Saturday, October 25, 2014

The power on Pembro! don't leave home without it (in head and neck cancers)!

Why not combine Pembrolizumab and Methotrexate in head and Neck cancer
and break them up into HPV positive and negative. There is reason to believe this combination would be just as powerful as any Cisplatin based treatment.

Wikipedia
"
Pembrolizumab (Trade name Keytruda formerly lambrolizumab;[1]also known as MK-3475) is a drug marketed by Merck that targets the programmed cell death 1 (PD-1) receptor. The drug is intended for use in treating metastatic melanoma.[2][3] Pembrolizumab was invented by Gregory Carven, Hans van Eenennaam and John Dulos at Organon Biosciences which later became Schering Plough Research Institute and then Merck & Co. [4]
On September 4, 2014 the US Food and Drug Administration (FDA) approved Pembrolizumab as a breakthrough therapy. It is approved for use following treatment with ipilimumab, or after treatment with ipilimumab and a BRAF inhibitor in patients who carry a BRAF mutation.[5]"   and "Methorexate  acts by inhibiting the metabolism of folic acid.[3] Methotrexate began to replace the more toxic antifolate aminopterin starting in the 1950s. The drug was originally synthesised by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatrician Sidney Farber.[6][7]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[8]'

Givem the relative tolerance of these two medications, one must surmise this combination of treatment to be the most tolerable yet effective in disease that seems so virally driven!  We are at the gate of excitement in cancer reaserch and cancer target therapy has just began!
The thing is treatment of locally head and neck cancer has left us hanging,   most people who treat this disease will notice that at the end of radiation  treatment most patient are left with residual mass.  And you keep scratching yourself...should we give additional chemotherapy, watch, of have some form of maintenance therapy?
A lot of patient end up being watched...would maintenance with pembro help survival  ?  How about Pembro+Methotrexate?

Sunday, October 19, 2014

Sentinel node in BREAST CANCER, FROM THE LITERATURE!

a 39 YEAR old Hispanic woman present to us with T2N1 Breast Cancer, she had a Lumpectomy with sentinel node biopsy, the controlateral breast had a reduction to balance her chest, ER positive PR positive, the immunohistochemical for Her-2 2+ however the FISH did not amplify!  DOES SHE NEED ALND?

This case raises many issues
1.at age 39, should we obtain a BRCA gene?
2.frequency of triple positive breast
3.should BRAC be positive should with push for bilateral Mastectomy and Bilateral Oophorectomy
4.should BRCA be positive, what are the proximity genes to look at?
5.what is the frequency of lymphedema post RT
6.Is AC-T the best chemotherapy regimen
7. should T be weekly even though Herceptin is not offered?
8.What is the role of PET in helping decide ALND  Vs RT

but first thing first


"MEDSCAPE

For Node-Positive Breast Cancer, Axillary Radiation Is Best

Kate Johnson
June 06, 2013
The AMAROS trial involved patients with cT1-2N0 breast cancer up to 5 cm and clinically node-negative axilla who were undergoing either breast conservation or mastectomy with sentinel lymph node mapping.
Of the patients with positive lymph nodes, 744 went on to receive ALND and 681 received axillary radiotherapy.
Radiotherapy (50 Gy in 25 fractions of 2 Gy, 5 days a week) was started within 12 weeks of surgery, and directed at 3 levels of the axilla and the medial part of the supraclavicular fossa, Dr. Rutgers explained. Levels I and II of the axilla were mandatory and level III was optional.
There were no significant differences in between the radiotherapy and surgery groups at baseline. Median age was 55 to 56 years, and 38% to 42% of the patients were premenopausal. Median tumor size was 17 to 18 mm, and 75% of patients had grade 2 or 3 cancer.
In the cohort, 82% underwent breast conservation and the remainder underwent mastectomy; 90% received systemic treatments. A median of 2 sentinel nodes were removed from each woman.
For patients who received axillary clearance, the sentinel node was the only positive node in 67%; 33% had further node involvement and 8% had 4 or more positive nodes.
After 5 years of follow-up, the axillary recurrence rate was "extremely low" in the surgery and radiotherapy groups (0.54% vs 1.03%), Dr. Rutgers reported.
Because "this was far below what we anticipated, the trial was underpowered for a noninferiority comparison," he explained.
There were no significant differences between the surgery and radiotherapy groups in disease-free survival (86.9% vs 82.7%; P = .1788) or overall survival (93.3% vs 92.5%; P = .3386).
However, 5 years after therapy, the rate of lymphedema in the surgery group was twice that of the radiotherapy group (28% vs 14%).
"The AMAROS trial provides very important evidence that the kind of regional nodal treatment used after a positive sentinel node biopsy will not substantially affect the risk for subsequent regional nodal failure, rates of metastasis-free breast-cancer-specific, or overall survival in most patients," Dr. Recht told Medscape Medical News.
He explained that a more important question than whether to choose radiotherapy is which type to choose.
"Is axillary radiotherapy better at preventing regional nodal failure than just irradiating the breast, which includes the lower portion of the axilla in many individuals?" he asked.
Dr. Recht said that previous studies that compared breast radiotherapy with ALND — such as the"

