keeping you in the festivity of independance day!

 To the Inova family,

 

When I was in high school, one of the most enjoyable experiences I had was playing in the concert band.  I was a saxophone player, or a baritone saxophone player to be more precise.  I wasn’t very good due to lack of practice and presumably talent as well,  but I had the opportunity frequently to travel to the “big city” of Asheville, N.C. to audition for a seat on the all-state band.  You see, there are very few baritone sax players and even if you weren’t very good, you had a chance to be chosen for this highly selective band due to lack of competition.  I always used to get nervous despite my reasonably good prospects and can still remember the tension of those auditions as if it were yesterday.

 

So it struck a chord when someone recently shared with me the story of an aspiring French horn  player who tried out for a highly coveted spot on a prestigious symphony orchestra.  The  player had practiced for endless hours and had worked with a coach to gain all the fine points of style and finesse that mark the truly excellent players of the instrument.  To prevent any unintended bias in the selection process, each hopeful had to play behind a screen  to keep their identity hidden.  The orchestra’s other French horn players served as judges to select their new colleague for the orchestra and they were renowned for having extremely high standards.  Excellence in performance was EVERYTHING to them!  So after hearing over twenty auditioning players, it was a little surprising that they were unanimous in their choice and selected the French horn hopeful who had worked so hard.

 

It struck me in hearing that story that excellence really does matter.  Being good or even very good is nice but it’s really not what we at Inova are striving for.  As many of you may know, the Medicare program administrator (CMS) rates each hospital on the quality of its patient experience.  They ask a sample of patients to rate everything from how clean and quiet their room was  to how well the doctors and nurses answered their questions, managed their pain and helped them understand what they needed to do to actively help with their own recovery.  The interesting thing is that the way scores are calculated, they place the highest emphasis on how EXCELLENT the care was.  In many respects, it is the number of patients that rate our care as EXCELLENT that determines how our scores come out (and, as an aside, how much we get paid!).  I have written often that  our highest priorities are embedded in our “TRUE NORTH” goals of providing the highest quality, the best experience for our patients and their families, and reducing our costs  to make our care affordable for the most people.  Like the orchestra musicians, quality, experience and affordability are EVERYTHING to us!

 

And you know what—nothing but excellent IS acceptable!  Like the French horn player who “made the team”, we must remember “very good” just means on some occasions, our patients had pain, they were anxious or fearful,  they didn’t understand what was going on,  they didn’t understand their medicines, or the room was loud and they couldn’t sleep.  Sadly, on some occasions we did things that led to longer periods of recovery and in some instances, caused real harm! 

 

On July 4, we are reminded that some things count most when they are measured in absolutes—such as giving one’s life for your country, or preventing a terrorist bombing, or being there to treat the victims of a disaster.  You either prevail in your efforts or some people may pay dearly--sometimes people die or lose their freedom.  Today we celebrate our independence and similarly, I would invite you to remember that our patients depend on us absolutely. In short, they depend upon us for excellence and nothing less—their very lives may depend upon it. 

 

When the young French horn player who won the audition walked out from behind the screen, the judges” jaws dropped.  Their new colleague (did I mention that they were all men?) was a 29 year old, Asian woman—let’s face it, she didn’t fit the stereotype of what they were expecting at all.  Not by age, not by gender, not by ethnicity – now they had to face the fact that the old French horn section was going to look and be quite different in the future.  And you know what?  It proved to be the best French horn section that great orchestra ever had.  Because nothing less than EXCELLENT was acceptable to their new colleague.  Their true north was simple excellence, just like it is for our patients and their families.  So as we remember fireworks and cookouts, let’s also remember that freedom isn’t free; that excellence doesn’t come without persistent hard work; and that everyone should be judged on their commitment to true north rather than some outdated stereotype.  Our patients deserve nothing less.  Now that’s something we can all celebrate!!

 

God bless you all,

Knox

FURTHER EXPLORATION INTO THE GENES OF PROSTATE CANCER

Prostate cancer is one of the most interesting cancers from research perspective.  It has high Incidence but only 1 in seven patients diagnosed with it dies.  In 2011, close to 241,000 people were diagnosed with this cancer but only 34,000 died of this disease.  This fact points to the fact that some of the pathology in this disease,  has clearly an indolent course while other cases have a virulent course.  The Challenge remains how to best diagnosed those with the virulent course because they require multi-modality therapy for a cure.  It is believed that the virulence status of the disease can be attributed to a mean and bad genetic profile, but to this date the exact profile is being debated.  What is known or currently accepted is that "there is a loss of function of genes that detoxify carcinogens" leading to hypermethylation and silencing of some critical genes which include that of the "PI class Gluthation-S-transferase." (ASCO).

