LET IT BE KNOWN, NEW ANTI EGFR FOR LUNG CANCER

August 13, 2013

Lilly Announces Phase III Necitumumab Study Meets Primary Endpoint of Overall Survival

Study found improved overall survival in patients with stage IV squamous NSCLC

INDIANAPOLIS, Aug. 13, 2013 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced that SQUIRE, a recently completed Phase III study, met its primary endpoint, finding that patients with stage IV metastatic squamous non-small cell lung cancer (NSCLC) experienced increased overall survival (OS) when administered necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin as a first-line treatment, as compared to chemotherapy alone.
The most common adverse events occurring more frequently in patients on the necitumumab arm were rash and hypomagnesemia. Serious, but less frequent, adverse events occurring more often on the necitumumab arm included thromboembolism.
"We are pleased with these data which represent a potential advance in treatment for patients with squamous non-small cell lung cancer, which is a difficult cancer to treat," said Richard Gaynor, M.D., vice president, product development and medical affairs for Lilly Oncology. "If approved, necitumumab could be the first biologic therapy indicated to treat patients with squamous lung cancer."
Lung cancer is the leading cause of cancer death in the US and most other countries.^[1] Non-small cell lung cancer (NSCLC) is much more common than other types of lung cancer, and accounts for 85 percent of all lung cancer cases.^[2] Patients with squamous cell carcinoma represent about 30% of all patients affected by NSCLC.¹
Lilly plans to present results from this study at a scientific meeting in 2014, and currently anticipates submitting to regulatory authorities before the end of 2014.
About the Study
SQUIRE enrolled 1093 patients (age greater than or equal to 18 years, ECOG PS 0-2) with histologically- or cytologically-confirmed, stage IV squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Patients underwent  radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each arm (or until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent); patients in Arm A continued to receive necitumumab (IMC-11F8) until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent.
About Necitumumab
Necitumumab is a fully human IgG1 monoclonal antibody that is designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR). Activation of EGFR has been correlated with malignant progression, induction of angiogenesis and inhibition of apoptosis or cell death.
About Lilly Oncology
For more than four decades, Lilly Oncology, a division of Eli Lilly and Company, has been dedicated to delivering innovative solutions that improve the care of people living with cancer.  Because no two cancer patients are alike, Lilly Oncology is committed to developing novel treatment approaches. To learn more about Lilly's commitment to cancer, please visit www.LillyOncology.com
About Eli Lilly and Company
Lilly, a leading innovation-driven corporation is developing a growing portfolio of pharmaceutical products by applying the latest research from its own worldwide laboratories and from collaborations with eminent scientific organizations. Headquartered in Indianapolis, Ind., Lilly provides answers — through medicines and information — for some of the world's most urgent medical needs.  Additional information about Lilly is available at www.lilly.com.
P-LLY
This press release contains forward-looking statements about the potential of necitumumab as a treatment for patients with squamous non small cell lung cancer and reflects Lilly's current beliefs. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. There is no guarantee that future studies will be positive or that necitumumab will receive regulatory approvals or prove to be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's filings with the United States Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.
Important Safety Information for GEMZAR^® (gemcitabine for injection)
Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.
ContraindicationGEMZAR is contraindicated in patients with a known hypersensitivity to gemcitabine.
Warnings and PrecautionsPatients receiving therapy with GEMZAR should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents.
Infusions of GEMZAR longer than 60 minutes or dosing more frequently than weekly resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of GEMZAR is influenced by the length of the infusion.
Myelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with GEMZAR as a single agent, and the risks are increased when GEMZAR is combined with other cytotoxic drugs. Patients should be monitored for myelosuppression during therapy including a complete blood count with differential prior to each dose.
Pulmonary toxicity, sometimes fatal, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of GEMZAR. Discontinue GEMZAR in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy.
Hemolytic Uremic Syndrome (HUS), including fatalities from renal failure or the requirement of dialysis, can occur in patients treated with GEMZAR. Always monitor renal function prior to initiation of GEMZAR therapy and periodically during treatment. Use GEMZAR with caution in patients with renal impairment. Permanently discontinue GEMZAR in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy.
Drug-induced liver injury, including liver failure and death, has been reported in patients receiving GEMZAR alone or in combination with other potentially hepatotoxic drugs. Administration of GEMZAR in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of hepatic insufficiency. Assess hepatic function prior to initiation of GEMZAR and periodically during treatment. Discontinue GEMZAR in patients that develop severe liver injury.
GEMZAR can cause fetal harm when administered to a pregnant woman. Advise women of potential risks to the fetus.
GEMZAR is not indicated for use in combination with radiation therapy. When GEMZAR was administered within 7 days of receiving radiation therapy or concurrent with radiation therapy, toxicity of radiation therapy was increased. In a clinical trial, life-threatening mucositis, especially esophagitis and pneumonitis, occurred. Excessive toxicity has not been observed when GEMZAR is administered more than 7 days before or after radiation (nonconcurrent). Radiation recall has been reported in patients who receive GEMZAR after prior radiation.
Capillary Leak Syndrome (CLS) with severe consequences has been reported in patients receiving GEMZAR as a single agent or in combination with other chemotherapeutic agents. Discontinue GEMZAR if CLS develops during therapy.
Use in Specific Populations
GEMZAR is Pregnancy Category D. GEMZAR can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, GEMZAR is expected to result in adverse reproductive effects. It is not known whether GEMZAR is excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and efficacy of GEMZAR in pediatric patients have not been established.
No clinical studies have been conducted with gemcitabine in patients with decreased renal or hepatic function.
GEMZAR clearance is affected by age as well as gender.
Dose Modifications and Administration Guidelines
GEMZAR is for intravenous use only. Immediately and permanently discontinue GEMZAR for any of the following: unexplained dyspnea or other evidence of severe pulmonary toxicity, severe hepatic toxicity, Hemolytic Uremic Syndrome, or Capillary Leak Syndrome. Consider immediate discontinuation or dose modifications for severe nonhematologic toxicity according to the Dosage and Administration guidelines in the full Prescribing Information.
Serum creatinine, potassium, calcium, and magnesium should be monitored during combination therapy with cisplatin. See the manufacturers' prescribing information for more information on any drug indicated in combination with GEMZAR.
Abbreviated Adverse Reactions (%-incidence) — Patients receiving single-agent GEMZAR across 5 trials
The most severe adverse reactions (grades 3/4) in all patients receiving single-agent GEMZAR across five clinical trials were anemia (8), neutropenia (25), thrombocytopenia (5), hepatic transaminitis (increased ALT, 10; increased AST, 8), increased alkaline phosphatase (9), hyperbilirubinemia (3), nausea and vomiting (14), fever (2), and dyspnea (3).
The most common adverse reactions (all grades) in the same patient population were anemia (68), neutropenia (63), thrombocytopenia (24), increased ALT (68), increased AST (67), increased alkaline phosphatase (55), hyperbilirubinemia (13), proteinuria (45), hematuria (35), increased BUN (16), increased creatinine (8), nausea and vomiting (69), fever (41), rash (30), dyspnea (23), diarrhea (19), hemorrhage (17), infection (16), alopecia (15), stomatitis (11), somnolence (11), and paresthesias (10).
Abbreviated Adverse Reactions (%-incidence) − 1st-line advanced NSCLC
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus cisplatin for the first-line treatment of patients with NSCLC in comparative trials of a 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and a 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were neutropenia (57 vs 4, 64 vs 76); thrombocytopenia (50 vs 4, 55 vs 13); lymphopenia 28d (43 vs 17); anemia (25 vs 7, 22 vs 15); nausea and vomiting 21d (39 vs 26); nausea 28d (27 vs 21); vomiting 28d (23 vs 19); alopecia 21d (13 vs 51); neuromotor 28d (12 vs 3); hypomagnesemia 28d (7 vs 2); creatinine elevation 28d (5 vs 3); and infection (5 vs 1, 4 vs 8).
The most common adverse reactions (all grades, with incidence of 20% or greater) of the 28-day regimen (GEMZAR plus cisplatin versus cisplatin alone) and the 21-day regimen (GEMZAR plus cisplatin versus etoposide plus cisplatin), respectively, were anemia (89 vs 67, 88 vs 77); neutropenia (79 vs 20, 88 vs 87); thrombocytopenia (85 vs 13, 81 vs 45); lymphopenia 28d (75 vs 51); RBC transfusion (39 vs 13, 29 vs 21); platelet transfusions (21 vs 1, 3 vs 8); increased transaminases 28d (22 vs 10); nausea 28d (93 vs 87); vomiting 28d (78 vs 71); nausea and vomiting 21d (96 vs 86); alopecia (53 vs 33, 77 vs 92); creatinine elevation (38 vs 31, 2 vs 2); paresthesias 21d (38 vs 16); neuromotor 28d (35 vs 15); hyperglycemia 28d (30 vs 23); hypomagnesemia 28d (30 vs 17); infection (18 vs 12, 28 vs 21); neurohearing 28d (25 vs 21); diarrhea (24 vs 13, 14 vs 13); proteinuria (23 vs 18, 12 vs 5); neurosensory 28d (23 vs 18); hematuria (15 vs 13, 22 vs 10); and stomatitis (14 vs 5, 20 vs 18).
Abbreviated Adverse Reactions (%-incidence) − 1st-line metastatic breast cancer
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus paclitaxel versus paclitaxel alone, respectively, for the treatment of patients with metastatic breast cancer were neutropenia (48 vs 11); anemia (7 vs 4); thrombocytopenia (6 vs 2); alopecia (18 vs 22); fatigue (7 vs 2); increased ALT (6 vs 1); and neuropathy-sensory (6 vs 3).
The most common adverse reactions (all grades, with incidence of 20% or greater) in the same patient population were anemia (69 vs 51); neutropenia (69 vs 31); thrombocytopenia (26 vs 7); leukopenia (21 vs 12); alopecia (90 vs 92); neuropathy-sensory (64 vs 58); nausea (50 vs 31); fatigue (40 vs 28); vomiting (29 vs 15); and diarrhea (20 vs 13).
Abbreviated Adverse Reactions (%-incidence) − Advanced recurrent ovarian cancer
The most severe adverse reactions (grades 3/4, with incidence of 5% or greater) with GEMZAR plus carboplatin versus carboplatin alone, respectively, for the treatment of patients with advanced ovarian cancer were neutropenia (71 vs 12); thrombocytopenia (35 vs 11); anemia (28 vs 11); constipation (7 vs 3); nausea (6 vs 3); and vomiting (6 vs 3).
The most common adverse reactions (all grades, with incidence of 20% or greater) in the same patient population were neutropenia (90 vs 58); anemia (86 vs 75); thrombocytopenia (78 vs 57); RBC transfusion (38 vs 15); nausea (69 vs 61); alopecia (49 vs 17); vomiting (46 vs 36); constipation (42 vs 37); fatigue (40 vs 32); diarrhea (25 vs 14); and stomatitis/pharyngitis (22 vs 13).
For safety and dosing guidelines, see complete Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections in the accompanying full Prescribing Information.
GC HCP ISI ALL 14MAY2013
¹ "Squamous cell carcinoma-similarities and differences among anatomical sites" - Am. J Cancer Re 2011;1(3):276)
² U.S. National Institutes of Health. National Cancer Institute: SEER Cancer Statistics Review, 1973-2006
Refer to: Keri McGrath Happe (317) 370-8394 mcgrath_happe_keri_s@lilly.com