ASCO recommendation
Kristen Golberg
"The guideline updates three recommendations based on evidence from randomized controlled trials:
• Women without sentinel lymph node (SLN) metastases should not receive axillary lymph node dissection (ALND).
• Most women with 1 to 2 metastatic SLNs planning to receive breast conserving surgery with whole breast radiotherapy should not undergo ALND.
• Women with SLN metastases who will receive mastectomy may be offered ALND.
The guideline updates two groups of recommendations based on cohort studies and/or informal consensus: 
• Women with operable breast cancer and multicentric tumors, and/or DCIS who will have mastectomy, and/or had prior breast and/or axillary surgery, and/or had preoperative/neoadjuvant systemic therapy may be offered sentinel lymph node biopsy (SNB).
• Women who have large or locally advanced invasive breast cancers (tumor size T3/T4), and/or inflammatory breast cancer, and/or DCIS, when breast-conserving surgery is planned, and/or are pregnant should not receive SNB.
The ASCO committee noted that in some cases, evidence was insufficient to update previous recommendations."

Wednesday, October 15, 2014

We have crossed 50,000 reviews!

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Functional proximity of main genes

It is striking to notice that during the daily practice of Medicine, it seems that despite the big number of genes in the cell, there seem that most pathology in human seems to coalesce in just a few abnormalities ultimately.  Disturbances seem to be mostly
1. In Cholesterol or lipid disturbances
2. which are linked to thyroid or endocrine (hormone) disturbances
3.which are linked to Autoimmune diseases
4,linked to vitamins (D) disturbances
5. and linked to neoplastic phenomena, linked to Glucose derangements
6. and to neurologic and psychiatric disturbances...
The only new phenomena that may be separate but linked is Infection because indeed Infection involves a foreign body looking in!  And fight against infection seems to follow cellular pathways which depend of the nature of the infectious agent...with Viral infections involving the mitochondrial process more than bacterial infection...

Yes indeed, we see for example that a patient may have an elevated white blood cell could have an infection, but in most cases, it is an autoimmune disease, usually associated to a thyroid dysfuction and a depressive or anxiety component.

Now this notion that Prostate cancer recurrence may be associated with dyslipidemia...
or that polycystic kidney disease be accompanied by depression.

Disturbances in anexins and other supportive structures are somewhat hidden but their importance remains in full force...Now I can see why so many genes are somewhat or definitively silent...so much is left un attended to.   My day to day is globally busy with the few genes that I still have my finger up ready to point!  Even when I see the NF1 gene and many growth gene dancing with the BRAC gene...and that triple negative breast cancer in some race is dancing with autoimmune disease that affect the skin (psoriasis)!

Sunday, October 12, 2014

Where don't we dance enough: managing life span, an independent factor in managing cancer patient, and may increase the cure rate!

