Friday, March 8, 2013

CABOZANTINIB



COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).
Learn More COMETRIQ (cabozantinib) -- NOW AVAILABLE
COMETRIQ inhibits the activity of tyrosine kinases including RET, MET, and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment.
COMETRIQ was approved based on a pivotal trial in metastatic MTC patients (N=330) who were required to have radiographic evidence of actively progressive disease within 14 months prior to study entry.
Significantly prolonged progression-free survival (PFS) vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001)
— Median PFS was 11.2 months with COMETRIQ vs 4.0 months with placebo
Objective response rate (ORR) was 27% with COMETRIQ vs 0% with placebo (P<0.0001)
— Median duration of tumor response was 14.7 months (95% CI: 11.1, 19.3)
Adverse reactions occurring in ≥25% of patients treated with COMETRIQ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia.
Exelixis Access Services comprehensive support program Exelixis® Access Services comprehensive support program*

For you and your patients —
call 1-855-253-EASE (1-855-253-3273)
8:00 am to 11:00 pm ET, Monday to Friday
Easing access to COMETRIQ with a full range of services, provided by trained professionals, to meet the needs of healthcare professionals in prescribing and of patients in obtaining COMETRIQ.
Access and reimbursement support (including benefit coverage and appeals)
Assistance with coding information and obtaining COMETRIQ
Financial assistance to enroll eligible patients into available programs (Co-pay Assistance, Patient Assistance, and Alternate Funding Investigation)
* This description of the Exelixis Access Services program is for informational purposes only. Exelixis makes no representation or guarantee concerning reimbursement or coverage for any service or item. Information provided through the Exelixis Access Services program does not constitute medical or legal advice and is not intended to be a substitute for a consultation with a licensed healthcare provider, legal counsel, or applicable third-party payer(s). Exelixis reserves the right to modify the program at any time without notice.

Financial aid for people in need may be available from certain government programs and charities. These include state pharmaceutical assistance programs (SPAPs), Medicaid, Medicare Part D, low-income subsidies, and charitable foundations. An Exelixis Access Services program specialist can explain these options to you.
IMPORTANT SAFETY INFORMATION
BOXED WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE
See full prescribing information for complete boxed warning.
Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula.
Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage.
ADDITIONAL IMPORTANT SAFETY INFORMATION
Gastrointestinal (GI) perforations (3%) and GI fistulas (1%), all serious, were reported with COMETRIQ, including 1 (<1%) fatal GI fistula. Non-GI fistulas including tracheal/esophageal were reported (4%), including 2 (1%) fatal events. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula.
Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher with COMETRIQ (3%) than with placebo (1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis.
Increased incidence of thrombotic events (venous thromboembolism: 6% vs 3%; arterial thromboembolism: 2% vs 0%) was reported with COMETRIQ vs placebo, respectively. Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication.
Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ ≥28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention.
Increased incidence of treatment-emergent hypertension, stage 1 or 2 (modified JNC criteria), was identified with COMETRIQ (61% vs 30% with placebo). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy.
Osteonecrosis of the jaw (ONJ) occurred with COMETRIQ (1%). ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for ≥28 days prior to scheduled surgery, if possible.
Palmar-plantar erythrodysesthesia syndrome (PPES) occurred (50%) with COMETRIQ and was severe (Grade ≥3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose.
Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome, compared with 0 patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome.
Reversible posterior leukoencephalopathy syndrome (RPLS) occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS.
Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors.
COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment.
COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus.
The COMETRIQ dose was reduced in 79% of patients vs 9% for placebo.
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
For the full Prescribing Information, including Boxed Warning, please click here.

To unsubscribe from this type of informational e-mail as delivered by Exelixis, Inc., please click here.
EXELIXIS © 2013 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080     02/13     [03-13-00043-B]

Challenge with diet and food supplements

It is nice to understand the potential activity or mechanism of action of food supplements and act on it. Example: "Vitamin C: MedlinePlus Medical Encyclopedia

www.nlm.nih.gov/medlineplus/ency/article/002404.htm

Function. Vitamin C is needed for the growth and repair of tissues in all parts of your body. It is used to: Form an important protein used to make skin, tendons, ..."

That knowledge empowers you and helps you take action.  You run to the store and buy a good supply of vitamin C and take it for now and the future.  What the information can not tell you is just as important.  How much Vitamin C you need to actually have the benefit described? How long you should be doing this?  Is your body just getting rid of the extra or all of it?  Based on your chromosome heterogeneity, was it safe for you to have done it?  Are you missing a critical enzyme to process the vitamin?
The NIH is finding out that things that are promised by food supplements, when put to the test and scientific scrutiny, do not deliver a clearly evident output.  "Taking an apple a day" (low methionine food item) will prolong your life.  While the scientific evidence as to how this is possible is established:  Does it really happen? No.  Why? Because what is left out is even more important.  How many apples  a day should you eat, what type of apple, what else should accompany this practice to make this goal achievable (low calory diet)? And so on and so forth. We all know that food supplements can impact some of the signal transduction pathways in our cells and, as a result, they could potentially impact our lives in some beneficial ways.  But is it safe to constantly be bothering our signal transduction pathways?  Do you believe it is right to do so constantly?  Who said this pathway needs to be switched on all the time?  What guarantees you that the body will not respond and shut it off anyway as it always reacts to action that we deliberately impose upon it!
Keeping a pathway on all the time may impact another pathway all the time, and if you just happen to have the wrong gene for this particular game, you may start on some road you should not be on!  So please, just because it may make sense, it does not yet mean that it is true and relevant for YOU! 

ACTIVITY AT THE CRBCM:

*WAITING FOR IRS TO FINALIZE ITS WORK INVOLVING THE CRBCM.  THIS WILL BE APPRECIATED, REALLY.
*WE HAVE SUBMITTED ON TIME 3 LETTERS OF INTENT (LOI) FOR RESEARCH WORK
FOR ONCE NOW WE HAVE A LOT OF SUPPORT FROM THE  NIH.
*REPORTING TO CHICAGO FOR UPDATE IN CANCER TREATMENT CONFERENCE, WILL GIVE YOU ALL KIND OF REPORTS FROM THIS CONFERENCE. THIS IS DATA MINING.
(CRBCM IS ON THE MOVE)
*WILL START FIELD WORK FOR 4 WEEKS.
*BY THE WAY, THE MD ANDERSON HAS AGREED TO SEE OUR PATIENT WITH METASTATIC PENILE CANCER.  THANKS!