Then there is the fusion of TMPRSS2 with ERG or ETS.  Mutation at SPINK-1  and the involvement RAF kinase are not small businesses!   The RAF Kinase amplification ensures the survival of the disease because with the MAPK (and a little bit of the MTOR) downstream, this pathways is anti-apoptotic.  Therefore it ensures the survival of Prostatic cancer cells.   The SPINK1 is globally a control gene which represses Catalytic enzymes (such as Trypsin) in order to control their activity and keep their activities within normal range.  With SPINK-1 Mutated, there is an uncontrolled cleavage of gene target substrates by relevant Proteases!   and Guess what?  TMPRSS-2 is just such a PROTEASE.
(wikipedia on TMPRSS2-"The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. The biological function of this gene is unknown.^{[2]")
The association of TMPRSS2 with ERG amplify the action of TMPRSS2.  Yes ERG give the Multiplication power of Red cell to a protease.  A multiplied TMPRSS2 product, a protease, goes  to work on its targets and the rest is History!  It will amplified IL-2, CDK 10, splicing factors (SF3B4 which acts on TOP2A), CHEK1, BMPR1A,and CDC5L and DNA-PKC, CID and CHUK!  Through ZMYND1 it activates C11orf30 and blocks BRAC2 to remove gene repair function and cellular tolerance of genetic errors.  Basically the neoplastic process is set and through BMP, metastasis to the bone is set to occur!
With this understanding-please go to work!
The CRBCM is on your side!
HOW MUCH THE KU HELPS TEMPRSS2 IN ITS LOCALIZATION AT NUCLEAR LEVEL IS STILL TO BE DEFINED!  IF VERIFIED IT WILL MAKE THE KU A SUBSTANTIAL TARGET IN PROSTATE AND PANCREATIC CANCERS!}

SO YOU KNOW THIS HAPPENED!

Phase II study of weekly PM00104 (ZALYPSIS) in patients with pretreated advanced/metastatic endometrial or cervical cancer
Medical Oncology, 06/19/2013  Clinical Article

Martin LP et al. – This open–label, two–arm, phase II clinical trial evaluated the antitumor activity and safety profile of PM00104 (Zalypsis) administered as a 1–h, weekly, intravenous infusion (days 1, 8 and 15; every 4 weeks) at a dose of 2 mg/m2 to patients with advanced and/or metastatic endometrial (EC) or cervical cancer (CC) after one previous line of systemic chemotherapy. Despite PM00104 showing mostly mild, predictable, manageable and reversible toxicity, protocol criteria for further recruitment were not met in EC, a futility analysis was done and recruitment was stopped; a low patient recruitment rate together with no evidence of activity in CC resulted in early study closure.


ALSO ONGOING

Study of Zalypsis® (PM00104) in Patients With Unresectable Locally Advanced and/or Metastatic Ewing Family of Tumors (EFT) Progressing After at Least One Prior Line of Chemotherapy

AND 

 

 

Zalypsis: a novel marine-derived compound with potent antimyeloma activity that reveals high sensitivity of malignant plasma cells to DNA double-strand breaks.

Ocio EM, Maiso P, Chen X, Garayoa M, Alvarez-Fernández S, San-Segundo L, Vilanova D, López-Corral L, Montero JC, Hernández-Iglesias T, de Alava E, Galmarini C, Avilés P, Cuevas C, San-Miguel JF, Pandiella A.

Source

Centro de Investigación del Cáncer, Instituto de Biologia Molecular y Celular del Cancer/Centro de Superior de Investigaciones Cientificas-Universidad de Salamanca, Spain. emocio@usal.es

Erratum in

• Blood. 2010 Jul 8;116(1):151.

Abstract

Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC(50) values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.

GENES in Pancreatic cancer

*The gene in pancreatic cancer
1.BRCA1, BRCA2,P16,
2.DPC4,
3.STK11/LKB1 (PART OF THE PEUTZ JEGHERS SYNDROME)
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.^[1]WIKIPEDIA

4.KRAS "WHICH IS INTEGRATED IN THE SIGNALING PATHWAYS OF SEVERAL RECEPTOR KINASE INCLUDING EGFR AND THE INSULIN GROWTH FACTOR RECEPTOR-1
5.ATAXIA TELANGIECTASIA
------------------------------------------------------------------------------------------------
 Testosterone
 ESTROGEN
        !
COMPLEX                      !---------cAMPK------cell polarity and inhibition of abnormal morphology
-LBK1 +      -----------------!
-STRAD                           !----------CDC37 and HSP90 ----NFkB (MAPK)
-MO25                             !-----------SMARCA4-------------BRCA1 and P53

if you use this, please quote wikipedia and CRBCM for your own good!

GANETESPIB AND GENES IN PACREATIC CANCER DUE TO PEUTZ JEGHERS SYNDROME (FROM NCI AND WIKIPEDIA)

DO NOT BELIEVE I NEED FURTHER COMMENTS, JUST THINK ABOUT THIS
RESEARCH HAS BEEN DONE! AND SEE IT THROUGH!
==================================================================
Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.^[2]
However in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.<sup>[3]WIKIPEDIA

 =========================================================================================</sup>

• Terminology Resources

Search for Search text box Starts with Contains

ganetespib 
A synthetic small-molecule inhibitor of heat shock protein 90 (Hsp90) with potential antineoplastic activity. Ganetespib binds to and inhibits Hsp90, resulting in the proteasomal degradation of oncogenic client proteins, the inhibition of cell proliferation and the elevation of heat shock protein 72 (Hsp72); it may inhibit the activity of multiple kinases, such as c-Kit, EGFR, and Bcr-Abl, which as client proteins depend on functional HsP90 for maintenance. Hsp90, a 90 kDa molecular chaperone upregulated in a variety of tumor cells, plays a key role in the conformational maturation, stability and function of "client" proteins within the cell, many of which are involved in signal transduction, cell cycle regulation and apoptosis, including kinases, transcription factors and hormone receptors. Hsp72 exhibits anti-apoptotic functions; its up-regulation may be used as a surrogate marker for Hsp90 inhibition. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

SOCINSKI "Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC)."Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m² ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.

Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.

Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.

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

Signaling pathway of toll-like receptors. Dashed grey lines represent unknown associations

 ^{============================================================}


 SMARCA4 has been shown to interact with Beta-catenin,^[7] SIN3A,^[8][9] Myc,^[10][11] CBX5,^[12] SMARCE1,^[13][14] HSP90B1,^[15] STAT2,^[16] CREB-binding protein,^[17][18] Glucocorticoid receptor,^[19][20] FANCA,^[15][21] STK11,^[22] BRCA1,^[23][24] ACTL6A,^[13][14] POLR2A,^[8][13][14] ING1,^[9] Cyclin E1,^[25][26] P53,^[27] Estrogen receptor alpha,^[17][28] Prohibitin,^[29] SMARCC2,^[13][14][15] SMARCC1,^{[8][13][14][15]} SMARCB1,^{[8][13][14][15][30]} ARID1B^[31][32] and ARID1A.^[13][14]


The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SWI/SNF, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44.^[2]
BRG1 works to activate or repress transcription. Having functional BRG1 is important for development past the pre-implantation stage. Without having a functional BRG1, exhibited with knockout research, the embryo will not hatch out of the zona pellucida which will inhibit implantation from occurring on the endometrium (uterine wall). BRG1 is also crucial to the development of sperm. During the first stages of meiosis in spermatogenesis there are high levels of BRG1. When BRG1 is genetically damaged, meiosis is stopped in prophase 1, hindering the development of sperm and would result in infertility. More knockout research has concluded BRG1’s aid in the development of smooth muscle. In a BRG1 knockout, smooth muscle in the gastrointestinal tract lacks contractility, and intestines are incomplete in some cases. Another defect occurring in knocking out BRG1 in smooth muscle development is heart complications such as an open ductus arteriosus after birth.<sup>[3][4]

=====================================================================</sup>
 Heat shock protein 90kDa alpha (cytosolic), member A1 has been shown to interact with TGF beta receptor 2,^[3] FKBP5,^[4] TGF beta receptor 1,^[3] Glucocorticoid receptor,^{[5][6][7][8][9][10][11]} AKT1,^[12][13][14] Hop,^[15][16] Peroxisome proliferator-activated receptor alpha,^[17] AHSA1,^[18] HSF1,^[19][20] STK11,^[21] C-Raf,^[22][23] ERN1,^[24] PIM1,^[25] GNA12,^[26] Endothelial NOS,^[27][28][29] Androgen receptor,^[30][31] CDC37,^[32][33] DAP3,^[6] SMYD3,^[34] Telomerase reverse transcriptase,^[12][13] HER2/neu,^[35][36] EPRS,^[37] P53,^[38][39][40] Estrogen receptor alpha^[20][41] and GUCY1B3.^[27]

AIDS and lymphoma

*Since HAART, there has been a decrease of Lymphoma and CNS Lymphoma but not that much for Burkitt Lymphoma suggesting different pathology pathways in these various lymphoproliferative disorder in AIDS!
*3 factors impact Lymphoma occurrence inAIDS pt :
lack of HAART, age and low level of CD4
*The protective effect of HAART comes from the immune restoration following HAART.
*Incidence of CNS lymphoma, 5.6 /1000
*patient with HIV who developed Lymphoma had higher IL6, IL10, and expression of CD30. High serum free light chains was also observed!
*c-MYC is related to Plamablastic Lymphoma
whereas CCR5 has low risk for lymphoma
and stromal cell derived factor-1 Mutation has a higher risk of Lymphoma.

*Lymphoma can happen at any CD4 count and T cell count whereas Burkitt tend to occur at relatively high CD4 count where as Immunoblastic lymphoma and CNS lumphoma seem to prefer lower CD4 (around 50 or less).
*Plasmablastic Lymphoma involving mostly the Oral cavity is EBV related and characterized by CD138 and VS38s.
and Keratinization differ it from Oral Carcinoma!
*Hodgkin disease alone does not make it AIDS per CDC!

THE CRBCM

THE CRBCM

There are increasing signs the CRBCM will make it, and everyday that passes reaffirm this.
We are working on several projects, our Medicare payments are coming through finally and more and more contacts are generated.  We have submitted more grant applications and we are feverishly looking for collaboration with good intention institutions, we know where we are headed and our consultation work in Indiana is still ongoing as we advance into the future.
Of course as we advance, some have elected to ignore us, some even have their knifes pulled waiting for an occasion to stab...but remember for those who are ready, no fears will stop us.  We know where we are heading!
Our cause is just, come into our wagon or get out of the way, we will not back down because we feel we are righteous!
We come from Zero, so anything to us is a plus and everyday that passes is the sign of greatness awaiting.  We keep advancing!
THE CRBCM our strength is build from a life full of fights, strong 16 years of Oncology practice full of memories and recognitions.  It is not your isolate opinion that will shake us because we realize it is tainted with politics  and no reality!  We respond to higher good spirits!
The CRBCM, an original Coalition for the reversal of Mortality for all Cancers!

