Denosumab: The Better Option for Bone Metastases in NSCLC?

H. Jack West, MD

Jan 23, 2013

 

 Overall Survival Improvement in Patients With Lung Cancer and Bone Metastases Treated With Denosumab versus Zoledronic Acid Scagliotti GV, Hirsh V, Siena S, et al

J Thorac Oncol. 2012;7:1823-1829

Background

Patients with bone metastases from solid tumors typically are treated with either zoledronic acid or denosumab to reduce the risk for future skeletal metastases. However, therapy for bone metastases is usually a secondary focus, with greater emphasis placed on systemic therapies to improve survival and/or directly reduce a patient's cancer-related symptoms.
Denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), is administered subcutaneously once every 28 days. The treatment became a feasible and arguably superior option in the wake of several trials demonstrating a significantly superior reduction in the rate of skeletal complications as compared with zoledronic acid.^[1-3] In the absence of a difference in overall survival (OS) or any major differences in adverse events, combined with the notably greater cost for denosumab, I concluded in the editorial^[4] that accompanied the publication of one of the studies^[1] that denosumab was an appealing option but there was no mandate to consider it the standard of care.
Oncologists and patients have historically been most motivated by improvements in OS. Consequently, when a subset analysis of patients with lung cancer from the trial of denosumab vs zoledronic acid reveals a significant improvement in OS, as published by Scagliotti and colleagues, I view this as a very relevant factor to consider in our clinical management decisions.

Study Summary

Specifically, the broader trial enrolled 1776 patients, and the leading subtype was lung cancer, including both non-small cell lung cancer (NSCLC) (n = 702) and small cell lung cancer (SCLC) (n = 109). Denosumab when compared with zoledronic acid was associated with a statistically significant improvement in skeletal-related complications of new or progressive bone lesions that required palliative radiation, opioid pain medication, or caused a pathologic fracture. More important, denosumab was associated with a significantly superior OS by 1.2 months (8.9 vs 7.7 months; HR = 0.80). Also, an improvement in survival was seen across tumor histologies, including adenocarcinoma and squamous NSCLC, as well as SCLC, in which denosumab was associated with a difference in survival of 2.5 months (7.6 vs 5.1 months; HR = 0.81).

Viewpoint

The oncology community is typically somewhat skeptical about exploratory subset analyses, which are often viewed as "fishing expeditions" for positive results that might not be borne out in prospective testing. I think it is quite fair to view the results of this subset analysis with some skepticism, but I consider these results to be more robust than many post-hoc subset analyses because of the large size of the study (having a total of 811 patients), the hard endpoint of OS, and the consistency of the results across multiple histologically defined groups of lung cancer patients.

Importance of biomarker testing in advanced NSCLC

Which patients should you test for biomarkers?

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OC468600PROF-D 10/12

Information from Industry

Overall, my view is that even without the difference in OS, denosumab offered some compelling arguments to favor it over zoledronic acid, but with evidence supporting a 1.2-month improvement in OS -- seen in SCLC and squamous cell NSCLC patients, 2 groups for which we have had great difficulty offering any interventions with a survival difference -- the cost of denosumab over zoledronic acid seems to be a relative bargain. I'm inclined to accept the shortcomings of a retrospective subset analysis because I would argue that these data only move denosumab from a justifiable, compelling option to a very strong leading consideration for my patients with bone metastases from lung cancer. If denosumab can improve survival at a relatively low cost compared with so many of our other interventions, the oncology community should be more proactive about providing denosumab to appropriate patients and not relegating it to the status of an afterthought compared with other systemic interventions.
Abstract

 

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Medscape Oncology © 2013  WebMD, LLC

Cite this article: H. Jack West. Denosumab: The Better Option for Bone Metastases in NSCLC? Medscape. Jan 23, 2013.

MTOR INHIBITOR, changing Oncology practice,

I confess that after the Taxanes and Velcade,  the MTOR inhibitors are one of the most powerful drugs that came to the market, inducing critical change in oncology clinical practice.  It seems that if you have resistance to Hormone, the MTOR inhibitors answer the call and break the barrier, if you meet resistance to Octreotide in Neuroendocrine disease, the MTOR inhibitors emerge with an answer, if you are dealing with a refractory condition such as clear cell renal cell cancer, go to MTOR inhibitors. And the list is rapidly growing as we move forward.
When you look at the site of action, you quickly understand why.  Not only do they take their momentum deep into the nucleus (FOXO 3 and crisscross with the deep MYC amplification pathways), it has also Mitochondrial effects!  I believe this is why it is so effective!  The MTOR inhibitors, harvesting new ways to Caspases and Apoptosis.  Cure is still within reach!

In advanced prostate cancer
TREAT FIRST-LINE WITH PROVENGE TO
EXTEND SURVIVAL

Pivotal trial results

The PROVENGE pivotal trial was designed to demonstrate an overall survival benefit

The pivotal trial was a Phase 3, randomized, double-blind, controlled study¹

• Primary endpoint—Overall survival
• Secondary endpoint—Time to objective disease progression

Trial Design¹

*Eligible patients were hormone refractory and had metastatic disease in the soft tissue and/or bone with evidence of progression; 18% had received prior chemotherapy (including docetaxel).
^†Control was nonactivated, autologous, peripheral blood mononuclear cells.
^‡Progression=radiographic evidence of disease progression.
^§Autologous, peripheral blood mononuclear cells that were cryopreserved at the time of control generation and subsequently activated.