THE "WEAKNESS" OF MEN HAS GOT TO BE IN THEIR ANDROGEN

One thing is certain, women seem to live longer than men...There seem to be many more widows than widowers!  If you look at statistics of elderly who live the longest, you are more likely to find women than men.  It is easy to say that men live a more stressful life and therefore die sooner, but one may also want to look into the main difference between men and women.  And the Androgen level comes quickly to mind!
Androgen and related receptors are part of "wild genes", that is their effect here involves many genes downstream.
When you look at the span of genes which interact with the Androgen gene, one is struck by the deep epigenetic distribution of their effects!
One particular interacting gene stands out:

"NCOA4 has been shown to interact with Peroxisome proliferator-activated receptor gamma^[4] and Androgen receptor.[ "(wikipedia)

The involvement of the PPAR gamma point to weakness of Antigen presentation and therefore a weakness in our defense mechanism.  This perhaps opens the door to understanding why men having sex with men still have the highest Kaposi Sarcoma burden?  I believe we are onto something here! look this up! NCOA4, a new target indeed!

A few notes on Prostate Cancer Prevention

Prostate cancer prevention by Finasteride and Dutasteride
Yes, these 5 alpha-Reductase Inhibitors did reduce Prostate cancer occurrence,
but in those where it did occur, it seems to be high grade when exposed to these drugs.
That is why the advisory Committee felt that these were not the best as a prevention intervention!

Vitamin E, on the other end, at 400 IU (a high dose), increased the risk of prostate cancer!

When it comes to Saw Palmetto, Wikipedia adds:

"It is also an expectorant, and controls irritation of mucous tissues. It has proved useful in irritative cough, chronic bronchial coughs, whooping-cough, laryngitis, acute and chronic, acute catarrh, asthma, tubercular laryngitis, and in the cough of phthisis pulmonalis. Upon the digestive organs it acts kindly, improving the appetite, digestion, and assimilation. However, its most pronounced effects appear to be those exerted upon the urino-genital tracts of both male and female, and upon all the organs concerned in reproduction. It is said to enlarge wasted organs, as the breasts, ovaries, and testicles, while the paradoxical claim is also made that it reduces hypertrophy of the prostate. Possibly this may be explained by claiming that it tends toward the production of a normal condition, reducing parts when unhealthily enlarged, and increasing them when atrophied.^[4]