COLLABORATION, THE SAME SONG EVERYWHERE!

Every time I turn around, people are championing Collaboration in research, people embrace it as the way to go!  People see it as a broader way to reach new opportunities and prove to the world.  My experience in El Paso has been rather humbling and sad...People here find an invitation to collaborate as a shrewd way to get them, they see competition and threats!
The CRBCM has approached local universities with funded project, so far no result.  I am told it is this kind of communities of researchers.   Every one fight for survival !  We are now talking with University in Arizona.  This is just pitiful!
===================================closes mind leads to a narrow world=========
07/02/2013.
"Team,

As we have discussed the new normal facing healthcare, we’ve talked about the value of creating strategic partnerships not only to provide highly coordinated care, but also as a way to meet the changing healthcare needs in our community.

Today, I want to tell you about a strategic partnership Inova has entered into with Valley Health System. Our partnership provides for future collaboration in the areas of clinical research, information technology, population health, and clinical service delivery.

The immediate impact of this partnership is Valley Health’s ability to expand its IT capabilities through Inova’s EpicCare platform.

For more information about this partnership, please read the press release that is posted on Inova’s News page.

Thanks,

Mark"

-----------------------------THIS IS WHAT IS HAPPENING IN THE REAL WORLD------------PEOPLE EMBRACE COLLABORATION, AS IN UNITED WE STAND!  ----------------------------------------------------------

CANCER RISK IN COMPLEX RENAL CYSTS

KIDNEY CYST
THE COMPLEX ONE ARE JUST A HEADACHE BUT BEAR A CANCER RISK
MELISSA HEUER ET AL HELPS!

The risk that a complex kidney cyst is, or may become, a kidney cancer depends on its appearance on radiographic imaging (CT scan or MRI). A system to grade kidney cysts by their appearance on CAT scan has been developed, which help doctors to predict which complex kidney cysts are more likely to have kidney cancer inside. This system is known as the Bosniak classification. The Bosniak classification provides specific definitions to classify cysts by the risk of kidney cancer.

Bosniak Categories of Complex Kidney Cysts

Category	Description	Risk of Kidney Cancer
Category I	A simple benign cyst with a hairline thin wall that does not contain septa, calcifications, or solid components. It measures as water density and does not enhance with contrast material.	0% to < 2%
Category II	A cyst that might contain a few hairline thin septa. Fine calcifications might be present in the wall or septa. Uniformly high-attenuation (hyperdense) lesions of <3 cm that are well marginated and do not enhance.	13.7%
Category IIF	These cysts might contain more hairline thin septa. No measurable enhancement of a hairline thin septum or wall can be seen.  There can be minimal thickening of the septa or wall. The cyst might contain calcifications that are nodular and thick but there is no contrast enhancement. No enhancing soft tissue elements are seen. Totally intrarenal non-enhancing high-attenuation renal lesions equal to or greater than 3 cm are also included in this category. These lesions are generally well marginated.	14.3% to 24%
Category III	These lesions are indeterminate cystic masses that have thickened irregular walls or septa in which enhancement can be measured.	50.8%
Category IV	All of the criteria of category III along with enhancing soft-tissue components adjacent to, but independent of the wall or septum.  These cysts are usually malignant cystic masses.	90.1%

The Bosniak classification above, is designed to help your doctor predict the chances that your complex renal cyst is associated with a kidney cancer. This predictive ability is very important in helping you work with your urologist to determine the best treatment strategy for you.  The risk that your kidney cyst harbors a kidney cancer must be balanced with your overall health to so that a proper treatment strategy can be created.

Bosniak category I complex kidney cysts have a less than 2% chance of being associated with a kidney cancer. Bosniak category II complex kidney cysts have an approximately 14% chance of being associated with kidney cancer.  Bosniak category IIF lesions are complex kidney cysts that have more irregularities and are typically larger than category II cysts.  Also, category IIF cysts do not have measurable enhancement on imaging and therefore do not qualify as category III complex kidney cysts.  The “F” in the IIF designation is meant to suggest “Follow” or observe this cyst rather than perform a procedure such as partial nephrectomy or kidney cryoablation to treat the cyst.  However, the category IIF cysts have a higher rate of malignancy which is up to 24%, and therefore it is important to discuss the merits of treatment versus observation with your urologist.  Bosniak catagory III and category IV complex kidney cysts have a 50% and 90.1% chance respectively of being kidney cancer and are often recommended for surgical removal or treatment with cyst ablation."

FOR FULL INFO GO TO THE ARTICLE!

I have not finished speaking about osteonecrosis of the jaw, Medscape comes to the rescue!