BRCA1 and BRCA2: Cancer Risk and Genetic Testing


Key Points  (THIS BEAUTIFUL ARTICLE IS WORK OF THE NIH, PLEASE KNOW THIS!)
  • BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors. Mutation of these genes has been linked to hereditary breast and ovarian cancer.
  • A woman's risk of developing breast and/or ovarian cancer is greatly increased if she inherits a deleterious (harmful) BRCA1 or BRCA2 mutation. Men with these mutations also have an increased risk of breast cancer. Both men and women who have harmful BRCA1 or BRCA2 mutations may be at increased risk of other cancers.
  • Genetic tests are available to check for BRCA1 and BRCA2 mutations. A blood sample is required for these tests, and genetic counseling is recommended before and after the tests.
  • If a harmful BRCA1 or BRCA2 mutation is found, several options are available to help a person manage their cancer risk.
  • Federal and state laws help ensure the privacy of a person’s genetic information and provide protection against discrimination in health insurance and employment practices.
  • Many research studies are being conducted to find newer and better ways of detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutation carriers. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.
  1. What are BRCA1 and BRCA2?

    BRCA1 and BRCA2 are human genes that belong to a class of genes known as tumor suppressors.
    In normal cells, BRCA1 and BRCA2 help ensure the stability of the cell’s genetic material (DNA) and help prevent uncontrolled cell growth. Mutation of these genes has been linked to the development of hereditary breast and ovarian cancer.
    The names BRCA1 and BRCA2 stand for breast cancer susceptibility gene 1 and breast cancer susceptibility gene 2, respectively.
  2. How do BRCA1 and BRCA2 gene mutations affect a person's risk of cancer?

    Not all gene changes, or mutations, are deleterious (harmful). Some mutations may be beneficial, whereas others may have no obvious effect (neutral). Harmful mutations can increase a person’s risk of developing a disease, such as cancer.
    A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2. Such a woman has an increased risk of developing breast and/or ovarian cancer at an early age (before menopause) and often has multiple, close family members who have been diagnosed with these diseases. Harmful BRCA1 mutations may also increase a woman’s risk of developing cervical, uterine, pancreatic, and colon cancer (1, 2). Harmful BRCA2 mutations may additionally increase the risk of pancreatic cancer, stomach cancer, gallbladder and bile duct cancer, and melanoma (3).
    Men with harmful BRCA1 mutations also have an increased risk of breast cancer and, possibly, of pancreatic cancer, testicular cancer, and early-onset prostate cancer. However, male breast cancer, pancreatic cancer, and prostate cancer appear to be more strongly associated with BRCA2 gene mutations (2–4).
    The likelihood that a breast and/or ovarian cancer is associated with a harmful mutation in BRCA1 or BRCA2 is highest in families with a history of multiple cases of breast cancer, cases of both breast and ovarian cancer, one or more family members with two primary cancers (original tumors that develop at different sites in the body), or an Ashkenazi (Central and Eastern European) Jewish background (see Question 6). However, not every woman in such families carries a harmful BRCA1 or BRCA2 mutation, and not every cancer in such families is linked to a harmful mutation in one of these genes. Furthermore, not every woman who has a harmful BRCA1 or BRCA2 mutation will develop breast and/or ovarian cancer.
    According to estimates of lifetime risk, about 12.0 percent of women (120 out of 1,000) in the general population will develop breast cancer sometime during their lives compared with about 60 percent of women (600 out of 1,000) who have inherited a harmful mutation in BRCA1 or BRCA2 (4, 5). In other words, a woman who has inherited a harmful mutation in BRCA1 or BRCA2 is about five times more likely to develop breast cancer than a woman who does not have such a mutation.
    Lifetime risk estimates for ovarian cancer among women in the general population indicate that 1.4 percent (14 out of 1,000) will be diagnosed with ovarian cancer compared with 15 to 40 percent of women (150–400 out of 1,000) who have a harmful BRCA1 or BRCA2 mutation (4, 5).
    It is important to note, however, that most research related to BRCA1 and BRCA2 has been done on large families with many individuals affected by cancer. Estimates of breast and ovarian cancer risk associated with BRCA1 and BRCA2 mutations have been calculated from studies of these families. Because family members share a proportion of their genes and, often, their environment, it is possible that the large number of cancer cases seen in these families may be due in part to other genetic or environmental factors. Therefore, risk estimates that are based on families with many affected members may not accurately reflect the levels of risk for BRCA1 and BRCA2 mutation carriers in the general population. In addition, no data are available from long-term studies of the general population comparing cancer risk in women who have harmful BRCA1 or BRCA2 mutations with women who do not have such mutations. Therefore, the percentages given above are estimates that may change as more data become available.
  3. Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

    Yes. Mutations in several other genes, including TP53, PTEN, STK11/LKB1, CDH1, CHEK2, ATM, MLH1, and MSH2, have been associated with hereditary breast and/or ovarian tumors (4, 6, 7). However, the majority of hereditary breast cancers can be accounted for by inherited mutations in BRCA1 and BRCA2 (8). Overall, it has been estimated that inherited BRCA1 and BRCA2 mutations account for 5 to 10 percent of breast cancers and 10 to 15 percent of ovarian cancers among white women in the United States (6).
  4. Are specific mutations in BRCA1 and BRCA2 more common in certain populations?

    Yes. For example, three specific mutations, two in the BRCA1 gene and one in the BRCA2 gene, are the most common mutations found in these genes in the Ashkenazi Jewish population. In one study, 2.3 percent of participants (120 out of 5,318) carried one of these three mutations (9). This frequency is about five times higher than that found in the general population (10). It is not known whether the increased frequency of these mutations is responsible for the increased risk of breast cancer in Jewish populations compared with non-Jewish populations.
    Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have higher frequencies of specific BRCA1 and BRCA2 mutations.
    In addition, limited data indicate that the frequencies of specific BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (11–13).
    This information about genetic differences between racial and ethnic groups may help health care providers in selecting the most appropriate genetic test(s) (see Question 5).
  5. Are genetic tests available to detect BRCA1 and BRCA2 mutations, and how are they performed?