64% of patients in the control group, following progression, crossed over to a nonrandomized open-label protocol to receive an investigational autologous immunotherapy made from cryopreserved cells¹

• Treatment in the open-label protocol was at the physician's discretion

PROVENGE extends median survival beyond 2 years

PROVENGE reduced the risk of death by 22.5% vs the control group (P=0.032)¹

Overall Survival Benefit of PROVENGE^1,2

Data originally published in The New England Journal of Medicine: Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
Average time to subsequent therapy with docetaxel in the IMPACT trial was approximately 1 year.¹

PROVENGE provides a sustained survival benefit and a durable immune response

PROVENGE provided a survival benefit every year studied³

Overall Survival Benefit for PROVENGE³

^||(Percent PROVENGE-percent control)/percent control.

	Percentage of Patients Alive: ITT Population (95% CI)3
	1 year	2 years	3 years	4 years
PROVENGE	81.1% (76.9, 85.3) n=274	52.1% (46.4, 57.7) n=129	31.7% (25.7, 37.8) n=49	20.5% (14.0, 26.9) n=14
Control	72.4% (65.6, 79.1) n=123	41.2% (33.5, 49.9) n=55	23.0% (15.5, 30.5) n=19	16.0% (8.5, 23.4) n=4

ITT=intent-to-treat.

PROVENGE provided a durable immune response³

• A sustained immune response to PROVENGE was seen out to 26 weeks in the pivotal study (the last time point measured)

PROVENGE provides a safety profile you and your patients can manage

Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events³

92% of patients in the PROVENGE group in the pivotal trial received all 3 infusions³

The most common adverse events (≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache³

PROVENGE is not cleared by the liver or the kidneys and does not require dose adjustments or monitoring of liver/kidney functions

PROVENGE does not require concomitant steroids

Autologous use

• PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

Serious adverse events

• In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Common adverse events

• The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

NEXT ARTICLE
NCCN Category 1 recommendation and patient selection

INDICATION

PROVENGE^® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.
Please see the Full Prescribing Information.

References

1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
2. PROVENGE [package insert]. Dendreon Corporation; June 2011.
3. Data on file. Dendreon Corporation.
4.  
5. ==========================================================
6. THIS NOTE COME FROM THE MANUFACTURER, NOT CRBCM, JUST FOR YOUR FYI

DON'T SAY I DID NOT MAKE YOU AWARE

The Indiana State Department of Health, the Tippecanoe County Health Department and Purdue University are investigating a positive case of typhoid fever in a food handler at Purdue University.

Anyone who ate at the Boiler Bistro, John Purdue Room, or the coffee shop, Lavazza, at Marriott Hall on the Purdue campus from January 23-25 2013 may be at risk. Health officials advise these individuals to see a healthcare provider right away if they start to experience symptoms such as a high fever (103° to 104° F), weakness, stomach pains, headache, nausea, vomiting, constipation or diarrhea, or loss of appetite. In some cases, a rash of flat, rose-colored spots may appear. Symptoms usually begin within 8-14 days after exposure, but could potentially appear for up to 30 days.

 

Health care providers are encouraged to ask those who present with these symptoms about potential exposure and consider testing for typhoid fever.  Stool and blood are appropriate specimens for testing.  Suspect cases should be reported immediately to your local health department.

People are at risk of typhoid fever if they eat food or drink beverages that have been handled by someone who infected with Salmonella Typhi or if sewage contaminated with the bacteria gets into the water used for drinking or washing food. Typhoid fever is more common in areas where hand washing is less frequent and water can be contaminated with sewage.

Typhoid fever is a life-threatening illness caused by the bacterium Salmonella Typhi. In the United States, approximately 400 cases of typhoid fever occur each year with 75 percent of these acquired while traveling internationally. Typhoid fever is still common in the developing world, where it affects about 21.5 million persons each year. The case being investigated recently traveled internationally and this is where the infection was acquired.

 

For questions, please contact Sarah Slette, ISDH Enteric Epidemiologist, at 317-234-2808 or sslette@isdh.in.gov.

William C. VanNess II, MD

State Health Commissioner

ROLE OF UNDERSTANDING THE "LAWS OF NATURE" IN CELLULAR BIOLOGY.

Although cells pathways have now been described, harvesting this information with no discrimination will not lead to a cure in a timely fashion.  There is a perception that combining therapeutic agents will always be better than using one agent.  Extremists have even believed that throwing to the patient a kitchen sink of medications could yield better results.  And time and again these approaches failed to show an improvement of survival.
One of the most memorable example is the CHOP story which led to keeping CHOP as standard of care for lymphoma over at least 2 decades.  The CHOP reign ended with the Arrival of Rituxan, a target therapy.
What we have learned over the years is that there could be minimal or no improvement in attacking the cell by focusing  on one pathways.  Attacking the cell on different steps of the pathway works only if that Pathway has the DRIVER mutation.  Otherwise the cell will easily escape the attack using its inter-connections, loopholes, redundancy and heterozygosity mechanism.  The NF-kB would allow adaptative transformation.
For a clear clear improvement in effect, combined drug should affect 2 different pathways as they relate to different laws of Nature:
1. DNA Break  (compromising cell division) include P53 arrest
2. Microtubule Break (compromising Mitosis, cell division, cell migration, and Embryogenesis) lead directly to Caspase in the Mitochondia
3. Receptors (impairment of signal generation and amplification and Angiogenesis) Growth factors, cyclins, anti VGEF, FGFR,
4. Impairment of Amplification  (blocking signal amplification, includes Proteasome inhibitor which dampen signal transduction by harvesting an overall feedback-negative effect of ubiquitinated compounds )
5. Impairment of Differentiation (RAS)
6. Immune Modulation
7. Opening Hidden traps to Apoptosis or program cell death (FOXO3, histone deacetylase)
8.  Impairing Migration to block Metastasis and cellular sensing of its environment lead to Anoikis.