Because of limited resources available in research, society falls short in the management of cancer patients.  The notion that cancer patient should be managed by affecting only their driver Mutation has been popular lately and most research has focused on this emphasis.  There is a rush to discovering  the driver mutation in each disease.   The truth is that driver mutation although very effective (ie. BRAF inhibitor) for a short time, are quickly overwhelmed by what we have come to know as "mechanisms of resistance"  The point is that cells are constantly exposed to new environmental stimulants.  And their natural TASK is to die or adapt.  And naturally we try to forget or underestimate the adaptative capability of cells, including neoplastic (cancer) cells.  Cure will remain fleeting until a closer look is taken into these adjustment techniques used by the cancer cells.  and it is within that contest that I bring this statement to your mind:

" that SHC-1 not only opposes IIS but also activates JNK signaling. Loss of shc-1 function results in accelerated aging and enhanced sensitivity to heat, oxidative stress, and heavy metals, whereas expression of human p52Shc rescues the shc-1 mutant phenotype. SHC-1 acts upstream of the insulin/IGF receptor DAF-2 and the PI3 kinase AGE-1 and directly interacts with DAF-2. Moreover, SHC-1 activates JNK signaling by binding to MEK-1 kinase. Both aspects converge on controlling the nuclear translocation and activation of the FOXO transcription factor DAF-16." Elke Neuman-Haeflin et al.

If you are shocked and troubled by the placement of this statement here, you are completely within the norm! but let's go back and recapitulate.   Most cells succumbs to external pressure by cellular environmental stimulations.   Hypoxia, autocrine cytokines, chemicals and minerals end up exciting receptors including VEGFRs  (the MEK is close by).  But really when you speak of the VEGF, you imply SHC1,2 and stimulation of Annexins and from there p52, p42, and the famous p66SHC....then you can understand the above sentence...In Gastric cancer for example,  VEGFR2 is stimulated and therefore the effectiveness of Ramucirumab.  (CYRAMZA.)

Please note that the statement speak about p52 and does not even address the main RAS cofactor p66 which may affect Cyclin D and deplete MCI-1 the main depletor of SHC-1. (through PTPNs)
RAS autophosphorylation driving the cancerous process may be hidden here.

These facts point to the truth that independent of cancer driven mutation, control of these processes must occur concurrently to improve the cure!  cancer deaths are produced by progression of cancer but also involvement of cellular maturation and lifespan determinants that most Oncologist do not measure! (we dance very little away from guidelines (NCCN))...

Saturday, October 11, 2014

Pathogenesis of Neoplastic transformations.

Speculative sources of Neoplastic disease

As we plan Cancer Prevention, it seems logical to target potential mechanisms that likely could initiate the neoplastic process in order to propose logical steps.  And clearly, from a beginner stand of view, and from data screening of various cancer, this task could be daunting.  However major patterns have to be proposed as we examine what works, and what are the main metabolic disturbances in each disease.
*In Kidney cancer for example, Here abnormality in the Von Hippel Lindau gene (gene that promote UBIQUINATION) has supported strongly the involvement of an exaggeration of deficient Hypoxia induced factors (HIF) and related proteins.  This facts lead to the removal of inhibitor forces leading to the expansion of VEGF and PDGF.   It takes blocking the either the the VEGF (Avastin) or blocking the MTOR down the line (Everolimus) to slow down the neoplastic process.   Anything in between may have not been efficient.   Hypoxic conditions often found in patient with obesity (associated with sleep Apnea) may favor the frequency of this disease.   The involvement of VEGF explain the importance of abnormal Angiogenesis in this disease...the tumor is bloody ...Therefore, optimizing Oxygenation (CPAP use in obese patient with sleep Apnea), decreasing or impairing VEGF, could have significant prevention use.   Optimizing Iron level may also have a positive impact should studies initiated here further support that iron deficiency may exacerbate the various cellular metabolites.   Interferon and IL-2 should be consider under this light (as to their effect on the VEGF-MTOR  axe. The involvement of Ubiquination beg the question on whether Velcade and anti-TNF related compound may add to the therapy in Kidney cancer.  One thing is for sure, all cancerous transformation try to escape the immune system, and Pembrolizumab could be discussed further within the contest of this disease!   our knowledge is rapidly expanding.

*In Lung Cancer, the neoplastic transformation is diverse since some non smokers are known to develop the disease.  Here we believe that diet based on high levels of anti-oxidant without sufficient compensatory iron (iron deficiency in women particularly) and HIF gene isoforms may lead to  chronic intoxication triggering once again EGFR/VEGF expansion.   Susceptibility of these cancers to Cetuximab/ERBITUX strongly support this hypothesis. Detoxification may also be influenced by CYP1A1 and GSTM1.