    Yes. Several methods are available to test for BRCA1 and BRCA2 mutations (14). Most of these methods look for changes in BRCA1 and BRCA2 DNA. At least one method looks for changes in the proteins produced by these genes. Frequently, a combination of methods is used.
    A blood sample is needed for these tests. The blood is drawn in a laboratory, doctor's office, hospital, or clinic and then sent to a laboratory that specializes in the tests. It usually takes several weeks or longer to get the test results. Individuals who decide to get tested should check with their health care provider to find out when their test results might be available.
    Genetic counseling is generally recommended before and after a genetic test. This counseling should be performed by a health care professional who is experienced in cancer genetics (see Question 17). Genetic counseling usually involves a risk assessment based on the individual’s personal and family medical history and discussions about the appropriateness of genetic testing, the specific test(s) that might be used and the technical accuracy of the test(s), the medical implications of a positive or a negative test result, the possibility that a test result might not be informative (an ambiguous result) (see below), the psychological risks and benefits of genetic test results, and the risk of passing a mutation to children.
  6. How do people know if they should consider genetic testing for BRCA1 and BRCA2 mutations?

    Currently, there are no standard criteria for recommending or referring someone for BRCA1 or BRCA2 mutation testing.
    In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has breast or ovarian cancer. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members can be tested to see if they also have the mutation.
    Regardless, women who have a relative with a harmful BRCA1 or BRCA2 mutation and women who appear to be at increased risk of breast and/or ovarian cancer because of their family history should consider genetic counseling to learn more about their potential risks and about BRCA1 and BRCA2 genetic tests.
    The likelihood of a harmful mutation in BRCA1 or BRCA2 is increased with certain familial patterns of cancer. These patterns include the following (15):
    • For women who are not of Ashkenazi Jewish descent:
      • two first-degree relatives (mother, daughter, or sister) diagnosed with breast cancer, one of whom was diagnosed at age 50 or younger;
      • three or more first-degree or second-degree (grandmother or aunt) relatives diagnosed with breast cancer regardless of their age at diagnosis;
      • a combination of first- and second-degree relatives diagnosed with breast cancer and ovarian cancer (one cancer type per person);
      • a first-degree relative with cancer diagnosed in both breasts (bilateral breast cancer);
      • a combination of two or more first- or second-degree relatives diagnosed with ovarian cancer regardless of age at diagnosis;
      • a first- or second-degree relative diagnosed with both breast and ovarian cancer regardless of age at diagnosis; and
      • breast cancer diagnosed in a male relative.
    • For women of Ashkenazi Jewish descent:
      • any first-degree relative diagnosed with breast or ovarian cancer; and
      • two second-degree relatives on the same side of the family diagnosed with breast or ovarian cancer.
    These family history patterns apply to about 2 percent of adult women in the general population. Women who have none of these family history patterns have a low probability of having a harmful BRCA1 or BRCA2 mutation.
  7. How much does BRCA1 and BRCA2 mutation testing cost?

    The cost for BRCA1 and BRCA2 mutation testing usually ranges from several hundred to several thousand dollars. Insurance policies vary with regard to whether or not the cost of testing is covered. People who are considering BRCA1 and BRCA2 mutation testing may want to find out about their insurance company’s policies regarding genetic tests.
  8. What does a positive BRCA1 or BRCA2 test result mean?

    A positive test result generally indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers, as described above. However, a positive test result provides information only about a person’s risk of developing cancer. It cannot tell whether an individual will actually develop cancer or when. Not all women who inherit a harmful BRCA1 or BRCA2 mutation will develop breast or ovarian cancer.
    A positive genetic test result may have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person’s relatives. Both men and women who inherit harmful BRCA1 or BRCA2 mutations, whether they develop cancer themselves or not, may pass the mutations on to their sons and daughters. However, not all children of people who have a harmful mutation will inherit the mutation. 
  9. What does a negative BRCA1 or BRCA2 test result mean?

    How a negative test result will be interpreted depends on whether or not someone in the tested person’s family is known to carry a harmful BRCA1 or BRCA2 mutation. If someone in the family has a known mutation, testing other family members for the same mutation can provide information about their cancer risk. If a person tests negative for a known mutation in his or her family, it is unlikely that they have an inherited susceptibility to cancer associated with BRCA1 or BRCA2. Such a test result is called a “true negative.” Having a true negative test result does not mean that a person will not develop cancer; it means that the person’s risk of cancer is probably the same as that of people in the general population.
    In cases in which a family has a history of breast and/or ovarian cancer and no known mutation in BRCA1 or BRCA2 has been previously identified, a negative test result is not informative. It is not possible to tell whether an individual has a harmful BRCA1 or BRCA2 mutation that was not detected by testing (a “false negative”) or whether the result is a true negative. In addition, it is possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test(s) used.
  10. What does an ambiguous BRCA1 or BRCA2 test result mean?

    If genetic testing shows a change in BRCA1 or BRCA2 that has not been previously associated with cancer in other people, the person’s test result may be interpreted as “ambiguous” (uncertain). One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (16).
    Because everyone has genetic differences that are not associated with an increased risk of disease, it is sometimes not known whether a specific DNA change affects a person’s risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 changes, scientists will learn more about these changes and cancer risk.
  11. What are the options for a person who has a positive test result?