Most combination fail because they focus on 1 of the 8 aspects.

Taxol carboplatin has been good to us because of the Microtubule and DNA.  This combination works better in standard rate of cell division.  In higher rate, breaking the DNA faster with Etopside-Cisplatin prove to be beneficial (small cell lung cancer, c-MYC is the amplifier like in Burkitt).  But it is until you involve the Mirotubule that you see benefit such as in Gastric cancers.  Adding 5-FU based product did not show benefit particularly in Gastric cancer.
CAF in Breast cancer was incremental because of DNA breakage but also because of the Adriamycin effect of cellular membrane which disturb the Microtubule at this location.

DRUGS AFFECTING one each path generally surprised us

1 here are CISPLATIN, etoposide,Oxaliplatin
2. Taxanes
3. Avastin, Erbitux
4. Velcade, Afinitor, Cabozantinib
5. anti-BRAF, anti-Hedgehog, Ibrutinib
6. Interferon, Rituxan
7. M-tor, Dasatinib
8. Anti-Integrins

 significant combinations should cross these 8 lines! And choice should be based on
1. Solid Vs Hematologic disease
2. Knowledge of Driver Mutations if any
3. Knowledge of driver pathways if any
4. knowledge of Resistance mechanism if any
5. knowledge of preponderant specific Receptor
6. Importance of Cyclins and growth factors
7. Exclusive Seeding niche if any

CABOZANTINE COULD BE THE ANSWER IN PAPILLARY RENAL CANCER AND ANGIOSARCOMA.

Based on the fact that Cabozantine is an inhibitor of RET, MET,VEGF 1through 3, KIT, TRKB, FLT and TIE-2.   It needs to be tried in papillary renal cancer, angiosarcoma, and VHL were amplification of MET is important.  in VHL however, proof of concept studies should be done when Cabozantine is combine to MTOR or Velcade.

Cabozantine and Velcade would have an exclusive role in Myeloma

cabozantine and MTOR would have an exclusive role in Clear Cell Renal cancer
 A role in Pheochromocytoma is anticipated!

NEWS from ASCO

1.The kitchen sink thrown to the patient when it comes to combination chemotherapy, sometimes, works!
It was the case for FOLFOXIRI in Colon cancers, and sometime Pancreatic cancers.   In Myeloma, DR Palumbo from the Italian Gimena reportedly suggested the Bortezomib, Melphalan,Prednisone and Thalidomide, (BMPT) followed by 2 years of maintenance BT was better than BMP alone.
Median progression free survival 35.3 months Vs 24.8 months.
5 Year Survival  (OS) 61%  Vs 51%.

2.patients with history of 30 pack year and still smoking, or have quit within 15 years, 55-74 years of age. can now be offered low dose Cat scan (CT) instead of a Chest X-ray.  This new National Cancer Society standard is based review of the literature since 1996, and the new National Lung Screening study (NLST) suggesting a 20% reduction in Mortality between the 2 groups.

3.  MCL1, MYC,JAK2, PIM1,BRCA would be the gene mostly involved in Triple negative Breast cancer. Some common pathways also listed  (Researcher from Vanderbilt suggested)

4.Ibrutinib ?becoming an important option in Mantle cell. with a 70% response rate as compared with   30% achieved by other drugs in relapsed/refractory cases.  Target therapy is in!

5. Telintra, Ezatiostat was granted Orphan drug status by the FDA for treatment of Myelodysplastic Syndrome.

AMERICAN DIABETES ASSOCIATION AND THE EUROPEAN ASSOCIATION FOR THE STUDY OF DIABETES UPDATED THE ALGORITHM FOR DIABETES TREATMENT IN 2012.

The new algorithm suggest
1. lifestyle modification (diet and physical exercice)
2. Metformin; REDUCE RELEASE OF GLUCOSE BY THE LIEVR, NO WEIGHT GAIN
3.Sulfonylureas (Glimepiride,Glipizide (Glucotrol), Glyburide(Micronase) are secretaogogue complicated by hypoglycemia and weight gain
4.Thiazolidinediones(glitazones) (Actos and Avandia)  Avandia has Heart attack concerns and is of limited use in the US..Weight and fluid retention are of concern
5.GLP-1 Receptor Agonist:  Glucagon like peptide increases secretion of Insulin by the pancreas, decreases Glucagon, increase sens of satiety and therefore weight loss.
5.DPP-4 Inhibitor, blocks GLP-1 degradation, and therefore behave as inhibitor of GLP1
6.Insulin
other meglitinides (to be taken 30 min before the meal because they are short acting "Sulfonylureas like", alpha Glucosidase Inhibitors (slow degradation of larger carbohydrates to slow the spike of Glucose in the blood)  ,Colesevelam (Anticholesterol that slow down absorption of glucose in the gut), Bromocriptine (effect on circadian control of hormones) and pramlintide (Amilin like, regulate gllucose after meal).  (to be continued)

RENAL CANCER PREVENTION (CHRONIC USE OF DECONGESTANT -AFRIN- COULD DECREASE RENAL CANCER.) and so does a CPAP mask for patients with Sleep Apnea