In standard lung cancer however, not only HIF is involved, but there is now increasing suspicion that alterations at the MDM-2 has entered the possibility of initiating the disease process forcing further Ubiquination or intervening at some point, affecting the P53, c-MYC, NPM1 and even prot 14-3-3 ("Phosphorylation of Cdc25C by CDS1 and CHK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.[wikipedia) effect on Ubiquitination should be re-emphasized.   With stimulation and amplification of the EGFR/VEGF come the importance of ALK, BRAF, again factors that have enterec lung cancer therapeutics since agents active here have become available (to be continued)

Friday, October 10, 2014

Warsaw Indiana, an interesting case

We are back in Warsaw Indiana completing obligations here for CRBCM.
This exercise also expose us to local pathology and ways they are managed by local Oncologist.
An interesting case encounter here is that of a 22 year young mother who had 2 c-sections and was referred for Menorrhagia, she had a Biopsy of the Uterus, and a Von-Willebrand screen suggested very elevated Factor VIII  (3 times the upper limit).    She is obese and suffers from Hypothyroidism.  Now elevation of Factor VIII has been identified as an independent factor determining an Hypercoagulable state.  We may soon be quantifying related gene.  This Hypercoagulable state is however confusing because it is indeed associated with higher risk of stroke and Coronary events.  However, independent of thrombotic event, does it really require Anti-Coagulation for life?
The patient has been advised Aspirin,  do we  justify Xarelto at preventive dosage?  Should weight loss be a sufficient intervention, should we look for coexisting Hercoagulable factor such as Factor V leyden, or Homocystein for that matter...we are checking TSH level of course...Elimination of this factor is associated with certain Blood Group,  should we type and cross ?  Very puzzling case indeed!  What are the genes proximate to this gene?
BREAST CANCER
familial predisposition has been appreciated by the presence of BRCA1 and BRCA2
but increasingly we find young women with breast cancers who do not carry the mutation expected.  By their age and family history, we know there must be a genetic predisposition for the particular cancer of the breast to occur.
1.Mutation in the genes regulating or acting in the vicinity of the BRCA.
For medicine to advance and allow better use of limited resources and decrease the burden of side effects for our patients, It would be critical that new sets of genes enter the standard detection/category testing in the management of Breast Cancer. There are over 100 Mutations knwon!

2As far as BRCA2 is concerned, interaction with RAD51 has been suggested.   Ween et al:"versican and hyaluronan (HA) which interacts with the HA receptor, CD44, have been shown to play critical roles in ovarian cancer metastasis."  These molecule states (isoforms) have been found to be increasingly affected by interaction with growth factors   TGF and even PDGF.  (early detection of metastatic disease).  They should enter biomarker testing.

3.BRCAs are "wild gene"  first because there are hundred of these Mutations
and also because Wikipidea describes multiple various interactions:

"BRCA1 has been shown to interact with

Monday, October 6, 2014

Getting more training in research, full schedule.....this is my outlook Calendar

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Saturday, October 4, 2014

Treatment in advanced Head and neck cancer

Cetuximab-Cisplatin-5-FU
adding Taxane does not change survival
question maintenance of Cetuximab
weekly Taxol - carbo
Afatinib
weekly Methotrexate
Gemzar - Cisplatin
Pembrolizumab


for early stage of course
------------------------------chemotherapy and weekly Cisplatin +/-Cetuximab
or RT with Cetuximab

Monday, September 29, 2014

ROLE OF SOX5, A DRIVER FORCE. FROM EPITHELIALIZATION TO METASTASIS





                                              TWIST1 ------!
                                                    !                !
                                                    !                !..................E-CADHERIN
                                                    !                !                                !
                                                 SOX5--------!                                !
                                                    !                        miR125B  - - - SNAIL-1------FGF
                                                    !                                                   !        !
                                                    !                                                   !        !
                                                    !                                              SIP-1  MMP
                                                    !
                                                    !
      _______________________!__________________________________
      !                     !               !                       !                !                   !
   COL2A        AGC-1       PPARs              AP-1        ATF1            C-jun

Saturday, September 27, 2014



Dannemiller Mutombo Kankonde, MD
11601 Pellicano Rd
El Apso, TX 79936
Certificate
Dannemiller certifies that the above individual has participated in the enduring material titled Evolving Strategies for Management of Early-Stage and Metastatic Triple-Negative Breast Cancer on September 27, 2014 and is awarded 2.00 AMA PRA Category 1 Credit(s).