Medscape Medical News

Osteonecrosis of the Jaw Linked to Adjuvant Zoledronic Acid

Laurie Barclay, MD

Jul 01, 2013

 

Editors' Recommendations

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• Mammography in Breast Cancer
• Breast Cancer Risk Factors
• Breast Cancer and HER2

Adjuvant zoledronic acid (Zometa, Novartis) used for bone strengthening in women with breast cancer was associated with a 2.1% rate of osteonecrosis of the jaw (ONJ), in a randomized controlled trial published online June 24 in the Journal of Clinical Oncology.
The study authors consider this rate of ONJ to be "encouragingly low," but an expert writing in an accompanying editorial say this rate is "not acceptable," because zoledronate did not improve disease-free survival or overall survival in the study population as a whole.
These latest findings on ONJ come from an analysis of the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, which was negative overall in that zoledronic acid (also known as zoledronate) did not reduce breast-cancer recurrence in the total study population, although a significant reduction was seen in a subset of postmenopausal women.
The AZURE trial involved 3360 women with stage II or III breast cancer randomized to receive standard adjuvant systemic therapy alone or with intensive zoledronate therapy (4 mg for 19 doses over 5 years). The investigators reported all potential cases of ONJ as serious adverse events (AEs), and these were reviewed centrally.
The current study focused on reports of osteonecrosis of the jaw and also on oral health, explain the authors, headed by Emma Rathbone, MD, from Weston Park Hospital, Sheffield, United Kingdom.
After completion of 5 years of study treatment, 486 participants were asked to complete the Oral Health Impact Profile-14 (OHIP-14) as a measure of oral quality of life (QOL). The investigators used multivariable linear regression to calculate mean scores and to identify independent prognostic factors.
Osteonecrosis and Oral-Health Findings
Median follow-up was 73.9 months (interquartile range, 60.7 – 84.2 months). Of 33 reports of possible ONJ during follow-up, all in patients treated with zoledronate, 26 were confirmed to be consistent with the diagnosis of ONJ. In the zoledronate group, cumulative incidence of ONJ was 2.1% (95% CI, 0.9% – 3.3%).
Among the 26 women with ONJ, 35% were said to be "completely recovered," 19% "improving," 12% "recovered with sequela," and in 31% ONJ was "present and unchanged" after treatment.
Based on 362 completed OHIP-14 questionnaires (74% response rate), participants given or not given zoledronate did not differ significantly in prevalence or severity of effects on oral QOL. Among 45 patients who reported 55 dental AEs, 84% were in the zoledronate group. Only 2 of these events were grade 3 (1 episode of jaw pain and 1 of loose teeth), and no grade 4 events were reported.
"Although the cumulative incidence of confirmed ONJ is encouragingly low at 2.1% after a median follow-up of 73.9 months and less than that associated with zoledronic-acid use in the setting of metastatic bone disease, it is higher than that observed in other trials of adjuvant zoledronate that have used a less intense schedule and fewer infusions (6 to 10 infusions) over 3 to 5 years," the study authors write. "There was also an apparent additional increase in reported dental-specific AEs, including jaw pain and dental infections, in the zoledronate arm."
Study Limitations and Clinical Implications
Limitations of this study include open-label design, which could have affected AE reporting; evaluation of oral QOL at a single time point at completion of 5 years of study; and reliance on retrospective patient evaluation of QOL at only 2 time points.
"Our data provide reassurance to clinicians and patients that zoledronate does not seem to significantly affect oral QOL," note the study authors. "The relationship between reporting of a dental AE during the study and worse oral QOL scores strongly suggests that the OHIP-14 is sensitive to oral-health events in patients with early breast cancer. The knowledge that there seems to be no demonstrable adverse impact on quality of life is encouraging, given the widespread use of zoledronate and the recent results in the adjuvant setting indicating that bisphosphonates may improve both disease-free survival (DFS) and overall survival (OS) in certain disease settings."
The problem of ONJ is not unique to zoledronate, as it has been reported with variable frequency in patients receiving intravenous or oral bisphosphonates, and it has also been reported with denosumab (Xgeva, Amgen), which is a RANK-ligand inhibitor.
The cumulative incidence of ONJ in patients receiving intravenous bisphosphonate as adjuvant cancer treatment ranges from 0.8% to 12%, according to an updated position paper from the American Association of Oral and Maxillofacial Surgeons. Significant potential risk factors include treatment potency and duration as well as dentoalveolar surgery.
In February 2004, on the basis of an awareness of these risk factors, the AZURE study protocol was amended to exclude patients with significant active dental problems or recent jaw surgery. All patients received dental-hygiene advice, and investigators received guidance on ONJ diagnosis, prevention, and treatment of ONJ based on emerging clinical guidelines. Exclusion of patients with risk factors for ONJ might have resulted in underestimation of ONJ prevalence, whereas increased vigilance by clinicians might have increased reports of possible ONJ, the authors comment.
"It seems unlikely that a bone-targeted agent will become available in the foreseeable future that is not associated with the development of ONJ," the study authors write. "We need to understand the potential genetic, oral-health, and treatment risk factors; incidence; and resolution of this uncommon problem somewhat better than we do at the present time."
In an accompanying editorial, Charles L. Shapiro, MD, from Wexner Medical Center and Comprehensive Cancer Center, Ohio State University, in Columbus, elaborates on unanswered questions regarding bisphosphonate-related ONJ (BONJ). These include specific underlying mechanism(s), why it is confined to the jaw, predisposing risk factors other than dental extractions, optimal treatments, outcomes, and health-related QOL.