Renal cell cancer risk is associated to smoking and Obesity (hypertension is a corollary risk we claim).   These 2 conditions lead to Hypoxia generally through sleep Apnea  which in turn leads to a relative increase of Hemoglobin. The rise of Hemoglobin increases the portion of Desaturated hemoglobin. After many years of such exposure desaturated Heme enhances Phosphorylation at Tyr-530 of the SRC leading to its deactivation. In some individuals with the right MEK, suppression pf the SRC could lead to persistent amplification at the MEK which is a versatile activator of almost all signals, but particularly VEGF receptor.  This in turn usually lead to papillary cancers. Amplification of signal transduction started at the MEK (which amplifies almost all major known pathways) will lead to increased ubiquitination and proteasome destruction of the HYPOXIA-inducible factor  (following the Von Hippel-Lindau model.  This will lead to clear cell cancer. Associated desaturated Heme and hypoxia at the mitochondria will participate in the transformation (and possibly the Atypia/clear cell transformation).  The preponderance and center piece role of MEK amplification and subsequent VGEF/PDGF will justify the "bloody" nature of kidney cancers, and vessel involvement in these diseases  (MEK is the driver Mutation in papillary cancers).  IT ALSO EXPLAINS WHY SUTENT, NEXAVAR WORKS.  AND MITOCHONDRIAL DISTURBANCES AND SECONDARY AMPLIFICATION OF AKT, THE MTOR INHIBITORS WORK IN RENAL CANCERS  (MTOR participates more in clear cells)  (proof of concept pending)

In Western society, obesity is increasing, and so is Sleep Apnea.  Also, we live in closed homes (in some regions such as Texas and Louisiana, Mosquitoes are not helping) the level of dust participates in the increased level of allergic Rhinitis/ upper respiratory ailments.  It is not unusual to sleep and wake with closed Nostrils.  In obese individuals, this compounds the hypoxic episodes and worsened and prolonged hypoxia.  And we are back to depression of SRC, activation of MEK---akt, MAPK and so forth.
Keeping your nostrils open at night appears to be a critical strategy in preventing renal cancer, particularly in patients with breathing issues.   Lung cancer may be reduced for non smokers, but I wont touch that speculation, but do remember the role of VEGF in non-smoker lung cancers!

The involvement of PDGF which is by the way affected by Sutent seems to open a window in the frequency of strokes and heart attacks at night!  That's another debate to have...!

MTOR inhibitor in combination with Anti-VGEF/ MEK could have a significant role in non smoker lung cancer.?
Velcade could have a role in VHL prevention ? and in Pheochromocytoma?

Avastin and Mtor inhibitor could treat Leiomysarcoma of the Uterus if you follow this logic!

A FREED CPRIT AND THE NIH COULD HELP!

ANNOUNCEMENT : ACTIVITY AT CRBCM, EXPANDING ITS REACH.

Lunch with Dr. Padilla and Dr. Kankonde

WE ARE WORKING HARD AT CRBCM

to Martha, rojero, me, doctor.padilla, Martha, Peggy

Title: Lunch with Dr. Padilla and Dr. Kankonde When: Wed Feb 6, 2013 12pm – 1:30pm (MST) Where: Olive Garden - 1870 Joe Battle Who: 'Martha Contreras', ..

Your Agenda for Wed Feb 6, 2013 No earlier events 12pm Lunch with Dr. Padilla and Dr. Kankonde

NEW DEVELOPMENTS

Home > Blogs > Online First/Online Only > ONLINE FIRST: Pancreatic Cancer: Gemcitabine Plus Nab-Paclit...

Online First/Online Only Articles/items published ahead of print or only online.

Monday, January 28, 2013 ONLINE FIRST: Pancreatic Cancer: Gemcitabine Plus Nab-Paclitaxel Prolongs Survival in Patients with Metastatic Disease BY RABIYA S. TUMA, PHD SAN FRANCISCO -- Patients with metastatic pancreatic cancer now have another option for treatment, researchers reported here at the Gastrointestinal Cancers Symposium. In a Phase III randomized controlled trial, patients treated with nab-paclitaxel plus gemcitabine had a median overall survival of 8.5 months, compared with 6.7 months for patients receiving gemcitabine alone (Abstract LBA148).

THE CLEAN-UP AT CPRIT SHOULD BE EASY NOW!

I read again the good independent audit of CPRIT's operation and organization.  In a way, this is good, what happened to CPRIT.
The experiment/trial at CPRIT is over. An evaluation is in.  The powers will look at it and frame it better. From the bad will come the good. CPRIT will sharpen its image and work.  This, however, will not occur until a clean-up is completed.  Once again, I believe the task at the end should be easier than one would think.  The new leaders at CPRIT will have a clear map for their work thanks to this audit. Act on each recommendation, with honesty and leadership, and a solid dose of vision for the cure, and you put CPRIT back to work in no time, and elevate it to how grand it should be.

There is a key to success: A CLEAN-UP!
THOSE WHO SLEPT, SHRINK THE VISION, THE POLITICIZED CPRIT NEED TO BE REMOVED. NO NEW "BIDON (FALSE)" FOUNDATIONS OR NETWORK OR INCUBATED COMPANIES.  NO NEW INFORMATION GATHERING OR REFERRAL SERVICES CLOGGING THE SYSTEM WITH NON PRODUCING ENTITIES (WE HAVE THE GOOD OLD YELLOW PAGES FOR THAT).
4 REGIONAL  OFFICES with power to approve grants for a greater Texas, and dilute the fight among the universities.  I can't say this enough: 42% of funds to one single university is the worst thing done by CPRIT!  You and I agree on this very point.  CPRIT funds are coming from all Texans, not just Houstonians. These funds need to be redistributed accordingly to serve the cancer needs of all Texans.