Michelle Montgomery, MA, CCMEP
Director of Continuing Education
 
5711 Northwest Parkway – San Antonio, TX 78249 – Tel: (800) 328-2308 – Fax: (210) 641-8329

Breast cancer/TNBC

*when a woman expected to have BRCA1,or 2 fails to have it
should we go on to find PALB2

*for TNBC
1,Taxol or Taxotere weekly
+Carboplatin AUC6 Q4weeks
or
Eribulin (1.4mg/m2 day 1,8 Q21 )  + Carbo
or
Ixabepilone

or Gem-Carbo + Iniparib or olaparib

VELIPARIB +CARBO+TAXOL


Friday, September 26, 2014

Origin of solid/epithelial and some hematologic tumors: disturbance of Ubiquitilation...

Although there seem to come from every single where,
life seems to try to hide from us the single origin of sufficient disturbance that lead to neoplastic transformation, but every where you turn seems to impose upon us that the single most important process involved in the neoplastic process start as a deficiency in the Ubiquilation process!
Yes one of the E3 (or partner) is involved in many cancer.
The involvement may not be directly involving the cellular E(s), however in many instances, molecules containing a E receptor or attachment site will be involved.
In Breast cancer, the SWI/SNF HAS AN UBIQUITININ BINDING DOMAIN:

"SWI/SNF mutations were widespread across diverse human cancers, with an excess of deleterious mutations, and an overall frequency approaching TP53 mutation. Mutations occurred most commonly in the SMARCA4 enzymatic subunit, and in subunits thought to confer functional specificity (ARID1A, ARID1B, PBRM1, and ARID2). SWI/SNF mutations were not mutually-exclusive of other mutated cancer genes, including TP53 and EZH2 (both previously linked to SWI/SNF). Our findings implicate SWI/SNF as an important but under-recognized tumor suppressor in diverse human cancers, and provide a key resource to guide future investigations."  HUNTER SHAIN et al.
"Remarkably, mutations in SWI/SNF were present at high frequency across many different tumor types (Fig. 1A). The cancers with the highest SWI/SNF mutation rates were ovarian clear cell carcinoma (75%), clear cell renal cell carcinoma (57%), hepatocellular carcinoma (40%), gastric cancer (36%), melanoma (34%), and pancreatic cancer (26%). Across all tumor types, the average frequency of SWI/SNF mutations (19%) approached that of TP53 (26%; shown for comparison in Fig. 1A), the single-most mutated tumor suppressor gene." SHAIN AND JOHNATAN POLLACK

"

Mammalian SWI/SNF-A Subunit BAF250/ARID1 Is an E3 Ubiquitin Ligase That Targets Histone H2B[down-pointing small open triangle]

Xuan Shirley L et al"   " together with cullin 2 and Roc1, assemble into an E3 ubiquitin ligase. The BAF250b BC box mutant protein was unstable in vivo and was autoubiquitinated in a manner similar to that for the VHL BC box mutants. The discovery that BAF250 is part of an E3 ubiquitin ligase adds an enzymatic function to the chromatin-remodeling complex SWI/SNF-A."

The part were the SWI/SNF has Histone modulation activity is a relevant one since it points to new creation of sets of molecules that are going to help in the neoplastic transformation.   That in this part of the Silenced DNA, activity at the Ligase will "Unsilence" several genes that will be determinant to the future of the new cell.
=========================================================
In lung cancers, effects at the MDM-2 has now been recognized by studies by DR Zhang (UTEP) that this is one of the most amplified genetic mutation.  Putting the MDM-2 at the onset of cancer pathogenic production.    Yes the disease seems to start here with further secondary amplification of the NPM1 as a result: 

Robert Amson et al
"TPT1"
and

"recruitment of phosphorylated NPM1 to site of DNA damage through RNF-8-dependent Ubiquitin conjugates" Ayaka Koike et al!
implicating BRCA-1 ....