 

The 2% total cumulative incidence of ONJ, although low, is clearly not acceptable. Dr. Charles Shapiro

 

Dr. Shapiro describes the AZURE findings as "an important contribution" but points out an additional study limitation — namely, the lack of clarity regarding whether a standard approach to case ascertainment of ONJ was performed at every clinic visit. If not, there could be potential bias of under- or overreporting suspected cases of ONJ, he points out.

Paroxysmal nocturnal hemoglobinuria (PNH) can have severe health consequences for your patients
Patients with PNH are at increased risk for chronic kidney disease, thrombotic events, hypertension, and other serious health issues.

View presentation from 3 PNH experts

SOL-1572

Information from Industry

Furthermore, he notes that precise definitions were not given for descriptors regarding ONJ outcomes, nor were the details of specific treatments for ONJ.
"Overall, the AZURE trial results showed that IV zoledronic acid on an intensive schedule did not improve disease-free survival or overall survival, and therefore the 2% total cumulative incidence of ONJ, although low, is clearly not acceptable," Dr. Shapiro writes. "Whether there is a subpopulation of women with early-stage breast cancer as has been proposed — premenopausal receiving ovarian suppression or postmenopausal women — in which the therapeutic ratio favors using adjuvant zoledronic acid or clodronate vis-à-vis ONJ and other adverse effects remains to be verified in subsequent trials."
Novartis supported the study. Dr. Rathbone has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Shapiro has reported no relevant financial relationships.
J Clin Oncol . Published online June 24, 2013. Abstract Editorial

 

ABNORMAL HOMEOSTASIS, STOP LOOKING AT IT! THAT IS IF YOU WANT A DIFFERENT OUTCOME.

HAVE HAPPEN TO WONDER WHY SOUTHERN CHINA HAS A FORM OF NASOPHARYNGEAL CANCER, IS IT LINKED TO A PARTICULAR CLASS II MAJOR HISTOCOMPATIBILITY ANTIGENS, OR A PARTICULAR VIRUS RESERVOIR LOCAL TO THE AREA,OR IS THIS LINKED TO LOCAL FOOD ?

Have you wonder why some people will develop Osteonecrosis of the jaw while on biphosphonate, and why the jaw in particular, and why sometime after traumatic intervention, is the shear stress necessary to the pathophysiology of the events, is TNF and the NF-kB involved?

have you wonder why some patient on Phenytoin will develop gum hyperplasia ?

Events at the gene level is your answer, and don't sit there on research fund, we boast that we know the genes but yet we don't don't know events of these very days!  50 years from now, medicine of today will be completely obsolete. We keep looking at a comprehensive chemical panel as our ways of monitoring, looking at potassium level in the blood without knowing the status of related genes !  You and I know that for a normal K (potassium) level hormonal events are in play, kidney function, oral intake and other many components are also in play to maintain Homeostasis!
But do remember there is a right homeostasis where all components leading to it are functioning normally, there is also bad, unstable homeostasis, the abnormal Homeostasis that requires certain component to overwork to achieve such an homeostasis! ie Hyperparathyroidism secondary to renal failure but with normal calcium level...there are consequences to the high hormone maintaining a normal level reuired by homeostasis.  Why? because you realize that hormone is generated by a gene expression. that is the increased for hormone to be amplified, and gene is amplified.  A gene to be amplified some genes are repressed some where, and gene repression can start start something Neoplastic some where! ie PTEN repression!   Also Hormone are not fully specific to one receptor all the time, so there some unwarranted stimulation of some other pathways, and prolieration, evasion, and differentiation are triggered!

The point is we have 20% of people on dialysis dying every year for over a decade,  and we are there sleeping at wheels! our current monitoring is clearly inadequate.  We have no clue as to the status of the Notch and the Wnt in each individual, are we allowed to be surprise to observe a steady rate of sudden death in this population. And with their deaths, stops our observation...wake up people! fund research without politics!! put money where a difference will be made before other takes my message !  fund CRBCM! call 915-307-3354 and organizations such as us! Small but to the point!  Remember when you fund a University, only 20% percent of your funding goes to the true research, the rest is waste and overhead!  Check the budget of the MD Anderson, I am not kidding! fund CRBCM to get your money worth!

FROM FDA BY MEDSCAPE

MEDSCAPE KEEPS US INFORMED! FDA Approvals > Heartwire

FDA Refuses Rivaroxaban Stent-Thrombosis Indication for Now

Steve Stiles

DisclosuresJun 28, 2013

 

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Drug & Reference Information

• Percutaneous Transcatheter Treatment of Deep Venous Thrombosis
• Heparin Use in Deep Venous Thrombosis
• Deep Venous Thrombosis Risk Stratification

RARITAN, New Jersey — The FDA has given a complete response letter (CRL) to one of the companies behind rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals) indicating that it won't, for now, approve the oral factor Xa inhibitor for prevention of stent thrombosis in patients with acute coronary syndromes [1].