Saw palmetto extract is the most popular herbal treatment for benign prostatic hyperplasia,^[5] a common condition in older men. Early research indicated that the extract is well-tolerated and suggested "mild to moderate improvement in urinary symptoms and flow measures."^[5][6] Later trials of higher methodological quality indicated no difference from placebo.^[7][8] Questions of adequate blinding and delivery of any active ingredients remain.^[9] The latest Cochrane Database review (2009) concludes that "Serenoa repens was not more effective than placebo for treatment of urinary symptoms consistent with BPH."^[1]
A 2001 study published in JAMA (The Journal of the American Medical Association) reported on a double-blind study study that eleven North American clinics conducted on 369 men. The study found that saw palmetto fruit extract failed to reduce urinary tract symptoms more than placebo.^[10] Men in the experimental group experienced a 2.20 point drop in their American Urological Assn. Symptom Index (AUASI) score. However, men in the placebo group saw a 2.99 point drop. The Los Angeles Times reports, “42.6% of the men in the extract group saw their AUASI scores fall by at least three points; 44.2% of the men in the placebo group saw the same degree of benefit.” The study was funded by several offices within the NIH, including the National Center for Complementary and Alternative Medicine.”^[11]
Inhibition of both forms of 5-alpha-reductase with no reduction in cellular capacity to secrete prostate-specific antigen is indicated.^{[12][13][14][15]} Other proposals for mechanisms of action include interfering with dihydrotestosterone binding to the androgen receptor, relaxing smooth muscle tissue similarly to alpha antagonist drugs, and acting as a phytoestrogen.^[16][17]
Limited in vitro and animal model studies suggest possible anti-tumor activity and potential for use in the treatment of cancer.^[12][18][19] These results have not been substantiated with human trials.
Saw palmetto extract has been suggested as a potential treatment for male pattern baldness.^{[20]" wikipedia}

Broadening our local reach!

RE: Mayor Website Visitor Message

Inbox

x

Herrera, Ramon <HerreraRX1@elpasotexas.gov>	3:38 PM (1 hour ago)
to me

Dr. Kankonde,

Thank you for contacting the Office of the Mayor. We appreciate your input and always welcome your thoughts or concerns.

 

Sincerely,

 

Ramon Herrera

Executive Assistant

Office of the Mayor

HerreraRX1@elpasotexas.gov

 

Learning from Anal cancer

One of the cancer that exemplifies the importance of trauma and Viral or infectious influences, is surely the Anal cancer!  Globally decreasing, it remains increasing in those who continue to practice anal sex.   It is also associated with the irritation of infections (HIV, Herpes 16, Chlamydia Trachomatis, and Gonorrhea).  Occurrence of warts remains an intriguing aspect that need further examination as they most likely represent a disruption at Wnt (global disruption of adhesion molecule and sens of polarity) and the notch.  (proof of concept).  Most importantly, This disease seems to involve a strong disruption of the NF-kB and down the stream epigenetic disturbances and associated increase growth hormones (TGFs).  This perception is reenforced by the very low or rare Mutations of KRAS found in this disease, and the effectiveness or exclusive efficacy of Mitomycin, a drug which easily lead to Fibrosis of the lung (which is associated to cyclines/growth factor effect).  Stopping or reducing the infection intensity has proven effective in reducing per-cancerous (Intraepithelial Neoplasia) lesions by at least  half, leading to the recommendation of giving Quadrivalent HPV vaccine  to males at 11-12 years of age by the Advisory Committee on Immunization.

Let's quantify now the NF-kB and the Cytokines in this disease...It could be good for the patients!

?Role of Histone de-actylators?
?miRNA
Interferon and Etoposide better than Cisplatin-5FU alone?

10 RESEARCH QUESTIONS IN ORAL CANCERS AND MEDICINE!

1.Early detection of Oral cancer leads to 90% cure rates whereas lymph node involvement drops that rate to 50% and require combination therapy to be achieved"

Can MDM2 Mutation, decrease E-Cadherin depression, and c_MYC amplification be detected in Sample from Saliva, blood of heavy smoker?

Is RHOC gene mutation predict Node involvement, is WISP3 involved?

2.Can BMPR Mutation and avB3 Integrin (+ associated Metalloprotease) predict for Osteoporosis of the Jaw in patients on Biphosphonate

3.Can Asporidin bound to Nuclear Agent helps detect Metastatic disease In Oral cancers?   (Change in Asporidin increases its Binding of TGF to Increase destruction in Osteoarthritis, and TGF is the autocrine growth hormone in Metastatic disease

4.Using new Biomarkers in Autoimmune diseases, can we develop a Kit to detect Oral Ulcerations that will benefit for a short course of Prednisone?

5.Levels of Interferon-1 in Hairy Leukoplaquia? Why Immunodeficiency is linked to hairy Leukoplaquia Interferon-1 is linked to Immune dysregulation...

6.Cevimeline role in post Radiation "Sicca"

7. can Injection of Lubricin improve Temporo-Mandibular Arthritis

8.Genetic basis of Oral Ulcerations in Beta- blocker users?

9.Role of Androgen Receptors in the deposition of Melanin during the Use of hydroxychloroquin, Minocycline, Methyl dopa, Ketoconazole, and Cytoxan

10.Role of Syndecans in Gingival Hyperplasia (Syndecans bind Growth factor FGF) (Why Gingival Hyperplasia  in patient taking Phenytoins, Cyclosporin, Calcium channel blockers, disruption of genes involved in cellular polarity?)

AT CRBCM, RESEARCH IS OUR PRIORITY!

SPECULATIVE NOTES ABOUT MANTLE CELL LYMPHOMA

In Mantle Cell lymphoma, its most dreadful aspect is the fact that it is an incurable disease
which to most Oncologist means that there is an entrenched genetic driver that is not silenced by current therapy, and will go on to revive the disease.
The elevation of Cyclin-D1 is a patent suspect.
Our speculation however is that it is not that is present that gives a clue to this recalcitrant disease.  It is what is missing.   Why is it that a disease that look like CLL or small lymphocytic Lymphoma, would not have the CD-23 marker?
CD 23 expression seems to be linked to the protective Interleukin 4.
CD23 as commented here by several authors seems to not only be involved in Allergens presentation
but to overall presentation of Antigenes, and to DIFFERENTIATION AND DEDIFFERENTIATION.
ITS EXPRESSION SEEMS LINKED TO IL4.  INDEED INCREASE OF IL4 HAS BEEN LINKED TO AN HYPERSENSITIVITY REACTION.  Differentiation of white cell seems to be linked to favorable outcome through leading to Apoptosis, whereas dedifferentiation seems to be linked to cellular immortality.  Also as it can be apparent, CD23 help with Antigen presentation and activation of class II Major Histocompatibility defense.   The lack of CD23 therefore lead to a global tolerance of involved neoplastic cells and may contibute to tolerance of these cells as they penetrate tissues including the Central Nervous system.
One now wonder what would be the clinical consequence of Giving IL-4 to patient with mantle cell,  Will it increase CD23 expression?  will it have a role in Maintenance setting,  Adding it to Interferon gamma could boost its effectiveness
Can infusion of CD23 molecule makes a difference in this disease?
was the disappearance of CD23 driven by CD21 as one can speculate based of french researchers notes listed below?

Read for your self!
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THESE NOTES ARE FROM THE INTERNET! WE THANK RESEARCHERS MENTIONED HERE!
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Our study shows that grade 3 FLs are more often CD23- than lower grade FLs and that FLs in inguinal LNs are more frequently CD23+ than in LNs from other sites. Furthermore, our findings also indicate that survival is significantly better in CD23+ FLs.(OLTEANU H ET AL)

 Expression of CD23 was more frequently detected in grade 1 FLs than in other grades (grade 1, 37%; grade 2, 18%; grade 3, 23%; transformed, 6%). (THORNS ET AL)


There are two forms of CD23: CD23a and CD23b. CD23a is present on follicular B cells, whereas CD23b requires IL-4 to be expressed on T-cells, monocytes, Langerhans cells, eosinophils, and macrophages.^{[1] (WIKIPEDIA)}

Human lymphocytes shed a soluble form of CD21 (the C3dg/Epstein-Barr virus receptor, CR2) that binds iC3b and CD23

Véronique Frémeaux-Bacchi ET AL...