    Several options are available for managing cancer risk in individuals who have a harmful BRCA1 or BRCA2 mutation. However, high-quality data on the effectiveness of these options are limited.
    • Surveillance—Surveillance means cancer screening, or a way of detecting the disease early. Screening does not, however, change the risk of developing cancer. The goal is to find cancer early, when it may be most treatable.
      Surveillance methods for breast cancer may include mammography and clinical breast exams. Studies are currently under way to test the effectiveness of other breast cancer screening methods, such as magnetic resonance imaging (MRI), in women with BRCA1 or BRCA2 mutations. With careful surveillance, many breast cancers will be diagnosed early enough to be successfully treated.
      For ovarian cancer, surveillance methods may include transvaginal ultrasound, blood tests for CA–125 antigen, and clinical exams. Surveillance can sometimes find ovarian cancer at an early stage, but it is uncertain whether these methods can help reduce a woman's chance of dying from this disease.
    • Prophylactic Surgery—This type of surgery involves removing as much of the "at-risk" tissue as possible in order to reduce the chance of developing cancer. Bilateral prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingo-oophorectomy (removal of healthy fallopian tubes and ovaries) do not, however, offer a guarantee against developing cancer. Because not all at-risk tissue can be removed by these procedures, some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. In addition, some evidence suggests that the amount of protection salpingo-oophorectomy provides against the development of breast and ovarian cancer may differ between carriers of BRCA1 and BRCA2 mutations (17).
    • Risk Avoidance—Certain behaviors have been associated with breast and ovarian cancer risk in the general population (see Question 16). Research results on the benefits of modifying individual behaviors to reduce the risk of developing cancer among BRCA1 or BRCA2 mutation carriers are limited.
    • Chemoprevention—This approach involves the use of natural or synthetic substances to reduce the risk of developing cancer or to reduce the chance that cancer will come back. For example, the drug tamoxifen has been shown in numerous clinical studies to reduce the risk of developing breast cancer by about 50 percent in women who are at increased risk of this disease and to reduce the recurrence of breast cancer in women undergoing treatment for a previously diagnosed breast tumor. As a result, tamoxifen was approved by the U.S. Food and Drug Administration (FDA) as a breast cancer treatment and to reduce the risk of breast cancer development in premenopausal and postmenopausal women who are at increased risk of this disease. Few studies, however, have evaluated the effectiveness of tamoxifen in women with BRCA1 or BRCA2 mutations. Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (18–20). Two of these studies examined the effectiveness of tamoxifen in helping to reduce the development of cancer in the opposite breast of women undergoing treatment for an initial breast cancer (19, 20).
      Another drug, raloxifene, was shown in a large clinical trial sponsored by the National Cancer Institute (NCI) to reduce the risk of developing invasive breast cancer in postmenopausal women at increased risk of this disease by about the same amount as tamoxifen. As a result, raloxifene was approved by the FDA for breast cancer risk reduction in postmenopausal women. Since tamoxifen and raloxifene inhibit the growth of breast cancer cells in similar ways, raloxifene may be able to help reduce breast cancer risk in postmenopausal BRCA1 and BRCA2 mutation carriers. However, this has not been studied directly. 
  12. What are some of the benefits of genetic testing for breast and ovarian cancer risk?

    There can be benefits to genetic testing, whether a person receives a positive or a negative result. The potential benefits of a negative result include a sense of relief and the possibility that special preventive checkups, tests, or surgeries may not be needed. A positive test result can bring relief from uncertainty and allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, many people who have a positive test result may be able to participate in medical research that could, in the long run, help reduce deaths from breast cancer.
  13. What are some of the risks of genetic testing for breast and ovarian cancer risk?

    The direct medical risks, or harms, of genetic testing are very small, but test results may have an effect on a person’s emotions, social relationships, finances, and medical choices.
    People who receive a positive test result may feel anxious, depressed, or angry. They may choose to undergo preventive measures, such as prophylactic surgery, that have serious long-term implications and whose effectiveness is uncertain.
    People who receive a negative test result may experience “survivor guilt,” caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.
    Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal choices, such as marriage and childbearing. Issues surrounding the privacy and confidentiality of genetic test results are additional potential risks (see below).
  14. What can happen when genetic test results are placed in medical records?

    Clinical test results are normally included in a person’s medical records. Consequently, individuals considering genetic testing must understand that their results might not be kept private.
    Because a person’s genetic information is considered health information, it is covered by the Privacy Rule of the Health Information Portability and Accountability Act (HIPAA) of 1996 (21). The Privacy Rule requires that health care providers and others protect the privacy of health information, sets boundaries on the use and release of health records, and empowers individuals to control certain uses and disclosures of their health-related information. Many states also have laws to protect the privacy and limit the release of genetic and other health information.
    In 2008, the Genetic Information Nondiscrimination Act (GINA) became Federal law (see Question 15). GINA prohibits discrimination based on genetic information in relation to health insurance and employment, but the law does not cover life insurance, disability insurance, and long-term care insurance. When applying for these types of insurance, people may be asked to sign forms that give an insurance company permission to access their medical records. The insurance company may take genetic test results into account when making decisions about coverage.
    Some physicians keep genetic test results out of medical records. However, even if such results are not included in a person’s medical records, information about a person’s genetic profile can sometimes be gathered from that person’s family medical history.
  15. What is genetic discrimination, and are there laws to protect people from this type of discrimination?

    Genetic discrimination occurs when people are treated differently by insurance companies or employers because they have a gene mutation that increases their risk of a disease, such as cancer. However, in 2008, GINA was enacted to protect U.S. citizens against discrimination based on their genetic information in relation to health insurance and employment (22, 23). The parts of the law relating to health insurers will take effect between May 2009 and May 2010, and those relating to employers will take effect by November 2009. The law does not cover life insurance, disability insurance, and long-term care insurance. In addition, the law does not cover members of the military.
    Some of the protections under GINA with regard to health insurance include the following:
    • Premiums or contributions to a group health plan cannot be increased based on the genetic information of an individual(s) enrolled in the plan.
    • Insurers cannot require an individual or family member to undergo a genetic test before enrollment in a group health plan.
    • Insurers cannot request, require, or purchase genetic information about an individual before the person’s enrollment in a group health plan or in connection with that person’s enrollment in the plan.
    • Health insurers cannot use genetic information as the only basis upon which to claim a pre-existing condition is present and, therefore, to deny coverage.
    Some of the protections under GINA with regard to employment include the following:
    • Employers cannot refuse to hire and cannot fire individuals based on their genetic information.
    • Employers cannot discriminate against employees with regard to salary, terms and conditions of employment, privileges, and opportunities for the future because of their genetic information.
    • Employers cannot request, require, or purchase genetic information about an employee except under specific circumstances.
    • Employers cannot disclose an employee's genetic information except under specific circumstances.
    Before GINA was passed, many states enacted laws against genetic discrimination. The amount of protection provided by these laws varies widely from state to state. GINA sets a minimum standard of protection that must be met by all states. It does not weaken the protections provided by any state law.
  16. In general, what factors increase or decrease the chance of developing breast cancer and/or ovarian cancer?