Nobody knows how the cure will come, but an early attempt of a formulation must be made to
guide the research.  Prevention must be centered around Regional Survivorship centers, and all companies moving to Texas should not end up in only one town.  (Gridlock of Houston is not what you want anymore, I was there for 1 month doing home visits, I swear...!)   ALL IN ALL REMEMBER EL PASO, 4TH CITY OF TEXAS, with a meager 0.2% INVESTMENT FROM CPRIT DESPITE A LOCAL UNIVERSITY PRESENT (UTEP).  CRBCM spoke to university professors there at the Border Biomedical Research Center.  They have no clout, political muscle in CPRIT stalling all communication, they say.   But here is where CPRIT would have easily picked up the people's support...El Paso is an underserved city, and with a large low income population, prevention programs would and will have a huge impact.   Richer cities like Houston will not exerience similar per capita benefits.  Prevention programs have higher impact in low income areas where people are hungry for new directions and opportunities.  Its like feeding a rich man Vs a poor one.  The rich will send you a list of complaints on he quality of your offer, the poor will be mesmerized by a good looking loaf of bread!  Send a meaningful cancer prevention program our way (EL Paso), and you will see how the people will embrace it!

7 years left, lets get back to work, FREE CPRIT, cut our losses, and give the people another chance to find the cure!

BETTER IMAGING FOR BREAST CANCER: TOMOSYNTHESIS

*Tomosynthesis gives "200 one-millimeter-thick images for an average sized breast, compared to 4 images in a regular 2-D digital mammogram" leading to 41 to 61% increase of cancer detection compared to standard 2-D digital mammography.   It also reduces the return for additional imaging, according to a report by Donna Plecha, MD, Director of the Dept. of Radiology at UH, Case Western School of Medicine.

*Thomas Bachelot et al. submitted results of a phase II study related to use of Capecitabine and Lepatinib as first line therapy for patients with Brain metastasis from HER-2 positive Breast cancer.  45 patients enrolled, Median follow-up 21 months.  65.9% of patients had a partial response noted.

*Another Disparity:  Although white Americans have twice as high an incidence of Bladder cancers, at similar grade and stage of disease, Black Americans do have a higher mortality!".  There is a 5 fold relative risk for those who smoked  20cigarettes/day for over 40 years, compared, of course, to non smokers.

*Marginal Zone Lymphoma.includes:
-MALT
-Nodal type
-Primary splenic type which can have villious cells that can be confused with Hairy cell morphologically on peripheral blood.

has CD20+, CD5-, CD10-, CD23-
In extranodal cases, 60% have Trisomy 3 and t(11;18) which produce fusion API2and MLT, and will mark resistance to Antibiotics
API2 is an inhibitor of Apoptosis
MALT1 (procaspase) bind to Bcl-10 leading to activation of NF-bK which ultimately impair Apoptosis
Associated to Sjogren disease in some cases, in the stomach, associated with H.Pylori
Rituxan as a single agent, local RT,

NOMENCLATURE OF GENES AND PATHWAYS INVOLVED IN BUTEIN INHIBITIONS: IKK and Sirtuin

IKK:
The subunit to be inhibited for the activation of the Nuclear factor and pathway NF-kB which has versatile transforming capacity to combat, escape and resist various attackers including infection and chemotherapy.  Inhibition here reduces the cell capacity to adapt.  It appears that the Transcription factor NFkB is sitting there in the Cytosol totally inactive, touch the IKK through phosphorylation, wakes the NFkB which spring into motion and unleashes its power.  One of the best described pathway flow is TNF posphorylation of IKK which detaches and goes on to  being ubiquitinated and degraded through the Proteasome.  detachment of the IKK lead to a free NFkB kinase which enter the nucleus to unleash all kinds of genes of defense.  DO REMEMBER that upstream NFkB go through MEK (also involved in Angiogenesis) to reach MAP3K and you can see how through networking of these pathways the phenomena gets global.

Sirtuin:
This compound is SIRT1, it is  activated by BUTEIN
Butein actually activate SIRT1 and may induce aging in the cell.  Remember Butein by activating Sirtuin will have a role in Diabetes, Gout, Alzheimer dementia, and Amyloid related disease.  Butein, a versatile anti-inflammatory drug with effect on NAD (Nicotinamid), and may be a Histone De-acetylase inhibitor. This stuff has potential! 

BUTEIN, A POWERFUL INHIBITOR

As we speak with the University of Texas in El Paso, the CRBCM would like to look further into the clinical use of a potent Inhibitor in a phase I study.  We believe this compound will have a significant role in Triple Negative Breast Cancer.  Butein, a derivative of Charcone, a powerful anti-Oxidant and known anti-inflammatory used in ASIA, seems to have a global inhibitory effect.  It is one of the 3 inhibitors of the SRC, it is a Glutathione inhibitor, Blocker of EGF, inhibitor of IKK, and of the NF-kB signal transduction pathway, cause phosphorylation of the AKT, reduction of Cyclin D1 and D2,  activation of WAF1/p21 and KIP1/p27, Iron induced inhibitor of Xanthine Oxidase (love that enzyme since I first learned about Asthma).
This Butein stuff is a global inhibitor.  If you add this to MTOR inhibitors, you may end up with too toxic a combination for any cancer! This would be an overwhelming attack on cells!

It has demonstrated powerful Ex-vivo activity against breast and prostate cancer cell lines, and is empirically used against Gastric cancer.

This global and versatile inhibitor, Butein, should have activity in Sarcoma since it inhibits SRC and potentially the fibroblast.  Other Inhibitors of SRC, heme supported phosphorylation and CYIKYYF.  (of note CDK1, PTRC and PTK2)
  
Gave you so many letters, lets move to gene Nomenclature please!  we are still working hard at the CRBCM!