It has many biological roles, including the stimulation of activated B-cell and T-cell proliferation, and the differentiation B cells into plasma cells.
It is a key regulator in humoral and adaptive immunity.
IL-4 induces B-cell class switching to IgE, and up-regulates MHC class II production. IL-4 decreases the production of Th1 cells, macrophages, IFN-gamma, and dendritic cell IL-12.
Overproduction of IL-4 is associated with allergies.^[2]


The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure–function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets. (M. ACHARYA ET AL)

 The metalloprotease responsible for CD23 release from cells is ADAM10 [24,25],

 Affinity-based approaches demonstrated that αvβ3 was also a functional receptor for CD23 in monocytic cells [38], again leading to cytokine release, and that αvβ5 is a sCD23 receptor linked to growth and survival of human B cell precursors [51]. The αv integrins recognize a short tripeptide motif of arg–lys–cys (RKC) in CD23 in a carbohydrate-independent interaction [51] and the affinity of the αvβ5–derCD23 interaction is approximately micromolar [51], which is broadly equivalent to that found for the derCD23–CD21 interaction [44]. It is not known whether the β2 integrins also recognize the same RKC sequence bound by αv integrins. The binding sites for CD23 on the αv and β2 integrins remain to be elucidated, but available data suggest that this is distinct from the site on the integrin

Clinical and Experimental Immunology

Blackwell Science Inc

CD23/FcεRII: molecular multi-tasking

M Acharya, G Borland, [...], and W Cushley

Additional article information

Abstract

CD23 is the low-affinity receptor for immunoglobulin (Ig)E and plays important roles in the regulation of IgE responses. CD23 can be cleaved from cell surfaces to yield a range of soluble CD23 (sCD23) proteins that have pleiotropic cytokine-like activities. The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure–function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets.

Keywords: CD23, cytokines, IgE, immunoregulation, integrins

Introduction

Immune responses are subject to regulation at many levels, including the influence of different groups of cytokines, cell–cell contact via adhesion interactions and receptor-mediated positive and negative feedback circuits. The low-affinity receptor for immunoglobulin (Ig)E, also known as FcεRII or CD23, participates in all these regulatory processes, either as a membrane-bound glycoprotein or as a freely soluble protein. Structural biology approaches have revealed the fine molecular details of the soluble CD23 (sCD23) protein and the interaction surfaces used by sCD23 to bind its various ligands, and molecular biological and mutagenesis studies have defined critical residues involved in performance of biological functions. CD23 has been suggested to have utility as a diagnostic marker in a range of diseases and to be implicated in the cellular and molecular processes associated with a variety of pathological states; the latter feature has made CD23 a target for therapeutic intervention.

General features of CD23

CD23 was defined initially as the low-affinity receptor for IgE [1,2]. As a membrane protein, CD23 is a type II transmembrane glycoprotein of approximately 45 kDa molecular weight comprising a large C-terminal globular extracellular domain that is strikingly similar to C-type lectins, followed by a stalk region bearing several repeats that serve as a putative leucine zipper that are important in CD23 oligomerization; the stalk region is followed by a short extracellular sequence (in human CD23), a single hydrophobic membrane-spanning region and a short N-terminal cytoplasmic domain [3–7] (Fig. 1). CD23 is expressed in T and B lymphocytes [8], polymorphonuclear leucocytes [9–11], monocytes [10,12], follicular dendritic cells [13], intestinal epithelial cells [14] and bone marrow stromal cells [15], and its expression to subject to regulation by a number of stimuli. In humans, CD23 is encoded by an 11-exon gene, FCER2, located at chromosome 19p13.3 [16], in a cluster with the DC-SIGN and DC-SIGNR genes [17]; the murine equivalent is located on chromosome 8 [18]. CD23 differs dramatically from the high affinity receptor in terms of structure. FcεRI has multiple subunits [5,6,19], whereas FcεRII is comprised solely of a CD23 polypeptide. As the names suggest, their affinities for IgE differ (FcεRI binds IgE with a K_D∼ 1 nM while monomeric CD23 interacts with IgE with a K_D∼ 0·1–1 µM), although the membrane-bound form of CD23 is trimeric [20] and the contribution of the avidity of the trimer for ligand yields a net affinity closer to that of the high-affinity receptor and comparable to that of FcγRI for IgG monomers [21]). Signalling pathways and functional consequences of ligand binding to the receptors are also different [22,23]; for example, cross-linking of FcεRI leads to degranulation of mast cells and release of a number of potent pharmacologically active mediators, while engagement of membrane-bound CD23 suppresses the production of IgE by B lymphocytes.

Fig. 1

Primary structural features of human CD23. (a) The 321 amino acids that comprise the primary structure of human CD23a [1,2,55]. Individual contact residues or binding regions for CD23 ligands are shown in green (major histocompatibility complex class ...

In addition to its role as a low-affinity receptor for IgE, CD23 can also be released from cell surfaces as a range of freely soluble CD23 (sCD23) proteins of 37 kDa, 33 kDa, 25 kDa and 16 kDa, all of which bind IgE and have cytokine-like activities. The metalloprotease responsible for CD23 release from cells is ADAM10 [24,25], which cleaves at the C-terminal side of either ala⁸⁰ to generate the 37 kDa sCD23 molecule or arg¹⁰¹ to yield the 33 kDa species [25]. Mice lacking ADAM10 expression in B cells display defective release of CD23, confirming that ADAM10 is necessary for CD23 cleavage and release in vivo[26]. A further naturally occurring sCD23 fragment is derCD23, produced by action of the der p1 protease found in the faeces of the house dust mite Dermatophagoides pterronysinus; der p1 cleaves between ser¹⁵⁵/ser¹⁵⁶ and glu²⁹⁸/ser²⁹⁹ in CD23 to yield the 16 kDa derCD23 fragment [27,28]. The kinetics and affinity of the interaction of sCD23 with IgE and the ability of sCD23 to diminish or enhance IgE synthesis in stimulated B cells is linked to its oligomerization state. Thus, monomeric sCD23 species, such as derCD23, show monophasic kinetics of interaction with a Cε2–4 domain construct of the IgE Fc region that is of low (micromolar) affinity, and inhibit IgE synthesis in activated B cells [29]. By contrast, trimeric sCD23 molecules display a biphasic interaction with IgE Fc fragments, including a higher affinity component (10–100 nM), and enhance IgE synthesis by activated B cells [29]. The other cytokine activities of sCD23 species have been best studied in human models, and it is clear that sCD23 is highly pleiotropic (Fig. 2). Thus, in the B cell compartment, sCD23 sustains the growth of activated mature B lymphocytes, possibly via an autocrine mechanism [30–32], promotes differentiation of germinal centre centroblasts towards the plasma cell pool [in association with interleukin (IL)-1α][33], and allows B cell precursors to evade apoptosis [34]. In other lineages, sCD23 promotes differentiation of myeloid precursors [35], thymocytes [36] and bone marrow CD4⁺ T cells [37], again in association with IL-1α, and also drives cytokine release by monocytic cells [38]. Given its roles in lymphocyte survival and cytokine release by monocytes, it is no surprise that sCD23 has been linked to the pathophysiology of neoplastic and autoimmune inflammatory conditions (see below).