    The following factors have been associated with increased or decreased risk of developing breast and/or ovarian cancer in the general population. It is not yet known exactly how these factors influence risk in people with BRCA1 or BRCA2 mutations. In addition, a significant portion of hereditary breast cancers are not associated with BRCA1 or BRCA2 mutations (8).
    • Age—The risks of breast and ovarian cancer increase with age. Most breast and ovarian cancers occur in women over the age of 50. Women with harmful BRCA1 or BRCA2 mutations often develop breast or ovarian cancer before age 50.
    • Family History—Women who have a first-degree relative (mother, sister, or daughter) or other close relative with breast and/or ovarian cancer may be at increased risk of developing these cancers. In addition, women with relatives who have had colon cancer may be at increased risk of developing ovarian cancer.
    • Medical History—Women who have already had breast cancer are at increased risk of developing breast cancer again, or of developing ovarian cancer.
    • Hormonal InfluencesEstrogen is a hormone that is naturally produced by the body and stimulates the normal growth of breast tissue. It is thought that excess estrogen may contribute to breast cancer risk because of its natural role in stimulating breast cell growth. Women who had their first menstrual period before the age of 12 or experienced menopause after age 55 have a slightly increased risk of breast cancer, as do women who had their first child after age 30. Each of these factors increases the amount of time a woman’s body is exposed to estrogen. Removal of a woman’s ovaries, which are the main source of estrogen production, reduces the risk of breast cancer. Breast-feeding also reduces breast cancer risk and is thought to exert its effects through hormonal mechanisms (24).
    • Birth Control Pills (Oral Contraceptives)—Most studies have shown a slight increase or no change in risk of breast cancer among women taking birth control pills (24). In contrast, numerous studies have shown that taking birth control pills decreases a woman’s risk of developing ovarian cancer (25). This protective benefit appears to increase with the duration of oral contraceptive use and persists up to 25 years after discontinuing use. It also appears that the use of birth control pills lowers the risk of ovarian cancer in women who carry harmful BRCA1 or BRCA2 mutations (26).
    • Hormone Replacement Therapy—Doctors may prescribe hormone replacement therapy (HRT) to reduce the discomfort of certain symptoms of menopause, such as hot flashes. However, the results of the Women’s Health Initiative (WHI), a large clinical study conducted by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health (NIH), showed that HRT with the hormones estrogen and progestin is associated with harmful side effects, including an increased risk of breast cancer and increased risks of heart attack, blood clots, and stroke. The WHI also showed that HRT with estrogen alone was associated with increased risks of blood clots and stroke, but the effect on breast cancer risk was uncertain (27). In addition, the WHI showed an increase in ovarian cancer risk among women who received estrogen and progestin HRT, but this finding was not statistically significant (28). Because of these potential harmful side effects, the FDA has recommended that HRT be used only at the lowest doses for the shortest period of time needed to achieve treatment goals.
      No data have been reported to date regarding the effects of HRT on breast cancer risk among women carrying harmful BRCA1 or BRCA2 mutations, and only limited data are available regarding HRT use and ovarian cancer risk among such women. In one study, HRT use did not appear to affect ovarian cancer risk among women with BRCA1 or BRCA2 mutations (29).
      When considering HRT use, both the potential harms and benefits of this type of treatment should be discussed carefully by a woman and her health care provider.
    • Obesity—Substantial evidence indicates that obesity is associated with an increased risk of breast cancer, especially among postmenopausal women who have not used HRT (24). Evidence also suggests that obesity is associated with increased mortality (death) from ovarian cancer (30).
    • Physical Activity—Numerous studies have examined the relationship between physical activity and breast cancer risk, and most of these studies have shown that physical activity, especially strenuous physical activity, is associated with reduced risk. This decrease in risk appears to be more pronounced in premenopausal women and women with lower-than-normal body weight (24).
    • Alcohol—There is substantial evidence that alcohol consumption is associated with increased breast cancer risk. However, it is uncertain whether reducing alcohol consumption would decrease breast cancer risk (24).
    • Dietary Fat—Although early studies suggested a possible association between a high-fat diet and increased breast cancer risk, more recent studies have been inconclusive. In the WHI, a low-fat diet did not help reduce breast cancer risk (31).
  17. Where can people get more information about genetic testing for cancer risk?

    A person who is considering genetic testing should speak with a professional trained in genetics before deciding whether to be tested. These professionals may include doctors, genetic counselors, and other health care workers trained in genetics (such as nurses, psychologists, or social workers). For help finding a health care professional trained in genetics, please visit NCI’s Cancer Genetics Services Directory at http://www.cancer.gov/cancertopics/genetics/directory on the Internet. Alternatively, please contact NCI’s Cancer Information Service (CIS) (see below for contact information). The CIS can provide more information about genetic testing and help in finding a health care professional trained in genetics.
  18. What research is currently being done to help individuals with harmful BRCA1 or BRCA2 mutations?