CRBCM MET DR RENATO AGUILARE of the University of Texas in El Paso.

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

Aguilera, Renato	Feb 1 (3 days ago)
to me

Shown below is the parking pass –it needs to be displayed so please print it and follow the instructions below to avoid a ticket.  A campus map is also enclosed.  My office is located in the new Biosciences Research Bldg and I am in room 4.144

Renato J. Aguilera, Ph.D.

Professor of Biology

Deputy Director and

Director of the Cell Culture and HTS Core Facility

Border Biomedical Research Center

University of Texas at El Paso

500 W. University Dr.

El Paso, TX 79968-0519

Ph:(915)747-6852
======================================================================

The Meeting was centered on potential scientific collaboration between the BBRC and the CRBCM  &  Greater East Cancer Center.  The collaboration is called for by most grant funding source for both entities.  The Biomedical research (BBRC) needs cooperation with cancer centers, and the CRBCM needs ties with the local University.
We discussed the careful handling of exchanged study tissue or fluid samples which should follow NCI protocols related to studies on human subjecst (Dr Kankonde attended appropriate NCI training and is a certified investigator like most American Oncologists)  and proper handling of patient information should follow HIPPA guidleines.  Under the term of the understanding, no patient name will be released to the University staff.

CRBCM also met DR GIULIO FRANCIA, PHD, Assistant professor in the Dept. of Biological Sciences at UTEP.  The line of discussion was similar.  Collaboration on future investigations and publications was the bulk of the discussion.

The CRBCM has 2 grant request application letters pending before the BBRC.
Details of the plans are still waiting to be finalized.  The meeting was informative about the spectrum of clinical research projects at this Dept. at UTEP.

CELLULAR LANGUAGE (II)

In Cellular Language I published recently that we tried to emphasize that big functions of the cell start up with an on-and-off switch.  The Tic and The Tan like in MORSE language, the 1and 0 of the computer.  While this is true, there are many other simple things at the molecular level that are just as simple, but full of physiologic and scientific implications.

1.ON and OFF switch:
--------------------------
 Events that lead to cancer are sometimes an exaggeration of a signal.  The K-RAS (there exist many RAS (es) as we discussed in differentiation) has a switch called the Sons of the Sevenless which can stay on, sending signals down the cell continuously.  Activated RAS will light on 3 signal pathways:
-MAP kinase (through RAF)--->FOS, JUN (stress),  MYC (the dangerous  leading to Burkitt)-TF
-RAL/CDC42 (important in the movement of the membrane, Metastasis)
-PI3K (leading to affect on AKT/MTOR) FOXO downstream hiding the PUMA-remember) 

Mutations at the RAS itself can also cause it to stay on, as opposed to knocking it out.
Remember, Mutations of RAS occur in 80% of Pancreatic cancers and 50% of colon cancer. 
Therefore, a simple switch can kill you with one of the most devastating diseases.

2. Change of shape:
---------------------
To confuse and look smart, your scientist calls this post-translational conformation to emphasize that this change has occurred later because of the nteraction with another molecule (in general).

At the surface of the membrane, there are here and there some Molecules called INTEGRINS; these are of various types and increasing molecular diversity and are best known as Receptors. They are large complexes of molecules gathered in chunks called 'subunits'.  They basically cross the thickness of the cellular membrane and,  outside the cell, they sense what is going on. Integrins serve many great purposes including cell division, proliferation, migration, adhesion to each either, differentiation, sensing etc. You name it, they do it!  Only division of DNA, this, they don't do.  But the membrane has to be divided also to make 2 cells in cell divison.   Even anti-coagulation happens here.  The versatility of the integrins is linked to the variety of subunits it is composed with.  Some are nature of cell specific and some are contact specific.  By contact specific, I mean what molecule outside the cell it will attach to (ie fibronectin Vs GPIIb).

Suffice is to say that kinking of the Integrins causes exposure of some parts of the Integrin molecule not naturally exposed.  If one looks at the skin of the joint at the back of the finger, one will see folded skin. if you forcefully bend your finger, the fold you were looking at will unfold and the bottom of the fold will come out.  This is what happen to the integrin when it meets outside the cell another molecule such as TALIN.

That bending triggers the attachment of other molecules or ions (phosphorylation) to the now exposed skin, lighting up the Integrins for the cascade of events which will unfold, including the activation of SRC in Sarcoma.
The shape imposed by the bending is also Molecule specific.  Despite the resemblance of SRC with the c-ABL (leukemia), their bending does not offer the same shape, and therefore, different parts of the molecule are exposed and 2 different diseases result.

CELL ADHESION- "join at the hip"
----------------------------------------
At many points the cells are joined to each other at the hips of the Talins.  Say,  at the hip of the Talin which linked to one Integrin, there is a PLUS SIGN at Cell A, and at the next TALIN attached to the Integrin of cell B, there is a NEGATIVE sign.  These 2 integrins will be attached, and cell adhesion is achieved.  Simple as that!

Wheels of cellular migration,
-----------------------------,
Cells can roll over other cells by progressively attaching Talin to Talins and breaking the talin-talins (integrin-integrin) behind, engulfing the integrins and using them again in the forthcoming attachment like a wheel touching the ground.  The cell is that smart at the membrane.

More simple things to come...
Hiding the PUMA behind the FOXO to have a death TRAP (Apoptsosis) in case the FOXO is compromised!
Just simple, but effective tricks ...

GOOD REVIEWS OF  MY NOVEL! 
GOOD REVIEWS OF MY NOVEL!