Fig. 2

Pleiotropy of human sCD23. The effects of sCD23 on B cells, T cells and myeloid cells are illustrated showing biological responses and, where appropriate, signalling responses. An asterisk (*) indicates that the observed effect required the presence of ...

CD23 ligands and signalling

CD23 has multiple ligands, including IgE, CD21 and members of two families of integrins. The principal ligand is IgE, which is bound by both membrane-bound and soluble trimeric CD23 species. The site recognized by CD23 resides in the Cε3 domain of IgE protein and CD23 sterically hinders IgE binding to FcεRI; binding of IgE to CD23 is carbohydrate-independent (i.e. does not require any lectin-like activity of the head domain). The next best characterized ligand for CD23 is CD21 [39]. The interaction with CD21 depends on short consensus repeats in CD21 [40] and occurs when the proteins are freely soluble in solution (sCD21–sCD23 complexes are readily detected in plasma [41]), or are membrane proteins. In the case of membrane proteins, activation of human B cells promotes homotypic adhesion, and the cell clusters are disrupted by anti-CD21 or anti-CD23 antibodies [42], indicating that these two membrane proteins can interact functionally in trans. There is no equivalent homotypic adhesion in murine B cells [43]. The interaction of CD23 with CD21 involves both carbohydrate-dependent and independent interactions [40], and the interaction of derCD23 with CD21 is approximately micromolar (K_D∼ 8·7 × 10⁻⁷ M) [44]. CD23 can also interact in cis and trans with major histocompatibility complex (MHC) class II proteins, in a carbohydrate-independent manner, using structures in the CD23 protein that are located in the stalk region of the molecule [45]. This interaction is believed to facilitate antigen processing and presentation by antigen–IgE complexes captured by CD23 [46].

The first CD23-binding integrins to be identified were the αMβ2 [47,48] and αXβ2 [47] members of the leucocyte integrin family. The ability of anti-integrin antibodies to inhibit binding of CD23 to monocytes or to mimic the effects of CD23 on the cells indicated that these integrins bound CD23 and were linked functionally to monocyte responses to CD23 [47–50]. Affinity-based approaches demonstrated that αvβ3 was also a functional receptor for CD23 in monocytic cells [38], again leading to cytokine release, and that αvβ5 is a sCD23 receptor linked to growth and survival of human B cell precursors [51]. The αv integrins recognize a short tripeptide motif of arg–lys–cys (RKC) in CD23 in a carbohydrate-independent interaction [51] and the affinity of the αvβ5–derCD23 interaction is approximately micromolar [51], which is broadly equivalent to that found for the derCD23–CD21 interaction [44]. It is not known whether the β2 integrins also recognize the same RKC sequence bound by αv integrins. The binding sites for CD23 on the αv and β2 integrins remain to be elucidated, but available data suggest that this is distinct from the site on the integrin that binds matrix proteins by recognition of arg–gly–asp (RGD)-type sequences [51].

Because CD23 exists in membrane-bound and soluble forms, it can both deliver and receive signals. Thus, sCD23 has been demonstrated to drive nitric oxide (NO) production, cyclic adenosine-5′-monophosphate (cAMP) synthesis and cytokine release from monocytic cells [50] and, in this case, integrins appear to act as the receptors for the sCD23 protein. It is clear in human monocytic cells that stimulation of the αMβ2 and αXβ2 integrins with specific monoclonal antibodies (mAbs) both mimics the effect of sCD23 on the cells and triggers the mitogen-activated protein (MAP) kinase cascade [49] and activates nuclear factor (NF)-κB [50]. Similarly, sCD23 activates extracellular regulated kinase (ERK) phosphorylation and, to a much lesser extent, the phosphatidyl insitol 3 (PI-3) kinase pathway in human B cell precursors; the extent and kinetics of ERK phosphorylation are modified by inputs from both G-protein-coupled receptors (CXCR4) and receptors with intrinsic tyrosine kinase activity [platelet-derived growth factor receptor (PDGFR)][52].

  In broad terms, CD23a is expressed constitutively in B cells while transcription of the CD23b isoform is subject to up-regulation following Epstein–Barr virus (EBV) infection [56], stimulation by IL-4 in B cells [57] or monocytes [12] or by engagement of CD40 on B cells [58]. Elements in the human CD23a and CD23b promoters that are responsive to defined stimuli (e.g. IL-4, CD40L) have been mapped [56,59].

 Transitional immature B cells undergo apoptosis and fail to proliferate in response to BCR cross-linking, thus representing a target for negative selection of potentially autoreactive B cells in vivo. In agreement with recent reports, transitional B cells were divided into developmentally contiguous subsets based on their surface expression of CD23. When transferred, CD23⁺ transitional B cells readily localized to the splenic follicles and the outer PALS. Compared with CD23⁻ transitional B cells, CD23⁺ transitional B cells proliferated more vigorously and were rescued from BCR-induced apoptosis to a greater degree, by T cell help signals. However, both CD23⁻ and CD23⁺ transitional B cells failed to up-regulate CD86 (B7-2) in response to BCR ligation. These findings demonstrate that phenotypically defined subsets within the transitional B cell population are functionally distinct. Specifically, responsiveness to T cell help is a late acquisition corresponding to the stage when the B cells gain access to peripheral compartments enriched in antigen and activated T cells. The failure of transitional B cells to up-regulate CD86 to BCR-mediated stimulation suggests a unique interaction between transitional B cells and T cells with implications for tolerance in the T cell compartment. (chung ET al)

Update on Mantle cell( and speculative thoughts)

Mantle Cell Lymphoma is like Non hodgkin lymphoma with a twist
CD20 and CD 5 positive but no CD23 (CLL) nor CD 10 (follicular)

could be diffusely involving the Bowel (Lymphomatous polyposis)
and 20% CNS infiltrating as a late presentation
Cyclin D1 driven condition leading to incurable disease
with Median survival of 3-4 years

Now Ki-67 has been found to be prognotic

Treatment
1.R-CHOP
can be given
but remember here the Median survival is 20 months
It got to be followed by Maintenance Rituxan or transplant
so no good option, except may be in elderly and desperate
2. Most people would try R- HYPERCVAD, or R-Modified HYPERCVAD to make it palatable !
3. after HYPERCVAD comes
Rituxan-Fludarabine Mitoxantrone-Cytoxan  similar to CLL.

Intereferon has been given in Maintenance setting, but perception is that Rituxan Maintenance is better..

4.Now comes Bendamustin and Rituxan    superior to R-CHOP
                     CR     50%          VS                        27%
       Overall Resp     94%          Vs                        85%
                   Nausea and hypersensitivity             Alopecia,neuropathy, constipation


seems like for older patient R-HYPERCVAD folloed by Transplant
whereas Older patient will get more and more Bendamustine-Rituxan

5.Transplant in first remission beter than later!