    Research studies are being conducted to find newer and better ways of detecting, treating, and preventing cancer in BRCA1 and BRCA2 mutation carriers. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.
    Information about active clinical trials (research studies with people) for individuals with BRCA1 or BRCA2 mutations is available on NCI’s Web site. The following links will initiate searches of NCI’s clinical trials database and retrieve lists of trials open to individuals with BRCA1 or BRCA2 mutations.
    In addition, NCI’s CIS can provide information about clinical trials and help with clinical trial searches (see below for contact information).
Selected References
  1. Kadouri L, Hubert A, Rotenberg Y, et al. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. Journal of Medical Genetics 2007; 44(7):467–471.
  2. Thompson D, Easton DF, the Breast Cancer Linkage Consortium. Cancer incidence in BRCA1 mutation carriers. Journal of the National Cancer Institute 2002; 94(18):1358–1365.
  3. The Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. Journal of the National Cancer Institute 1999; 91(15):1310–1316.
  4. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Genetics of Breast and Ovarian Cancer (PDQ®) - Health Professional. Date last modified 04/24/2009. Available at: http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/healthprofessional. Accessed 05/15/2009.
  5. National Cancer Institute. SEER Cancer Statistics Review, 1975–2005. Retrieved April 20, 2009, from: http://seer.cancer.gov/csr/1975_2005/index.html.
  6. Campeau PM, Foulkes WD, Tischkowitz MD. Hereditary breast cancer: New genetic developments, new therapeutic avenues. Human Genetics 2008; 124(1):31–42.
  7. Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. Journal of the American Medical Association 2006; 295(12):1379–1388.
  8. Lynch HT, Silva E, Snyder C, Lynch JF. Hereditary breast cancer: Part I. Diagnosing hereditary breast cancer syndromes. The Breast Journal 2008; 14(1):3–13.
  9. Struewing JP, Hartge P, Wacholder S, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New England Journal of Medicine 1997; 336(20):1401–1408.
  10. Warner E, Foulkes W, Goodwin P, et al. Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer. Journal of the National Cancer Institute 1999; 91(14):1241–1247.
  11. John EM, Miron A, Gong G, et al. Prevalence of pathogenic BRCA1 mutation carriers in 5 U.S. racial/ethnic groups. Journal of the American Medical Association 2007; 298(24):2869–2876.
  12. Vogel KJ, Atchley DP, Erlichman J, et al. BRCA1 and BRCA2 genetic testing in Hispanic patients: Mutation prevalence and evaluation of the BRCAPRO risk assessment model. Journal of Clinical Oncology 2007; 25(29):4635–4641.
  13. Malone KE, Daling JR, Doody DR, et al. Prevalence and predictors of BRCA1 and BRCA2 mutations in a population-based study of breast cancer in white and black American women ages 35 to 64 years. Cancer Research 2006; 66(16):8297–8308.
  14. Palma M, Ristori E, Ricevuto E, Giannini G, Gulino A. BRCA1 and BRCA2: The genetic testing and the current management options for mutation carriers. Critical Reviews in Oncology/Hematology 2006; 57(1):1–23.
  15. U.S. Preventive Services Task Force. Genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. Retrieved April 20, 2009, from: http://www.ahrq.gov/clinic/uspstf05/brcagen/brcagenrs.htm.
  16. Peshkin BN, DeMarco TA, Brogan BM, Lerman C, Isaacs C. BRCA1/2 testing: Complex themes in result interpretation. Journal of Clinical Oncology 2001; 19(9):2555–2565.
  17. Kauff ND, Domchek SM, Friebel TM, et al. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: A multicenter, prospective study. Journal of Clinical Oncology 2008; 26(8):1331–1337.
  18. King MC, Wieand S, Hale K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP–P1) Breast Cancer Prevention Trial. Journal of the American Medical Association 2001; 286(18):2251–2256.
  19. Narod SA, Brunet JS, Ghadirian P, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Lancet 2000; 356(9245):1876–1881.
  20. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: An update. International Journal of Cancer 2006; 118(9):2281–2284.
  21. U.S. Department of Health and Human Services. HIPAA Frequent Questions: About the Privacy Rule FAQs. Retrieved April 20, 2009, from: http://www.hhs.gov/hipaafaq/about/354.html.
  22. H.R. 493. The Genetic Information Nondiscrimination Act of 2008. Retrieved April 20, 2009, from:
    http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_bills&docid=f:h493enr.txt.pdf.
  23. The National Human Genome Research Institute. GINA: The Genetic Information Nondiscrimination Act of 2008: Information for Researchers and Health Care Professionals. Retrieved April 30, 2009, from: http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf.
  24. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Breast Cancer Prevention (PDQ®) - Health Professional. Date last modified 04/30/2009. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/breast/healthprofessional.
  25. PDQ® Cancer Information Summary. National Cancer Institute; Bethesda, MD. Ovarian Cancer Prevention (PDQ®) - Health Professional. Date last modified 04/03/2008. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/ovarian/healthprofessional.
  26. Whittemore AS, Balise RR, Pharoah PDP, et al. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. British Journal of Cancer 2004; 91(11):1911–1915.
  27. National Heart, Lung, and Blood Institute. Women’s Health Initiative. Retrieved April 20, 2009, from: http://www.nhlbi.nih.gov/whi.
  28. Anderson GL, Judd HL, Kaunitz AM, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: The Women's Health Initiative randomized trial. Journal of the American Medical Association 2003; 290(13):1739–1748.
  29. Kotsopoulos J, Lubinski J, Neuhausen SL, et al. Hormone replacement therapy and the risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers. Gynecologic Oncology 2006; 100(1):83–88.
  30. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. New England Journal of Medicine 2003; 348(17):1625–1638.
  31. Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. Journal of the American Medical Association 2006; 295(6):629–642.
This text may be reproduced or reused freely. Please credit the National Cancer Institute as the source. Any graphics may be owned by the artist or publisher who created them, and permission may be needed for their reuse.

Thursday, March 7, 2013

NEWS from ASCO

*Avastin-Folfoxiri better than Avastin-Folfiri, no news there.  It is just a repeat of things we knew would happen.
*In Colon cancer patients with Wild type KRAS  Panitumumab (Vectibix) associated to 5-FU based combination gave an outcome comparable to results obtained in a different study with Avastin and 5-FU based combination.  2 phase II trials but 2 similar outcomes.   And this in first line and 2nd line.  Can't wait to see a phase III.
*40% Glioblastoma express EGFR
20% have EGFRvIII
with Lapatinip being looked at for treatment, will wait to see.
 

Expression of MTOR can be quantified by the following:

Expression of MTOR can be quantified
by following PIK
Raptor
mLst8
 Deptor
TORC2
SGK
Sin1
PRR5L

By Western Blot, Flowcytometry

Wednesday, March 6, 2013

Mantle Cell Lymphoma

*In Mantle cell lymphoma, Rituxan-Bendamustine beats R-CHOP
with progression  free survival of 69 months vs 31 months and with better toxicity profile
except for skin erythematous lesion often seen with Bendamustine.
*A new prognosis factor added to Metastatic Colon Cancer, STROMAL PARTICIPATION IN THE HISTOLOGY OF THE CANCER.  STRONG STROMAL PRESENCE OR INFILTRATION IMPLYING INTERCELLULAR EXCHANGE WITH THE STROMAL TISSUE, AND IS OF POORER PROGNOSIS.  THIS HAS BEEN REPORTEDLY VALIDATED.
This is an official CDC HEALTH UPDATE
 
Distributed via the CDC Health Alert Network March 4, 2013, 16:30 ET (4:30 PM ET) CDCHAN-00342
 