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A White Woman To The Congo: The Tale of Sumpi, a traditional Chief's Man & Ears

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• Anonymous
  Posted January 28, 2013

  Heard all sorts of things about Simba Beer mentioned in the stor

  Heard all sorts of things about Simba Beer mentioned in the story. Does it still exist? How does it taste?
  Wish I could try the traditional chicken and the peanut paste snack!

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• KONGOKONGA

  Posted January 28, 2013

  Just wish to go on such a river journey, for days on end, seeing

  Just wish to go on such a river journey, for days on end, seeing the lush forest pass by... vivid descriptions, the characters of the novel are well sketched and quickly feel like friends...

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FEW FACTS/10 news by HEMOnc today

1. BMI (body mass index) did not influence survival in early breast cancer women who received adhuvant therapy.  This the work by EWERTZ et al. like any thing these day there was a trend toward benefit for those with BMI less than 30.  

2. Reinfusion of Autologous T-cell containing a chimeric protein combining  CD19 Antigen (CART 19 cells)
showed effective therapeutic effect in CLL.

3.Xarelto, a new anti-Xa was approved by the FDA in November 2012. 

4. Adding Aspirin after discontinuation of Coumadin reduced recurrence rate of Thrombotic events.

5. BRAF inhibition and anti-CTLA4 Tremelimumab (+/- Interferon ) are the new kids on the Melanoma block!  On the other spectrum, Taxol Carboplatin and Sorafenib failed to improve survival.
Trametinib may have activity in BRAF mutated Melanoma.

6. Zaltrap /Regorafenib has been approved in Metastatic Colorectal cancer.  it is It is an anti-Angiogenesis agent by trapping VEGF A, B prior to its link to their respective receptors

7.  Fibulin-3 an early biomarker for Mesothelioma?  read the article...

8. Adding Avastin to Standard Taxane or Adriamycin based chemotherapy failed to improve survival in triple negative breast cancer as reported by Researcher in Scotland.

9. ZOLINZA (histone Deacetylase inhibitor ) may have a role in modulating Graft Vs Host (GVHD) in patients

10. Only a third of  ITP patients who stopped Thrombopoietin Receptor Agonist (ELtrombopag) maintained a Platelet count 20-30,000 above the initial PLT count after 6 months of stopping the drug.

Biotech firm credits CPRIT funds for experimental cancer-fighting drug

By: John A. Salazar

A 100-page report by the state auditor made public Monday slams the Cancer Research Institute of Texas, or CPRIT, with details of internal rule violations, misappropriated funds and grant applications not receiving proper scientific review.For now, all CPRIT grants have been put on hold at the direction of the governor's office. Following news of the State Audit report, a $25 Million CPRIT grant recipient shut down operations, causing 30 people to lose their job.
The audit is critical of how Statewide Clinical Trials Network of Texas was spending large portions of the grant.
The report is evidence of an ongoing statewide investigation of the five-year-old state agency. Widely celebrated upon being approved by Texas voters in 2007, CPRIT is now under criminal investigation after spending much of the past year in turmoil over questions surrounding several lucrative awards.
But scientists at local biotech research company Mirna Therapeutics says the CPRIT multimillion dollar grant it received is helping its battle against cancer.
The state’s Emerging Technology Fund gave $5 million to what scientists at the Mirna Therapeutics research lab call ‘pioneering research.’
The embattled CPRIT added another $10.3 million.
Mirna Therapeutics CEO Dr. Paul Lammers says the $15 million worth of public dollars has done its part inside his lab.
"Oh, absolutely vital, because it is very difficult time right now for funding in biotech," he said."Developing a new medicine, a new drug, doesn't matter if it's for cancer or for hypertension or diabetes, it is a long exercise.”
Scientists at Mirna have successfully created an experimental cocktail called the MRX34, which contains the mimic of a tumor suppressor called the miR-34. The miR-34 mimic can inhibit the growth of tumors related to lymphoma, liver, lung and prostate cancer. The drug is currently on its way to the U.S. Food Drug and Administration for clinical testing.
Lammers says the tumor suppressor wouldn’t have been created if it wasn’t for help from CPRIT funds.
“Beginning in 2008 was the first time we use that on animals where we saw tumors go away," Mirna Therapeutics Director of Research David Brown said.
Human clinical studies on MRX34 could begin in as early as two months.
The Associated Press contributed to this report.

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Comment:

We had warned CPRIT that some of these Biotech companies being bought or started-up will run off after the money dries out!  What a waste!  the ink is not even dried out...The FDA may not approve the so called advancement.  And then?

A little more about HUMAN PAPILLOMA VIRUS AND CANCER:
--------------------------------------------------------------------------
HPV, the most sexually transmitted disease, has been implicated in:
- Cervical cancer
- Head and neck cancer
- Anal and most vaginal  Cancers, penile cancers
- the role in lung and Esophageal cancers is not clear.
With over 130 types, only few have been implicated with cancer .  (HPV16, 18 being the most cited since the work by Durst and Boshart)
90 % of infected people will see their infection cleared.
10 % will develop chronic infection.  and by year 30 after original infection, 50% of the 10% will develop eventually a malignancy.  It is widely believed that in those who developed the disease, the HPV gene E6 and E7 and their proteins products have managed to inactivate suppressor genes such as P53 and RB1 as part of the mechanism to cancerous transformation with loss of regulation of  cellular proliferation, and control of chromosome instability. This process led to immortalization of Keratinocytes in the laboratory.