6.New Active drug and valid option in refractory disease

-----Velcade RR 33%  (prompting Velcade-Bendamustine trial)
-----Revlimid RR 28%
-----Temsorilimus response but not sustained
-----Ibrutinib is shaking things up now, at 560 mg, RR 65-75%, shaking things up so much that it is now being combined to -CHOP, Threatening to become standard therapy?
------And here come Idelalisib  PI3K oral Inhibitor  ?RR 52%
----------ABT-199 a BCL 2 inhibitor (watch for tumor lysis syndrome)

=========================================
THE WORLD OF ONCOLOGY IS BEING MOVED BY TARGET THERAPY

OH! DON'T FORGET REDUCED INTENSITY ALLOGENEIC TRANSPLANT IN THIS DISEASE, SOMEONE REPORTED 60-80% 2 YEARS SURVIVAL "IN SELECTED SERIES"
LOT OF EXCITING STUFF IN THIS DISEASE!

IN THE INTERIM !

Part of becoming Laboratory Director is to complete 20 CME units on laboratory management.
We have been hard at work to complete these CMEs.
Therefore, we have not published any communication for the last few days.
Something of exciting nature happened during this period:  WE HEARD FROM CPRIT!
CPRIT IS ALIVE AND BACK IN BUSINESS, WE WELCOME THE NEWS!

IF YOU HAPPEN TO WONDER WHAT LABORATORY WE WILL BE HEADING,  WONDER NO MORE:   THE EL PASO II GRIFOLS LABORATORY!

ACTIVITIES AT CRBCM

ACTIVITY AT CRBCM.

1. We are waiting for last word of the contract with the laboratory of Professor Jianying Zhang ( agreement between UTEP and the CRBCM and the Greater East Cancer Center. ) about the early lung cancer detection project.

2. We are conducting field work in fort Wayne Indiana (under contract)

3. AND THE LARGER NEWS TONIGHT IS THAT DR KANKONDE HAS BEEN RETAINED DIRECTOR OF AN IMPORTANT HEMATOLOGY LABORATORY IN EL PASO.  HE WILL SOON START FINAL ADAPTED TRAINING.  AND YOU WILL BE UPDATED!

4.WE CONTINUE TO SUBMIT GRANT REQUESTS.

5. WE ATTENDED SUCCESSFULLY THE CONFERENCE ON  HEMATOLOGIC MALIGNANCIES IN MIAMI SATURDAY AUGUST 10TH, 2013

THE CRBCM IS ADVANCING  DAY BY DAY!

Few Clues on Myeloma treatment

Some of the Key points in Myeloma Treatment
1. After the diagnosis of Myeloma, determination of presence of Del 17, and t(4:14) is the first step to treatment.  You may be "liable" if Velcade is not included in the first line treatment in patient with  del 17.
2. CYBORD is a good induction option
3. Use of Triplets always better than Doublets
4.In clinical practice, Bortezomib Sub Q is now adopted widely despite lack of clinical trial showing equivalency to IV route (in up front treatment) because it leads to  somewhat less Neuropathy and thrombocytopenia.
5. Dexamethasone is still a corner stone of Myeloma treatment.  Add it even to the newest drug for their full effect to be unleashed (even Pomalidomide has 3 times the effect when Dexamethasone is added!
6.Almost everybody is treating until progression or maintenance therapy is the alternative.  As if now are assuming that the driver of the disease are continuously present!`
Now for Maintenance therapy, not only Revlimid, but also Velcade can be given with Dex in Maintenance setting.
7."In myeloma, a CR (or complete response) is a CR no matter how you got there" meaning any CR give the same benefit to the patient in terms of progression frr survival.
8. The idea of Maintenance therapy was further re-enforced by the VPMT forwed by Maintenance MT in cases treated without transplant!
9.Remember Carfilzomib and Pomalidomide are 3rd live as approved by FDA.  Meaning 2 treatment have to fail before you can prescribe these meds!
10. With Carfilzomid  (approved in July 2012)watch the kidney and cardiac parameters (concerns here)
less Neuropathy noted.
11. With more drugs available, 2 new combination triplets
  Carfilzomib/Pom/Dex
 Velcade/Pom /Dex meds
12 New drugs to be incorporated "  Daratuzumab, Aratuzumab, ARRY520
new combination Len/Carfil/Dex
13 New salvage TD-PACE,  VTD-PACE
14. one trial Cytoxan/Carfilzomid?Dex, surprising Cytoxan an option in Renal failure patients!

IN MYELOMA ANY OPTION IS GOOD BUT WATCH FOR DEL 17 PRESENCE! (pom AND velcade ARE THEN SOME OF THE OPTIONS)

Questions in Vascular lesions of the liver, and some oustanding associations rising questions at CRBCM.

*Taking Oral Contraceptive is associated with Hepatic Adenoma.
*Association between chronic Hepatitis, Cirrhosis, and Hepatoma
*Association between Ulcerative Colitis with Primary biliary cholangitis and Cholangiocarcinoma
why Spider Angioma
why Palmar Erythema
why LDH is linked to Lymphoma
Does a patient with multiple large unresectable
 Angiosarcoma in the liver candidate for liver transplant if there is no evidence of Metastatsis!

Potential Genes to investigate in liver lesions of Vascular tone/component!

1.VEGF and its corollary the EGFR
yes Avastin works in Angiosarcoma of the liver, and these are vascular lesions. So these genes are in play!
2. VHL, HIF yes these lesions are vascular and hypoxia must be coming in,
3.Estrogen, yes remember the predominance in these lesion in women of child bearing age, and the fact that Oral contraceptive must be discontinued, and avoidance of pregnancy is advised.
4.Androgenic Receptor gene, yes user of Androgenic drugs are at increased risk of Adenoma
5. Wnt (yes the catenin are involved for cellular polarity to be alterated and hypertrophy to occur)
6.Insulin Receptor, There must be in intervention from these genes as most patients with these lesions are obese, with diabetes Mellitus or Glycogen storage disorder particularly type 1A and 3.
7"Irritation/Inflammation such as seen with Hemochromatosis and fibrosis point to hyperactivity of the NF-kB and cyclins (IL 1,6,23)
8. Src gene needs examination because of potential development of sarcomatous lesions.
9. Endothelial involvement gives it DIC propensity (Kasabach-Merritt syndrome) or is-it the ADAMS associated with Cyclines involvedin initiating DIC?

?ROS amplification here give it the Metastatic potentials

(to be continued)

keeping track of CME

CONTINUING MEDICAL EDUCATION CERTIFICATE

certifies that

Mutombo Kankonde, MD
2400 Trawood Drive
Suite 303
El Paso, TX 79936

has participated in the enduring material titled

Secondary Prevention in Patients With ACS and Diabetes: How Can We Optimize Therapy?

August 11, 2013

and is awarded 0.50  AMA PRA Category 1 Credit(s)™.

Medscape, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

For information on applicability and acceptance of continuing education credit for this activity, please consult your professional licensing board.

Certificate Number: 43874499

Cyndi Grimes Director, Continuing Medical Education Medscape, LLC

 

Triple Negative Breast cancer a result of amplification of the JNK and the wnt

Persistent Failure at the receptors leads to a stressful situation that stimulate continuously the JNK/ERK with 2 implications:
1. Through the Caveolin based molecules will affect p66hc, a regulator maintaining ROS phosphorylated and active on the triple molecule Actin-Caherin and Beta-catenin (CBF).   Through the Catenin, PTPRB and ultimately MAGI3 will be affected.  CTNN1 leads to loss of polarity and lumen formation, and will activate Angiopoietin 1 Receptor and VGEF amplification, which in turn further amplification of ROS, the agent of metastasis...
2. JNK/ERK will also have epigenetic increasing TGFBeta and NF-kB  amplification lead to RUNX3 amplification.  Subsequent amplification of PIAS3 and MITF3 will do the rest.