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

The high response rate of Velcade in Myeloma has provided further proof that ubiquitination is a major pathways in this disease
===========================================
In renal cancer
the answer is obvious,

Thursday, September 25, 2014

from ASCO 2014: Treatment of renal cancer

Renal cell cancer

                      setting                          phase III                                             Alternative
                                                           Sunitinib
1st line         Good or Intermediate      Avastin                                               HD-IL-2
                                                           Interferon-alpha
                                                            Pazopanib
                    Poor risk                   Tamsirolimus

================================================================
           Prior Cytokine                      Sorafenib                                           Sunitinib
                                                         Pazopanib                                         Avastin

2nd line      Prior EGFR                Everolimus
therapy       inhibitor                      Axitinib                                             clinical trial

                   Prior MTOR               Clinical trial

From ASCO



Challenges in treating immunocompromised patients

One of the many challenges in treating immunocompromised patient is the lack of predictive bio-markers that help guide treatments of these patients while they are undergoing chemotherapy or any other immunocompromising treatment. In most cases, the treatment is reactive that is we wait until the patient is sick and proceed on to catch up by giving him a combination of Antibiotics, anti-fungals, and other available anti-virals.
We know the patients have either a cellular deficiency or an humoral dysfunction linked to the primary hematologic disease or to treatment.   But we still can't predict what if any infection will be developed.  Perturbation of the integrity of the Gastro-intestinal or pulmonary membranes that could be induced by our therapeutic interventions, and dormant viral (CMV, HH-6,)and bacterial infections (Syphilis,Tuberculosis), all could contribute to an infection outbreak, but no predictive bio-markers are available for current clinical use!
The longer the patient remains neutropenic also impact on what infection can set in!  Briefly, we have no predictive definite Biomarkers to predict what infection will be developed, and in specific cases, in patient undergoing treatment preventive or otherwise.    Ongoing treatment on Tacrolimus or Cyclosporine must be monitored with specific biomarkers that will allow closer monitoring of these patients.  Current medical practice does not allow clear measurement indicators predicting what will happen to the patients.
Another component of these issues, is predicting who will develop a sweet syndrome in our neutropenic patients, and who are susceptible to other rare event such as the PRES (posterior reversible Encephalopathy Syndrome).   Genetic Bio-markers must be out there, our point is just to go get them to declare our readiness for future medicine....

Monday, September 22, 2014

So we said!

According to the US Government on Aging (at least seems to suggest)
to have eternal life you have to have or know some of the genes for these functions:
-Gene(s) to avoid unhealthy choices (ie. blocking Glucogen,controlling lipid,MTOR, CRE gene)
-Genes to keep life sparks (hormones,cytokine,physical exercise,what to eat)
-Gene(s) to keep eternal  youth (Telomeres,MTOR)
-Genes to stay spunky (hormone,routines, MTOR
-Genes that keep you fun (Hormones, cytokines)
-Genes to keep magical transformation (rejuvenating) (Cytokines,
-Genes to avoid physical decline (Exercice under cytokine control
-Genes to avoid vulnerability to disease (Flyn,Lyn directions for looking)

let's go find them!

Saturday, September 20, 2014

News in Prostate Cancer! Getting hot in Las Vegas!

With all the new options for therapy in Prostate cancer, one may wonder if there is still interesting topics and areas of unknown in Prostate cancer.  One thing is for certain, there is no definitive cure for Prostate Cancer and therefore research and progress in this field remain to be accomplished.  And with each conference, one continue to learn new areas of research emphasis.  In Prostate cancer, data free Zones continue to abound as discoveries are made!

Areas of Data free Zone!
------------------------------This is where in clinical practice things are done although there is no clear data to support our practice.

1.Although we all know that patient who fail Lupron should go onto "withdraw", there is no biomarkers to determine who should be chosen for this option.  Often we bypass this withdraw as an option to jump now to Abiraterone or Enzalutamide because we can!  This is however an important period of no therapy that our patients can enjoy with no therapy or side effects!