A therapy that has been shown to improve bone pain in as little as 3 months in patients with Type 1 Gaucher disease

This therapy has also been shown to improve bone mineral density after 24 months of treatment.

View data

Information from Industry

As noted in a statement today from Janssen, approval for that indication had been sought in a supplemental new drug application (sNDA) based largely on the ATLAS ACS 2 TIMI 51 trial. The CRL, which signals that the FDA wants to see additional data before it will further consider the sNDA, follows others that it sent the companies regarding approval of rivaroxaban for patients with ACS, as reported by heartwire . The drug is already approved for ACS secondary prevention in Europe.
"We remain confident in the results of the ATLAS ACS 2 TIMI 51 trial and are in ongoing discussions with the FDA regarding this sNDA," said a Janssen official in the company's press release on the stent-thrombosis CRL.
The agency has already approved rivaroxaban, an oral factor Xa inhibitor, for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and for preventing recurrences, for reducing the risk of DVT and PE after knee- or hip-replacement surgery, and for cutting the risk of stroke in nonvalvular atrial fibrillation.

METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE EGFR AND IGF CROSS-TALK

METFORMIN SHOULD BE GIVEN WHENEVER ERLOTINIB IS GIVEN, TO SILENCE  EGFR AND IGF CROSS-TALK
==========================================================
WIKIPEDIA

"Role in cancer

The IGF-1R is implicated in several cancers,^[4][5] including breast, prostate, and lung cancers. In some instances its anti-apoptotic properties allow cancerous cells to resist the cytotoxic properties of chemotherapeutic drugs or radiotherapy. In breast cancer, where EGFR inhibitors such as erlotinib are being used to inhibit the EGFR signaling pathway, IGF-1R confers resistance by forming one half of a heterodimer (see the description of EGFR signal transduction in the erlotinib page), allowing EGFR signaling to resume in the presence of a suitable inhibitor. This process is referred to as crosstalk between EGFR and IGF-1R. It is further implicated in breast cancer by increasing the metastatic potential of the original tumour by inferring the ability to promote vascularisation.
Increased levels of the IGF-IR are expressed in the majority of primary and metastatic prostate cancer patient tumors.^[6] Evidence suggests that IGF-IR signaling is required for survival and growth when prostate cancer cells progress to androgen independence.^[7] In addition, when immortalized prostate cancer cells mimicking advanced disease are treated with the IGF-1R ligand, IGF-1, the cells become more motile.^[8] Members of the IGF receptor family and their ligands also seem to be involved in the carcinogenesis of mammary tumors of dogs.^{[9][10]"
==============================================================
MOST OF OUR PATIENTS ARE OBESE, WE CAN EITHER MEASURE THE IGF OR ASSUME THAT OBESE PATIENT HAVE SOME INSULIN RECEPTOR RESISTANCE, AND THEREFORE MUST HAVE A RELATIVELY HIGH INSULIN, AND THEREFORE SOME METFORMIN WILL BE SAFE TO ADMINISTER.
WITH THE BROAD USE OF INSULIN, THE PERCEPTION IS THAT THIS WILL BE SAFE TO ADMINISTER.  TOLERANCE OF ERLOTINIB AND SIDE EFFECT PROFILE MAY ALSO SUGGEST, THE COMBINATION MAY BE EASILY TOLERATED!
PROOF OF CONCEPT WILL BE HOWEVER ESTABLISH THAT REDUCING CROSS TALK MAY MAXIMIZE ERLOTINIB EFFECTIVENESS!  REMEMBER METFORMIN HAS ITS OWN ANTIPROLIFERATIVE EFFECT!  A WIN-WIN SITUATION THAT WILL PROVE SYNERGY!
CAUTION: SIDE EFFECTS ARE UNKNOWN UNTIL A FORMAL TRIAL-DON'T DO THIS ON YOUR OWN!
==================================================================
A GOOD TRIAL THOUGH SHOULD REPORT OR TRACK THE STATUS OF CAVEOLIN-1  THOUGH}

Caveolin-1 is essential for metformin inhibitory effect on IGF1 action in non-small-cell lung cancer cells.

Salani B, Maffioli S, Hamoudane M, Parodi A, Ravera S, Passalacqua M, Alama A, Nhiri M, Cordera R, Maggi D.

Source

Department of Endocrinology and Medicine, University of Genoa, Genoa, Italy.