2 main targets!  p66Shc and PIAS3, 2 regulators!

(This information results from speculative interpretation of information readily available on the internet)!

JAK2 at the TGF-Beta receptor, Angiopoitin 1 Receptor Tie2, Receptor, VGEF Receptor 2, IQGAP1, ARF6, ROS and its regulator p66Shc, the cadherin, the RUNX3,   which:

The RUNX3 Tumor Suppressor Upregulates Bim in Gastric Epithelial Cells Undergoing Transforming Growth Factor β-Induced Apoptosis

Takashi Yano,

Are just few of the Targets in the slew of events !

News from Medscape!

*"Hematologist-oncologist Farid Fata, MD, in suburban Detroit, Michigan, was arrested August 6 and charged with Medicare fraud in a federal case that stands out from dozens of others recently brought against healthcare providers.
For one thing, the dollar amount of alleged fraud — $35 million — is higher than most for individual providers charged by the government. The potential physical harm to patients described by prosecutors also is far more substantial. In a criminal complaint filed in a federal district court in Detroit, prosecutors said that the 48-year-old Dr. Fata ordered toxic chemotherapy for patients who did not have cancer or whose cancer was in remission. Doing this "is simply poisoning the patient," prosecutors said in a later court filing."  (go to article"

Physician Gave Chemo to Patients Without Cancer, Feds Say

Robert Lowes

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"Diabetic men with prostate cancer (PC) had a 24% decreased risk for PC-specific death for each additional 6 months of metformin treatment after cancer diagnosis, David Margel, MD, PhD, and colleagues reported online August 5 in the Journal of Clinical Oncology. Cumulative metformin use was also associated with decreased risk for all-cause mortality for the first 6 months after diagnosis. "

Metformin Linked to Fewer Prostate Cancer Deaths in Diabetics

Janis C. Kelly

GO to FULL ARTICLES!

MIAMI CONFERENCE ON HEMATOLOGY MALIGNANCIES

Have completed the conference update here in Miami-Florida. The conference gathered close to 100 Oncologist, In the beautiful Hotel Loews at Corner of 16th Street and Collins avenue.
Subject covered went from Myeloma to Myelofibrosis and will be all make subjects of the upcoming blog this week.  Our approach will not only focus GIVING YOU THE HIGHLIGHTS but also discussing how they fit into our perspectives at CRBCM.  And what associated assumptions can be made based on fundamemtal knowledge discussed in the conference.
From the CRBCM stand point, 2 speaker stood out, Professor Jerry Spivak, Director of the Johns Hopkins Center for the chronic Myeloproliferative disorders who spoke enthusiastically about Myelofibrosis and the new drug Ruxolitinib,  And DR Elias Jabbour, an associate professor in the Leukemia Department at MD Anderson cancer Center.
Once again we will summarize all this week material from this conference starting with Myelodysplasia.  We should confess that some drugs earn significant excitement with Ibrutinib in CHronic Lymphocytic Leukemia.  We predict that this drug in combination Rituxan will soon become the standard of care because of its effect that appears independent of whatever genetic prognosis factors (activity across the board)! and also because of high rates of responses!  Potential Hepatic concerns however call for patient close observation and monitoring.  While Pralatrexate is now more chosen in peripheral T cell Lymphoma. Romidepsin is coming a close 2nd in this disease.
Dasatinib won the war against Nilotinib as the choice in practice for the 2nd generation TKI in CML except for those with lung concern as comorbidity.  In mantle cell lymphoma, the rise in importance of Ibrutinib can not be ignored. Pomalidomide strength is with Dex, emphasizing further once again the importance of DExamethasone in this disease!
In Chronic Myeloid leukemia, the importance of Bone marrow transplantation has shriken until you specifically looking for a cure (Allogeneic transplant) and until the TKI have failed or that the transformation (by high blast) is occuring.  Very exciting to see these new drugs trying to define their places in a filed invaded by Target therapy (Vs conventional chemotherapy which is increasingly pushed-by not forgotten).

COULD PHOSPHATONINS EXPLAIN THE CONCURRENCE OF VITAMIN D DEFICIENCY IN AUTOIMMUNE DISEASES

One thing is certain, autoimmune diseases affect Mesenchymal tisues, the tissues that are full of Fibroblast growth factor 23 or Phosphatonins.  and we know that Phosphatonins "inhibit both renal tubular phosphate reabsorption and 1-alpha-hydroxylation of 25-hydroxycalciferol' (YU).  This fact alone will justify low levels in blood of 1,25-dihydroxycalciferol.  Following this assumption, of course the worse the disease the more likely the vitamin deficiency.  Therefore Vitamin D levels could be a biomarker gauging the severity of the disease (prognostic).

It is clear that disturbance of Phosphorus could also contributes to other electrolytes inbalances, grossly increasing the risk level of arrhythmia and sudden death. Of course too much Vitamin D is not good for you either.
Aging and Autoimmune diseases are characterized by increased levels of cytokines, all of which can affects these Phosphatonins with deleterious impact on our systems!  The levels of Vitamin D receptors could also be directly affected by gene suppression by silencing as a result of epigenetic changes that occurs with the slew of cytokins, and may be the cytokins have a promoter effect on the Phosphatonin gene (s).  Proof of concept needed!

HIDDEN EXCITEMENT ABOUT NANOTECHNOLOGY

One of the thing that stops progress to its full expansion, is some time the secrecy that researchers keep around really exciting things happening today in order to reveal only when things are ripe and ready for a "big" disclosure!  Also, the sense that we own technology and fight hands and teeth to keep findings that can save life for ourselves so we can rip the most profits.  It is just a shame that technology brought about by Taxpayers through NIH is bundle up in a patent.  We are still seeing the unfolding the BRCA fight which is still going on.  We just hope that people will come to their sense and free progress in technology for the good of the world!
One thing excited going on in New York is this development of Nanotechnology, it is my understanding that the State gave money and several biotech companies are now pitching in to possess and develop further this area of science, so that the benefit reach us all in time, at least we hope!  In this world of greed, we still should expect another round of fight over this technology!  Brace for it!

One of the way this technology will make a significant difference is the improved specific delivery of potent chemotherapy drugs to specific area of certain cells!   This is a major problem in Oncology since lack of control where the chemotherapy goes lead to devastating and uncontrolled side effects!  It's like a smart Bomb versus a dumb bomb!  This is target therapy at its best.
Researchers are targeting tough cancers with this technology. (ie melanoma, sarcoma and Pancreatic cancers).
The miRNA-708 story stands out in my mind!  That story reported that there is in triple negative breast cancer this miRNA 708 that inhibit Metastatic lesions from Breast cancer.   And because it is a suppressor "gene" for Metastatic breast cancer, it is its lack or deficiency that leads to promotion of metastasis.  The reports suggested that increasing delivery of synthetic genes could restore the inhibition of Metastasis, and Nanotechnology could come to the rescue as a transport of gene here to help us fight advanced Breast cancer.
The story is even bigger when you think back about the implications of better controlling this technology!
It is increasingly recognized that some if not most, are caused by a gene suppression!  PTEN, E-Cadherin, P53, Rb1 to name just a few...One of the toughest thing is restoring  a gene level!   Creating a inhibitor is the stuff we know how to do.  We have all kinds of inhibitors But gene reamplification and activity restoration is a challenge.  NANOTECHNOLOGY will come to the rescue, that is if we have the gene to restore ready for delivery.  Other way to restore is by regulating the gene promoter, or through Liposomes (lamelle technology and E-coli-mechanistic ways!)  Never mind these, nanotechnology is the new way, and it is hugely promising!  (Lawyers, brace yourselves!)

