic effects when given with imatinib. St. John’s
wort increases imatinib clearance by 43%. Patients should avoid
excessive amounts of paracetamol as both are metabolized by CYP3A4 (
D’Amato et al 2005;
Novartis 2005).
What makes this case even more interesting are 2 additional informations (and believe me I would not bring forth this case if there are no more twists), few months back the dermatologist had seen the same patient for Neurofibromatosis. Indeed she has disseminated on her skin "NEVI" like lesions typical of this disease. NOT ONLY SHE HAS THE NF-1 RELATED GENE, BUT SHE ALSO HAVE "CAFE AU LAIT " SPOTS
--------------------------------------------------------------------------------------------------
RAISING THE POSSIBILITY :" Mutations in the NF1 gene have been linked to NF-1,
Juvenile myelomonocytic leukemia and
Watson syndrome. A condition with a separate gene mutation but similar
Café au lait spots is
Legius syndrome which has a mutation on the
SPRED1 gene.Patients without
Neurofibromin 1 or SPRED1 mutations may have
SPRED2,
SPRED3 or
SPRY1,
SPRY2,
SPRY3 or
SPRY4 mutations.
[5]...." WIKIPEDIA
and
Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation
Kaisa Haglund,"
(raising the possibility of anti-EFR in this disease)
AND A NEW CULPRIT IS BORN: ANDERSON ET AL.
"
Sprouty (Spry) proteins modulate the actions of receptor tyrosine
kinases during development and tumorigenesis. Decreases in cellular
levels of Spry, especially Sprouty2 (Spry2), have been implicated in the
growth and progression of tumors of the breast, prostate, lung, and
liver. During development and tumor growth, cells experience hypoxia.
Therefore, we investigated how hypoxia modulates the levels of Spry
proteins. Hypoxia elevated the levels of all four expressed Spry
isoforms in HeLa cells."
PLEASE INTERFERE WITH SPROUTY ABSOLUTELY......
AND THIS INCREASES THE ROLE OF THE RAS AMPLIFICATION IN THIS DISEASE, AND MAKES ANTI-MEK EVEN MORE IMPRORTANT....AS A POTENTIAL AMPLIFIER DOWNSTREAM!
CAN SPROUTY EXPRESSION BE A BIOMARKER IN THIS DISEASE?
====================================================
Just as you start to get comfortable with the case
let me bring up yet another twist to this genetic rich case,
as I examine the patient, I find out quickly she has been unable to raise her hands for years and has been told to be ANA antibody positive....Now if you have been a careful reader, you may have noted that Juvenile Myelomonocytic Leukemia is part of this syndrome, pointing to a potential disruption of Monocyte which are incriminated in autoimmune diseases. Polymyositis came to mind as I examine the woman
" Another important event in the pathogenesis of Polymyositis is the increased expression of
MHC
proteins by m/s cells. Auto-Ag is presented in association with MHC-I
molecules on the surface of Myocytes and is recognized by CD8 cytotoxic T
cells that subsequently initiate m/s destruction."wikipedia
Pachman et al!
" It is our premise that JDMS is a distinct disease entity and that the increase in HLA-B8 and -
DR3
in JDMS places this disease in the company of other immunopathic
disorders.
There are conflicting data concerning immunological abnormalities in
JDMS , but there appears to be impairment of natural killing and
evidence of complement activation.
The frequent positive ANA in JDMS raises the speculation of its
relationship to the antinuclear antibody, Jo-1, found in some adults
with PM, which has specificity for tRNAHis.
Most newly diagnosed JDMS patients have antibodies to Coxsackie B which
may be related to the
pathogenesis
of this disease.
Specific pathological findings of endothelial cells containing
reticulotubular inclusions are associated with vessel occlusion,
subsequent obliteration and increased Factor VIII levels in clinically
active disease."
SHOULD I TEST FOR COXSACKIE, WHO IS GOING TO PAY!
THE LADY WAS FOUND WITH A PULMONARY EMBOLUS
AND COULD NOT BE ANTICOAGULATED AND A FILTER WAS PLACED
SHE HAS AN HARDENED RIGHT THIGH
AND TO CONCLUDE, HER FATHER DIED OF PANCREATIC CANCER
AND SHE HAS AN INQUISITIVE DAUGHTER WHOM I MAY BE FORCED TO TEST ALSO AS TO HER PREDISPOSITION TO THIS CALAMITY SYNDROME!