Abstract

Metformin causes an AMP/ATP ratio increase and AMP-activated protein kinase (AMPK) activation. Since caveolin-1 (Cav-1) plays a role in AMPK activation and energy balance, we investigated whether Cav-1 could participate in metformin's inhibitory effect on IGF1 signaling. The effect of metformin was studied in two non-small-cell lung cancer (NSCLC) cell lines, Calu-1 and Calu-6, expressing higher and lower amounts of Cav-1, respectively. In Calu-1, but not in Calu-6 cells, metformin reduced phosphorylation of type 1 insulin-like growth factor receptor (IGF-IR) substrates Akt and Forkhead transcription factor 3a (FOXO3a), inhibited IGF1-dependent FOXO3a nuclear exit, and decreased IGF1-dependent cell proliferation. Here, we show that sensitivity of NSCLC cells to metformin was dependent on Cav-1 expression and that metformin required Cav-1 to induce AMPK phosphorylation and AMP/ATP ratio increase. Cav-1 silencing in Calu-1 and overexpression in Calu-6 reduced and improved, respectively, the inhibitory effect of metformin on IGF1-dependent Akt phosphorylation. Prolonged metformin treatment in Calu-6 cells induced a dose-dependent expression increase of Cav-1 and OCT1, a metformin transporter. Cav-1 and OCT1 expression was associated with the antiproliferative effect of metformin in Calu-6 cells (IC(50)=18 mM). In summary, these data suggest that Cav-1 is required for metformin action in NSCLC cells.

PMID:

22038047

[PubMed 

 

Communications of Public Heath Importance

The Indiana State Department of Health (ISDH), Indiana Board of Animal Health (BOAH) and the Grant County Health Department are continuing the investigation of cases of variant influenza A (H3N2v) associated with the Grant County Fair.  ISDH has also been conducting statewide surveillance since other county fairs are ongoing and others about to begin.  ISDH has received samples from another county within the state with reports of influenza-like illness (ILI) among swine exhibitors.  Laboratory results are pending and are expected on Monday July 1^st. 

According to BOAH, thirteen pigs at the Grant County fair tested positive for H3N2.  It is not uncommon for infected pigs to be asymptomatic. Pigs that are ill with influenza typically recover within several days.

Symptoms of H3N2v in humans include:  fever, cough, sore throat, chills, headache, and muscle aches.  Diarrhea and nausea may occur in children.  Symptoms usually start about 1 to 4 days after being exposed and last 2 to 7 days.

Many county fairs will open in the next few weeks, and the ISDH is increasing surveillance for ILI.  During the week of June 23-29, fairs are scheduled in the following nine counties:  Daviess, Hancock, Marion, Miami, Rush, Spencer, Vermillion, Washington, and Wayne.  A list of dates and fairs is available on the ISDH website at http://bit.ly/1axgXqE.

The ISDH strongly encourages influenza testing on patients presenting with ILI, defined as a fever of 100 degrees F or greater and either cough or sore throat.  Nasopharyngeal swab specimens from symptomatic persons who have attended a fair or had contact with swine should be sent to the ISDH Laboratory for polymerase chain reaction (PCR) testing.  A negative rapid test does not rule out H3N2v.  For questions regarding specimen collection and shipment, please contact Katie Masterson, ISDH Virology/Preparedness Supervisor at 317-921-5843.   

To collect the specimen, insert swab into the nasopharynx until resistance is felt, and place swab in the tube of viral transport medium.  Break the swab shaft at the scored mark before closing the screw cap tightly.  Label each tube with the patient's name and the collection date.  Transport the specimen on cold packs for overnight delivery to ISDH Virology Lab. The following video, available on the New England Journal of Medicine’s website, is an excellent guide for collecting NP swabs: http://content.nejm.org/cgi/content/full/NEJMe0903992/DC1

Health care providers should contact Shawn Richards at 317-233-7740 for specimen approval prior to submitting specimens to the ISDH Labs.  Only specimens with prior approval will be tested.  Submit specimens via LIMSnet, the ISDH lab's electronic submission system, if possible.  If you do not have an account, please contact the LIMS Help Desk at 317-921-5506 or 888-535-0011, or e-mail at LimsAppSupport@isdh.in.gov.  Before specimens are sent, please make sure that all sample tubes are labeled with the patient's name and ship the specimens to:

Indiana State Department of Health Laboratories

Attn: Virology Lab

550 W. 16th St. Suite B

Indianapolis, IN 46202

When seeing patients with ILI, please document exposure history for the four days prior to onset of illness, including contact with animals, and information about friends or family members with similar illness, including onset time and dates.  Contact your local health department about any patients presenting with ILI.

Current recommendations from the Centers for Disease Control and Prevention (CDC) on antiviral treatment are located at http://www.cdc.gov/flu/swineflu/h3n2v-clinician.htm and include:  

- Antiviral treatment with oral oseltamivir or inhaled zanamivir is recommended as soon as possible for any hospitalized patient and those with evidence of severe complications or progressive illness suspected to have influenza, including H3N2v virus infection, without waiting for the results of laboratory testing.

- Antiviral treatment with oral oseltamivir or inhaled zanamivir is recommended as soon as possible for outpatients suspected with influenza, including H3N2v virus infection, if they are in a group considered to be at high risk for complications from influenza, without waiting for the results of laboratory testing.

- Antiviral treatment with oral oseltamivir or inhaled zanamivir is encouraged as soon as possible for non high-risk outpatients without underlying medical conditions and suspected to have H3N2v virus infection, without waiting for the results of laboratory testing. These persons may benefit from antiviral treatment, if it can be started within 48 hours of illness onset.

For additional questions, please contact Shawn Richards, ISDH Respiratory Epidemiologist, at 317-233-7740 or srichard@isdh.in.gov.  For after-hours calls, please contact the ISDH Duty Officer at 317-233-1325.

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