If you don't take magnesium, take it!

There are so many ways of losing Magnesium, that it is surprising we may still have magnesium in our body any more!  every single thing we do to enjoy life and fight aliment seems to remove magnesium from our body.  You run and sweat, you lose magnesium, you take proton pump inhibitor to reduce acid from our stomach due to stressful life, you lose more magnesium, you take a diuretic to fight high blood pressure, you lose potassium and magnesium, you eat fatty food, well you lose magnesium. you take a stool softner, laxative, you lose magnesium.  Many chemotherapy drug will increase your loss of magnesium (Cetuximab, Tacrolimus, Cisplatin, cyclosporine,Panitumumab)
And the blood test do not reveal the story,you have to be fully depleted of magnesium before your blood level changes.  So by the time your blood level changes, it is too late!  So please just eat your green vegetables, nuts, and whole grain cereals, milk and seafood to keep up.
Now if your DR told you you have renal failure or Irritable Bowel disease, magnesium intake can be dangerous as it may lead to toxicity!  You may be a high absorber man or not lose enough to keep you balanced ...you need your DR help here to monitor this more closely...

DRUG WITH POTENTIAL MARKED EPIGENETIC EFFECTS

There are medications of which role or mechanism of action needs clearly further clarification because they may prevent cancer from occuring. One such medication is:  (from mayo site)   Imiquimod.
"Imiquimod topical is used to treat external warts around the genital and rectal areas called condyloma acuminatum. It is not used on warts inside the vagina, penis, or rectum. Imiquimod is also used to treat a skin condition of the face and scalp called actinic keratosis (AK), which is caused by too much sun exposure. Imiquimod may be used to treat certain types of skin cancer called superficial basal cell carcinoma (sBCC).
Imiquimod works on the immune system to help the body fight viruses that cause warts. It does not destroy the viruses directly. It is not known how imiquimod works for actinic keratosis or skin cancer."

Understanding the mode of action of this drug in better detail appears critical for further development of target therapy that may help prevent certain cancers induced by chronic irritation and viral drive!
(another Medication used for same pathology is Podophyllin)
All they say is  "Podophyllin is a cytotoxic agent that has been used topically in the treatment of genital warts. It arrests mitosis in metaphase, an effect it shares with other cytotoxic agents such as the vinca alkaloids⁽²⁾. The active agent is podophyllotoxin, whose concentration varies with the type of podophyllin used; the American source normally containing one-fourth the amount of podophyllotoxin as the Indian source⁽³⁾."

==========================================================
One thing for sure, viral driven neoplastic diseases can be caused by integral incorporation of the viral genome in that of the host, or induce molecular disturbances changing the course of Metabolism and gene amplification or overexpression of transcription factors by affecting modulator or regulatory genes.  Abnormality of splicing will alter major functional core binding molecules, giving  new patterns to metabolic events, boosting hypertrophy (by loss of sense of cell limits and perturbances at adhesion molecules) and proliferation.   And if the the" foreign" (antigen) sense of the viral presence is not completely suppressed, the cell will be superexcited and the NF-kB on overdrive inducing significant epigenetic events including hyperproduction of Cyclins, Tumor growth factors and disturbances at miRNAs and polymerases (RNA--->DNAs).

All in all significant epigenetic events ensue.  Drugs that will affect epigenetic events must have a role in the control or modulation of these events.  We have to assume that Imiquimod and Podophyllin must have significant tampering effects of epigenetic events.  Indeed Etoposide is known to control these kind of diseases. And it is not because of its topoisomerase II activity and DNA attack, but this drug must have significant epigenetic effects, that is why it can tamper even other epigenetic driven pathologies such as the leukemias.  It is surprising that CPT-11 is not as used as Etoposide.  Pointing to role of heterogeneity in variation of pathologic expression of epigenetic events!

One thing for sure, medications important in control of these epigenetic events have the bad side effects of causing pulmonary fibrosis (Mitomycin). This point to the conclusion that some Cyclins/ TGF (Interleukins in particular) are over expressed leading to fibrosis.  And we still don't screen these Cyclins as biomarkers for detections.  But we know it (pulmonary fibrosis) is dose dependent!  Head in a sand situation again!

(Written on the go at CRBCM...)

New study on older women with early Breast cancer, Role of Radiation...GO TO MEDSCAPE FOR FULL ARTICLE!

Lumpectomy Plus Tamoxifen With or Without Irradiation in Women Age 70 Years or Older With Early Breast Cancer: Long-term Follow-up of CALGB 9343

Hughes KS, Schnaper LA, Bellon JR, et al


"
Women over the age of 70 years with early ER-positive invasive breast cancer (tumor measuring no more than 2 cm) and clinically negative axillae were enrolled between 1994 and 1999. A total of 636 participants with stage I breast cancer who were all treated with lumpectomy (axillary exploration was left to the discretion of the treating surgeon) were randomly assigned to receive tamoxifen plus radiation therapy or tamoxifen alone. Primary endpoints were time to local or regional recurrence, frequency of mastectomy, breast cancer-specific survival, time to distant metastasis, and overall survival.

After a median follow-up of 12.6 years, investigators found no significant differences in time to mastectomy, time to distant recurrence, breast cancer-specific survival, or overall survival. At 10 years, 98% of patients who received dual-modality therapy were free from locoregional recurrence as compared with 90% in the group treated with tamoxifen alone. In the group that received tamoxifen alone, 42 of 319 women relapsed, compared with 23 of 317 in the group that received tamoxifen plus radiation therapy. More women in the tamoxifen group had local and regional relapses and were treated with surgery or radiation at the time of relapse. There was no significant difference in the number of distant relapses between the 2 treatment groups."

YOU BE THE JUDGE!

AND HERE HE COMES FROM BRISTOL MEYERS SQUIBB: CETUXIMAB

CRYSTAL REGIMEN IN FIRST LINE KRAS MUTATION NEGATIVE (WILD TYPE) EGFR EXPRESSING METASTATIC COLORECTAL CANCER...


------------------------------------------------------------------------------------------------
                                                  Crystal regimen       vs     Folfiri alone

Median survival                         23.5 months             Vs    19.5 months

Objective response                           57%                  Vs    39%

Median PFS                                  9.5 months           Vs     8.1 months

-----------------------------------------------------------------------------------------------

higher chance to respond to treatment, and higher survival, when you add Cetuximab to FOLFIRI.

Side effects:

Acne-like RASH  86%  Vs 13%
Diarrhea      66%   Vs 60
Neutropenia   31%  Vs  24%

Making Acnee-like-rash the most specific side effect to cetuximab!  Why is a good question for the CRCBM.