Notice to Clinicians: Continued Vigilance Urged for
Fungal Infections among Patients Who Received
Contaminated Steroid Injections
  Summary
CDC continues to receive new reports of fungal infection among patients who were given injections of contaminated methylprednisolone acetate (MPA1) from the New England Compounding Center (NECC) in Framingham, Mass.   Most of these recent cases have been localized spinal or paraspinal infections (e.g., epidural abscesses) in patients, although new cases of meningitis or arachnoiditis also have been reported. Because many of these new cases are among patients with minimal symptoms, CDC is re-emphasizing the recommendation for clinicians to remain vigilant for fungal infections, especially in patients with mild or even baseline symptoms, and consider evaluation with magnetic resonance imaging (MRI) if clinically warranted. This Health Alert Network (HAN) notice provides the following:
·         Information about the current status of the outbreak;
·         Recommendations for clinical management and follow-up of exposed patients;
·         Information about new revisions to web-based interim clinical guidance (http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html); and
·         Notice of an upcoming CDC conference call to provide clinicians with additional diagnostic and treatment information.
 
Status of Fungal Disease Outbreak
As of March 4, 2013, a total of 720 cases, which includes 48 deaths, have been reported in 20 states. Current information about the outbreak, including case counts and distribution by state, and clinician and patient guidance, is available online at
http://www.cdc.gov/hai/outbreaks/meningitis.html.
Fungal meningitis, often with a mild clinical presentation, was the predominant clinical syndrome reported among case-patients during the first several weeks of the outbreak (figure). Over the past several months, there has been a marked decrease in reports of fungal meningitis, but CDC continues to receive reports of localized spinal and paraspinal infections, which include epidural abscess, phlegmon, arachnoiditis, and discitis.  Additionally, some of these newly identified case-patients had initially tested negative for signs of a fungal infection (either by lumbar puncture or MRI) and have subsequently developed fungal infection, indicating a prolonged incubation period.
 
After the recall of NECC steroid medications on September 26, state and local health departments identified almost 14,000 people in 23 states who were potentially exposed to the implicated MPA; of these, an estimated 11,000 individuals received spinal or paraspinal injections. Through active notification by clinics with assistance from states and CDC in early October, nearly all of these exposed persons were contacted at least once and informed of their risk for fungal infection as a result of receiving injections with contaminated medication.
Despite this and subsequent patient outreach efforts, CDC and public health partners remain concerned   about the potential for some exposed patients to have localized fungal infections that have gone unrecognized. These infections may be unrecognized because some patients have not continued to receive close clinical follow-up or because they have not recognized symptoms suggestive of a localized infection, which may be difficult to distinguish from their baseline chronic pain. 
As described in CDC’s HAN update on December 20 (http://emergency.cdc.gov/HAN/han00338.asp), MRI testing was done on 128 patients in Michigan, Tennessee, and North Carolina who had no previous evidence of infection and had new or worsening symptoms at or near the site of their spinal or paraspinal injection. Of these, 67 (52%) had findings suggestive of localized infection.  In addition, of 109 different patients reporting persistent but baseline symptoms at or near the site of their spinal or paraspinal injection, 15 (14%) also had abnormal MRI findings suggestive of infection, and 27 (25%) had non-specific enhancement of soft tissue or other paraspinal structures.  The clinical significance of these findings is unclear; however, there is a theoretical risk that failure to diagnose these infections in a timely fashion could result in poor outcomes for patients (e.g., neurologic compromise, osteomyelitis, or progression to meningitis
Patient and Clinician Recommendations
Early in the outbreak, CDC advised clinicians to closely monitor and evaluate patients who received injections of implicated MPA. Additional guidance was provided in HAN updates issued on November 20 (http://emergency.cdc.gov/HAN/han00335.asp) and December 20 (http://emergency.cdc.gov/HAN/han00338.asp). Because of the possibility that some patients may have unrecognized, localized fungal infections, CDC is re-emphasizing the following recommendations for patients who received a spinal or paraspinal injection with implicated MPA: 
 
Patients
Patients who received an injection in or near their spine from one of the three implicated lots of MPA1 and who have any symptoms at or near the site of their injection should seek evaluation by their medical provider for the possibility of a localized infection, such as an epidural abscess.  This includes patients who initially received steroid injections for pain and continue to have persistent baseline pain. 
 
Clinicians
As a part of continued monitoring of patients who received an injection with implicated MPA, clinicians should consider re-evaluating patients who received a spinal or paraspinal injection with implicated MPA for signs and symptoms suggestive of infection, including any symptoms at or near the site of their injection.  Because of the prolonged incubation period for these infections, this guidance pertains both to patients who have not been previously evaluated and to those who have already had a prior negative evaluation (e.g., normal cerebrospinal fluid profile, normal findings on MRI) but continue to have complaints:
 
-          In patients with new or worsening symptoms at or near the site of their injection, clinicians should obtain an MRI with contrast of the symptomatic area(s).
-          In patients with persistent but baseline symptoms, clinicians should consider obtaining an MRI with contrast of the symptomatic area(s) because the presentation of spinal or paraspinal infections can be subtle, and may be difficult to distinguish from a patient’s baseline chronic pain.
-          In some cases, radiologic evidence of abscess or phlegmon has become apparent on repeat MRI studies performed subsequent to an initially normal imaging procedure. Clinicians should therefore have a low threshold for repeat MRI studies in patients who continue to have symptoms localizing to the site of injection, even after a normal study. However, the optimal duration between MRI studies is unknown.
-          Clinicians should also consider reviewing MRI results with a neuroradiologist because of potential difficulties in interpreting imaging results for these patients.
 