2.How to determine the most efficacious treatment? or what are the most predictive Bio-markers?
3.Are combination therapy better than sequential use of major therapeutic options
4.Is deterioration of performance status a clear indication of exclusion of spileucel-T use since this drug may take up to 6 months before the curb separation to indicate benefit, should Performance status be used for early initiation of chemotherapy...?
4.what is the role of new immune markers?
CD54 upregulation has been used for the appropriateness of use of spileucel-T?  what about CTC - ARv7 the so called "negative Predictor Biomarker"?
5.Given the impact of the marrow, should RAD 223 come always prior to Chemotherapy or after this?  should documented radiological progression in the bone be the indicator of RAD 223 in a pain bearing patient with metastatic Prostate cancer patient?  And how to interpret PSA fluctuation in RAD 223 treated patient?   Should we always continue to associate Lupron or other anti-androgen treatment that adress non bone disease (or visceral disease) while on RAD 223?
6. What in hell is "liquified semen" while on treatment for Prostate cancer?  And now the role of Eosinophilia in so called "good responders" ? should alkaline Phosphatase, or PAP be better biomarker in patient treated will spileucel-T. Or is-it PA-2024?  Could proof of long term memory by T-cell be evidence of further role for a boost in Spileucel-T.  What is the role of "Antigen spread"? and what that has to do with Cancer preservation and resistance?

7Notion of AR Variant that apparantly lack a binding domain for membrane area activity but can still act deeper into the Nucleus, and is -t here that Enzutamide may be more effective since it impairs deep localisation at AR cellular path...and what are the co-factors allowing this deep action of the variant AR.   Should we really look for AKT/PI3K upregulation in resistant diseases?  And actually which gene cross-talk with the AR in resistant cancers?  And the role of combination therapy in these setting...

8.Instead of fighting all these side effect, should we just push further Orchiectomy?
9.role of Gleason once treatment has been started?
10. Is testosterone level <50ng better than 20ng to define hormone resistance disease?
11. how to appreciate cardiac risk in patient on treatment for metastatic Prostate cancer

EH! patient on Abiraterone, always use Prednisone
but you don't have to for Enzalutamide
and always use GCSF while on Cabazitaxel because the one who died fron this chemotherapy did so after the first cycle of chemotherapy!  experimenting without it at your own risk!

etc...and I can go on for days...at CRBCM, we keep ourselves informed!  still a lot of work even in Prostate cancer....

Friday, September 19, 2014

Wynn Las Vegas, a review on Prostate Cancer...

The CRBCM is back in Las Vegas to sharpen its knowledge on Prostate Cancer
what is new ? Is there a new sequence to treating Prostate cancer...are there new bio-markers, new guidelines, new genes to be aware of? these are the few questions that we have forward. The actual conference will be tomorrow.  Here at the Wynn...the setting is perfect...we will update you as quickly as we get the info....for now just let's enjoy the Wynn...

Tuesday, September 16, 2014

Interesting case at CRBCM: Acute Myeloid Leukemia with myelomonocytic differentiation in a patient with possible Lupus

This is a 74 YOHM who presented to Sierra Providence with vomiting, nausea , poor appetite and weight loss, he was found with a severe anemia. A bone marrow biopsy obtained on 08/11/2014 suggested a Hypercellular Marrow involved with Acute myelogenous leukemia with myelomonocytic differentiation.  There was 70 to 80 % of myeloblasts by morphology and flow.  Further cytogenetic studies revealed a positive inversion 16 ( MYH1) with 7q- (DS486). The CBFB was found in 90% of cells and RUNX1-I mutation in 90% of cells. 
Of note: The ANA was positive.   HIV negative.
The patient received a course of hydroxyurea prior to a standard 7+3 induction therapy with Daunarubicin and ARA-C. A new bone marrow biopsy obtained on 09/02/2014 suggests residual disease with 3% blasts 10 to 15% myelomonoblasts.  the patient will need a reinduction therapy with Idarubicin and  ARA-C.
 Prior to this admission, the patient, an old teacher, was otherwise healthy. He has no history of hypertension, diabetes or asthma.
Of interest: The patient's sister has an open Lupus.
===================================================

This case is very interesting as it suggests progression of Lupus into a monocytic AML
did RUNX-1 under various pressure go awry,
did presence of RUNX-1 suggest activity of Etoposide or may be just activity of Decitabine.
but this is an inversion 16 case, should we forgo standard induction because of the patient age?  But he did tolerate induction treatment at the local Hospital.   He had the 7q minus deletion and therefore a bad prognosis indicator mitigating the Inv(16) presence.  Could he have transplant in good hands...the man has a good performance status and flew through his first attempt to induction!
your feed back appreciated! 