In the Oropharyngeal cancers, the verrucous squamous subtype is the most associated  with HPV.  HPV positive tumor however has a higher response rate with a better 2 year progression free disease.
Most of these cancers can be avoided by HPV immunization.  The HPV presence can be confirmed by in-situ Hybridization.   Expression of the P16 type appear to correlate with less P53 and RB1 inactivation and therefore leads to best prognosis whereas EGFR over expression tends to suggest a poorer outcome.

HERBIMYCIN AND AVASTIN

Based of the evidence presented on the Myristoylation story, we predict that the combination of dasatinib or Herbimycin  with Avastin will have a larger response  rate on Angiosarcoma and papillary cancers because of a combined suppression of VGEF and SRC/MEK.

Dasatinib

From Wikipedia, the free encyclopedia

Dasatinib

Systematic (IUPAC) name
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide monohydrate
Clinical data
Trade names	Sprycel
Pharmacokinetic data
Protein binding	96%
Metabolism	Hepatic
Half-life	1.3 to 5 hours
Excretion	Fecal (85%), renal (4%)
Chemical data
Formula	C22H26ClN7O2S

Dasatinib, previously known as BMS-354825, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral multi- BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is being evaluated for use in numerous other cancers, including advanced prostate cancer.
The drug is named after one of the inventor chemists, Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb.^[1]

Herbimycin

From Wikipedia, the free encyclopedia

Jump to: navigation, search

Herbimycin
Properties
Molecular formula	C30H42N2O9
Molar mass	574.66 g/mol
Hazards

Herbimycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and alters its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.
It was originally found by its herbicidal activity, and thus named.

Synonyms

• Antibiotic Tan 420F
• Herbimycin A

Biological activity

Herbimycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90.

 -----------------------------------------------------------------------------------------------------------
Interferon  will have a reasonable role, and studies have certainly reported cases of response of Angiosarcoma to Interferon. At CRBCM and the GREATER East cancer Center we are following a case of a young 38 year old female who has been referred to us after receiving Gemzar and Taxotere followed by MAID x 3 cycles for a 12 cm Angiosarcoma in the liver.  She had an extensive skin reaction with desquamative feature to the Taxane.  We plan to start her on Avastin alone at this point. We understand Navelbine could have a role.
Her case will be presented at Tumor Board to completely exhaust salvage surgical resection option.  We are still awaiting a gene profiling which was not obtained at onset. An update will be forthcoming.
We are still working hard at CRBCM.
 Role of Nexavar has also been discussed in Angiosarcoma...

Avastin versus Lucentis

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e3162 (Published 2 May 2012)

Cite this as: BMJ 2012;344:e31

1. Fiona Godlee, editor, BMJ

1. fgodlee@bmj.com

Drug treatment for age related macular degeneration is one of medicine’s success stories. As Ning Cheung and colleagues explain (doi:10.1136/bmj.e2970), anti-vascular endothelial growth factors are preserving and restoring vision to millions around the world. But a related and less edifying story is stealing the limelight: ranibuzimab (Lucentis) versus bevacizumab (Avastin). It casts a shadow over this great medical advance and puts the world’s drug development and licensing systems under the spotlight.

In its anti-cancer drug, bevacizumab, drug developer Genentech has created what may be the world’s first “not me” (as opposed to “me too”) drug, say Robert Campbell and colleagues (doi:10.1136/bmj.e2941). Despite evidence that it works in macular degeneration, the manufacturers and marketers (Roche in the US, Novartis in the UK and elsewhere) are actively discouraging its use for this condition, even going so far as taking legal action to prevent such off-label use. Why? Because they want people to use their other drug, ranibuzimab, which is licensed for treating macular degeneration.

The bottom line is that ranibuzimab is about 12 times more expensive: Cheung and colleagues report that the UK could save close to £300m (€368m; $485m) a year if it were standard treatment. So are Roche and Novartis simply fighting to protect their profits? They say no, that they are also protecting patients from the cheaper drug’s higher risk profile. Although data from the publicly funded CATT trial in the US found similar effectiveness and safety for the two drugs in treating macular degeneration, the safety of bevacizumab remains a worry. Concerns relate to its greater systemic absorption and the fact that it has to be decanted into smaller quantities for intraocular injection, which introduces the risk of infection.

Whatever the motivation, the company has done all it can to limit the use of bevacizumab outside cancer, most notably by not applying for regulatory approval for use in patients with macular degeneration. Some health systems are finding ways round this, as Campbell and colleagues explain. But the combination of legal threats, safety concerns, and financial incentives to use ranibuzimab has maintained the more expensive drug’s lucrative market. Sales in the US in 2010 topped $1.8bn.

In the UK, as Ingrid Torjesen reports (doi:10.1136/bmj.e3012), efforts are under way to get bevacizumab approved for use in macular degeneration despite resistance from Novartis. The National Institute for Health and Clinical Excellence has said it could appraise the drug if asked to by the Department of Health. Campbell and colleagues report that the department is waiting for the results of the IVAN trial in the UK, due to be published this month. But it is unlikely to resolve the safety concerns. Neither this nor the CATT trial was big enough to detect small but clinically relevant differences in adverse outcomes such as stroke, they say. Long term postmarketing surveillance is needed for that.

So what’s to be done in the best interests of patients and the public purse? Campbell and colleagues call for clear guidance to use bevacizumab from professional organisations, a review of policies that discourage off-label use if there is good evidence for a drug’s use, and better communication among health technology assessors in different parts of the world.

Notes

Cite this as: BMJ 2012;344:e3162

Footnotes

• Follow BMJ Editor Fiona Godlee on Twitter @fgodlee and the BMJ @bmj_latest