Revised Clinical Guidance and Clinician Information Call
In response to input from expert consultants on fungal disease and physicians who have been treating patients affected by this outbreak, CDC has revised its Interim Treatment and Diagnostic Guidance for Central Nervous System and Parameningeal Infections Associated with Injection of Contaminated Steroid Products (http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html). The revisions include addition of new information on several topics, including:
 
-          Surgical management of parameningeal disease
-          Duration of antifungal treatment
-          Monitoring clinical status after cessation of antifungal treatment
-          Information on non-first-line medications (e.g., posaconazole or itraconazole)
 
A conference call for clinicians interested in obtaining additional information about the management and treatment of patients with fungal illness associated with this outbreak has been scheduled for March 13 at 5:00 p.m.  The presenter will be Tom Chiller, M.D., medical officer, CDC. Registration and call-in information and other details about the conference call will be available on CDC’s website http://www.cdc.gov/hai/outbreaks/clinicians/index.html.
­___________________________________________________________
1NECC lots of methylprednisolone acetate (PF) 80mg/ml:
Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #05212012@68, BUD 11/17/2012
Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #06292012@26, BUD 12/26/2012
Methylprednisolone Acetate (PF) 80 mg/ml Injection, Lot #08102012@51, BUD 2/6/2013
 
The Centers for Disease Control and Prevention (CDC) protects people's health and safety by preventing and controlling diseases and injuries; enhances health decisions by providing credible information on critical health issues; and promotes healthy living through strong partnerships with local, national, and international organizations.
____________________________________________________________________________________
 
Categories of Health Alert Network messages:
Health Alert         Requires immediate action or attention; highest level of importance
Health Advisory   May not require immediate action; provides important information for a specific incident or situation
Health Update     Unlikely to require immediate action; provides updated information regarding an incident or situation
HAN Info Service                Does not require immediate action; provides general public health information

##This message was distributed to state and local health officers, public information officers, epidemiologists, HAN coordinators, and clinician organizations##
 
SUPPRESSION OF NF-kB IS ONE OF THE DOMINANT EVENT IN ACUTE MYELOID LEUKEMIA,

As we explore the major genes involved in Acute Myeloid leukemia, we quickly realize that the main initiating event is located in the Core binding factors or complex proteins located at the Histone-DNA.  At this level we already uncovered that the nature of molecule interacting and  involved are considerably important, and fundamentally different when you speak about Hematological neoplasm versus solid tumor.
Globally, they appear to be several levels of action:

1.  Nature of components of Histone (H1A, H2A etc..) as cover of DNA. 
2.  Complex involved in Histone remodeling  (H1Ax)
3.  Portion Alpha-subunit of protein complexes attached to the DNA to control its expression, and here we find the RUNX which control Hematologic differentiation
4. Portion of Alpha subunit that actually ensure just clear attachment to DNA so that the Histones do not run in the nuclear  solution.  But be careful in fact most of the time if not always, the place of attachment of histone is not random and varies according to nature of tissue involved.  That is Histones attachment contribute to gene silencing and tissue differentiation.
5. Then there Beta subunits which send tentacles dealing with
    5.1-pure Histone Deacyl transferase activity
    5-2- DNA uncoiling and coiling
    5.3- Interaction with Regulators
    5.4-Interactions with cytoplasmic  signal trasductions (MAPK, FOS/c-JUNK, RAS,PI1K ,VEGF)
    5.5-output back to the cytoplasm to inhibit or activate regulators of signal transduction.  The control of signal transduction pathways is done through enzymes production but through activation of switches (E3, SOS) and through control of Ubiquitination and the MDM2
   5.6- DNA replication controlled through P53, and check-point control molecules.
    5.7-signal to Mitochondria, the Ribosome AND AT C-MYC
  etc. (Transcription factors)
The Centrosome have a DNA attachment portion and an endonucleases portion and some endonucleases find their way to  this area of histone-DNA.

Suffice is to say that in AML, the RUNX is involved to ensure Hematologic differentiation, Many regulators are involved, but suppression of the NF-kB and therefore suppression of the TGF is an significant find!
One now speculate as to why it is so.  AND WITHOUT HESITATION, ONE CONCLUDE THAT IT IS BECAUSE AML DOES NOT NEED TO FORM A MASS!  THE SUPPRESSION OF TGF CAN BE INSUFFICIENT HOWEVER, AND A GRANULOCYTIC SARCOMA IS CREATED BUT THIS IS RARE.

(CLEARLY SOME OF THE CONCEPTS PRESENTED HAVE STILL TO BE FULLY VISITED BY RESEARCHER AND READERS-READ MORE TO ESTABLISH THIS IS SO!)

IT IS INTERESTING TO NOTE THAT WHILE IN THE STRUGGLE IS AT THE RUNX IN AML, IN BLADDER CANCER THE TGF IS IS FULL SWING, DNA REPAIR IS IN FULL SWING, BUT ALSO EVENTS AT THE HISTONE MODULATION AS ALSO IN FULL SWING

Tuesday, March 5, 2013

Bladder cancer in 2012:
Prevalence 73.5 Thousand patients in the USA
Deaths 14.9 thousands died with this disease.
Only 15% of patients have localized disease
50% of patients who have muscle invasion will eventually progress, Median survival in Metastatic disease is 14 months.
Smoking is an established risk factor for Bladder cancer

When the Bladder Muscle is invaded, Giving 3 cycles of chemotherapy (MVAC) before surgery is standard of care and lead to a 77 months median survival Versus 46 months with surgery alone (SWOG 8710.) . But only 20% of people receive Neoadjuvant Chemotherapy.   Mostly because the disease affect the elderly who's perfomance is judged poor for the chemotherapy, because of renal failure which preclude use of Cisplatin, and related comorbidilties which would make chemotherapy hazardous.

Genes reported in Bladder cancer:

MRE11
RAD50
NBS1
ATM
_______________________________________________-----These 4 genes all involves a close pathway.   Under chemical effect there is breakage of double chains DNA in bladder cells  The DNA Break trigger stimulate ATM by phosphorylation or similar activation, MRE1-RAD50-NBS1 is a complex molecule which must allow repair of the breakage by exposing it through "histone remodeling".  Mutations here will hamper this sequence of Activity.  "Breakage of DNA" and HOP, P53 activation is not far.  This is why intact P53 or wild type marks an early cancer. and Mutation of P53 is more a sign of an advanced Bladder cancer.
-----------------------------------------------------------------------------------------
H2AX-during Histone remodeling H2Ax replace H2A and participate in the triggering of check point arrest and therefore a key point to the Histone complex activity which is to control DNA transcription.
------------------------------------------------------------------------------------------------------
CSS (Calpain family) contain DeK1 and CysPc and other anchors/molecules (Now you are going closer to treating AML)
Resistance to Cisplatin: ERCC1
Bcl-2
Overexpression of HRAS (in early disease)
70% have Mutation in FGFR3
P53 and Rb more advanced disease
P21, and P16 are also bad prognosis predictors.

NMP22 may be identified in the Urine for early detection of superficial bladder cancer