Ida will do (
"Idarubicin /ˌdəˈrbɨsɪn/ or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA from unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy group increases its fat solubility and cellular uptake.[1] Similar to other anthracyclines, it also induces histone eviction from chromatin.[2]"  wikipedia

So it is! from the Indiana State commissionaire

State Health Commissioner
The Indiana State Department of Health (ISDH) has identified four confirmed cases of respiratory enterovirus EV-D68 among Indiana residents.  Testing was performed at the Centers for Disease Control and Prevention (CDC).  Several other suspect cases are pending testing at the Indiana State Department of Health Laboratory.  Syndromic surveillance of hospital emergency department chief complaints has indicated a higher than expected level of respiratory illness statewide for this time of year.  Several other states, including Colorado, Illinois, Iowa, Kentucky, Kansas, and Missouri, have also identified confirmed EV-D68 cases. 
 
EV-D68 infections can be mild and self-limited, but children with asthma are at risk for severe respiratory illness and may require hospitalization to receive intensive supportive therapy.  Patients with asthma should carefully maintain their current medical management and follow their asthma action plan to monitor for early signs of exacerbation.  People who smoke are also at higher risk for severe enterovirus infections.
 
The CDC recommends hospitals use standard, contact, and droplet precautions when caring for patients.  Alcohol-based hand sanitizers are not effective against EV-D68.  Bleach-based disinfectants, like those used for rhinovirus and norovirus, are effective for environmental cleaning.
 
Clinicians are advised to suspect enterovirus infection in patients hospitalized with asthma exacerbations or severe respiratory illness.  To confirm the presence of EV-D68 in Indiana and further characterize this illness, the ISDH Laboratory is temporarily requesting that clinicians send nasopharyngeal and oropharyngeal swabs in the same transport medium or upper respiratory aspirates:
·         Patients must test positive for rhinovirus/enterovirus before submission to the ISDH Laboratory.  Indicate this positive test result and the test method on the specimen submission form.  Specimen submissions lacking this information will not be tested.
·         Specimens from patients who test positive for rhinovirus/enterovirus do not need prior authorization.
·         Specimens do not need to be tested for influenza and respiratory syncytial virus (RSV) prior to submission.
 
Sequencing will be conducted to identify the specific viral strain.  Instructions for specimen submissions to ISDH for testing are located on the ISDH enterovirus page at http://www.in.gov/isdh/26487.htm under the laboratory specimen information section. Specimens should arrive at the ISDH Laboratory Monday-Friday excluding state holidays within three days of the collection date.  Specimens must be submitted using LIMSNET.  To sign up for a LIMSNET account, contact the ISDH LIMS HelpDesk at 317-921-5506 or 1-888-535-0011.
 
Healthcare providers who identify outbreaks or unusual occurrences of respiratory illness should contact Shawn Richards, Outbreak Supervisor, at srichard@isdh.in.gov or 317.233.7125 to inquire about specimen submission and further investigation to identify the cause of these outbreaks.
 
Most enterovirus infections in the U.S. occur seasonally during the summer and fall, and enterovirus outbreaks tend to occur in several-year cycles.  Respiratory enteroviruses include EV-D68 and rhinovirus and are transmitted through contact with secretions from the eyes, nose, and mouth (saliva, mucus, sputum) of an infected person; having close contact with an infected person, such as touching or shaking hands; and touching objects or surfaces that have been contaminated with infectious secretions.
 
No vaccine is available to prevent infection with respiratory enteroviruses, and no antiviral medication is available.  Health care providers should recommend the following:
·         Clean:  wash hands often with soap and water for 20 seconds
·         Cover:  cover sneezes and coughs with your sleeve or a tissue
·         Contain:  prevent spreading illness to others by staying home if you are sick
·         Avoid close contact and sharing cups or eating utensils with those who are ill
·         Disinfect frequently touched surfaces
·         Avoid smoking or exposure to second-hand smoke
                                                                                                                            
For questions regarding epidemiology/surveillance, please contact Shawn Richards at srichard@isdh.in.gov or 317.233.7740.   For questions on specimen collection or submission please contact Stephanie Dearth at stdearth@isdh.in.gov or 317.921.5843.  
 
For more information on enteroviruses, please visit the following websites:
 
Indiana State Department of Health website at http://www.in.gov/isdh/26487.htm.
 
Centers for Disease Control and Prevention (CDC) website at http://www.cdc.gov/non-polio-enterovirus
 
William C. VanNess II, MD
State Health Commissioner

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