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Variations in Five Genes May Identify Lethal Varieties of Prostate Cancer.

Danger lurks in southwest Florida; bj gabrielsen photo

For years, the general practice used in the initial screening for prostate cancer is a blood test for prostate-specific antigen (PSA) in conjunction with a digital rectal examination. These tests are then used to determine whether or not to subject the patient to a prostate biopsy, inherent with its own side effects and hopefully negative results. If the biopsy reveals cancer, then the questions of whether or not to treat the cancer, what treatment(s) would be most effective while minimizing potential side effects, and the possibility of no treatment or “watchful waiting” must be addressed. It would be extremely useful if a blood or urine test could identify genetic biomarkers (genes and their products such as proteins) whereby physicians could determine not only the presence or absence of prostate cancer but be able to predict whether or not the cancer would require treatment and if so, should aggressive treatment be necessary. For the many cases of prostate cancer which are identified, ‘no one size of treatment fits all.’ Methods are sorely needed to determine the appropriate level of treatment, if any.

More than 25 genetic subtypes of prostate cancer have been already identified. Some of these cancers might never require treatment and a man could die of other causes while other cancers require immediate, aggressive treatment. A team of researchers from Seattle and Sweden have recently identified a set of variations in five (5) genes which may be signatures for lethal prostate cancer thereby requiring aggressive treatment. These genetic variants might serve as the basis for a new blood test that could be given on initial diagnosis in order to determine which patients need aggressive treatment versus “watchful waiting.” To discover the five “disease genes” implicated in lethal prostate cancers, researchers looked for genetic variants that prostate cancer patients share in common. These variants in genes are called single-nucleotide polymorphisms, or SNPs (pronounced “snips”). Genes can be depicted as chains of thousands of beads comprised of four-five basic colors all arranged in a specific sequence. An example of a SNP would be the substitution of one blue bead in a gene by a red bead at a specific location along the chain of thousands of colored beads. These inherited genetic variants are certain genes that may signal the development of fatal varieties of prostate cancer. The five SNPs that were identified were linked to five genes that may affect prostate cancer progression, namely LEPR, RNASEL, IL4, CRY1, and ARVCF.  It was of special interest to note that two of the five genes studied (IL4 and RNASEL) were associated with inflammation of the prostate, thereby suggesting a possible link between chronic inflammation of the prostate and the triggering of prostate cancer. The state of this research requires much more validation and development before it could be used as a diagostic test for aggressive prostate cancer. But it is a significant finding and indicative of the type of biomarker which would eventually relieve the uncertainties associated with PSA tests.

The research findings were published in the September issue of Cancer Epidemiology, Biomarkers and Prevention, and summarized in the September 2011 issue of NewsPulse from the Prostate Cancer Foundation.

Prostate Cancer Stem Cells: A New Target for Treating Hormone-Refractory Cancer.

It has been known for over 60 years that in general, prostate cancer cells respond to androgen deprivation (hormonal) therapy. At some point however, the prostate cells no longer respond (they become hormone-refractory) and levels of prostate-specific antigen (PSA) begin to rise. Treating this hormone-refractory prostate cancer remains a major challenge. There is now evidence that the resulting hormone-refractory solid tumors originate from undifferentiated (less-specialized) stem cell-like cells which are thought to only comprise 0.1 percent of the original prostate tumors. Metastasis also arises from these stem cell-like cells. [Stem cells are found in all multicellular organisms; they can divide and change from being less-specialized into more-specialized cell types as well as producing more stem cells.]  These cancer stem cell-like cells often do not respond to chemotherapy or hormonal therapy, so a different approach that attacks these cells in advanced prostate cancer is needed.

In a recent report on Prostate.net and in the September 20th, 2011 ZeroHour Newsletter, a Swedish research team has found that a protein called STAT3 is active in the stem cell-like cells. In addition, a natural compound called galiellalactone was found to have an effect on STAT3 and inhibits prostate cancer growth. This research represents only the initial stages of the process of developing a drug that will attack the stem cell-like cells. Using the known compound galiellalactone as a model, other better drug-like substances will hopefully be identified that will inhibit STAT3 and become new therapies that attack the stem cell-like cancer cells in men who have prostate cancer and prevent growth and spread of the disease.

For Those Contemplating Radiation Therapy

Very few, if any, treatments are without side effects. Whatever route a person takes to treat prostate cancer, one is usually “never quite the same again.” Radiation therapy is no exception. Urinary tract and bowel effects can be encountered. You do not want to have to constantly focus on the nearest bathroom facility. Therefore, before undergoing radiation therapy, one would be wise to investigate the types of radiation technologies offered by various facilities. Carefully consider all potential side effects, success rates as well as comments from former patients as well as the levels of expertise of their personnel. Driving along highways in Florida, one can see numerous billboard advertisements all promoting “cutting edge” radiation facilities. Be a “wise consumer”; it’s your body and the side effects can last a long time. A good source to begin the learning process is from Johns Hopkins Hospital in Baltimore, MD, the “number one” urology department in the nation (as consistently rated in U.S. News and World Report). A recent issue of their October 5th, 2011 Health Alerts  (see link) provides a good summary of external beam radiation therapy.

Hormonal Therapy and Osteoporosis – New Options.

Near Bryce Canyon Utah; bj gabrielsen

Osteoporosis (bone loss) is one of several side effects which accompany androgen deprivation (hormonal) therapy (ADT). Fifty (50) percent of men will be affected by their fourth year of treatment, and more than 80 percent will be affected after10 years. The risk of fractures including those of the spine also increases with hormonal therapy treatment for a year or more. This enhanced risk is illustrated by a recent study in The New England Journal of Medicine where it was reported that “among men with prostate cancer who lived for at least five years after their diagnosis, the risk of a fracture was nearly 20 percent among androgen deprivation (hormonal) therapy users, compared with 13 percent for nonusers.” Men treated with hormonal therapy are generally advised to have annual bone density testing.

Medications are also often prescribed to halt bone loss. The well-known bisphosphonates (such as Fosamax) are the first treatments prescribed followed by selective estrogen receptor modulators (SERMs) such as tamoxifem, used in the treatment of breast cancer. For prostate cancer patients, a new alternative, a monoclonal antibody called denosumab (brand names Xgeva or Prolia), is now generating much attention. Denosumab is an injectable monoclonal antibody. Monoclonal antibodies are made to target and destroy only certain cells in the body thereby helping to protect healthy cells from damage. Xgeva is used to prevent bone fractures and other skeletal conditions in people with tumors that have spread to the bone.  Prolia is another brand of denosumab used to treat osteoporosis in postmenopausal women who have high risk of bone fracture. In November 2010, the Food and Drug Administration (FDA) approved Prolia (Xgeva) to help prevent skeletal-related events in prostate cancer patients treated with hormonal therapy whose cancer had already metastasized to bone. The use of this therapy has recently been expanded. On Friday, September 16, 2011, the FDA approved denosumab (Prolia) in prostate cancer patients undergoing androgen deprivation (hormonal) therapy whose cancer had not yet metastasized to bone. Denosumab is also approved by the FDA for additional indications. The brand Prolia was approved by the FDA on June 1, 2010 for the treatment of postmenopausal women with osteoporosis who are considered to be at high-risk for fractures.

For more details, see the Johns Hopkins Health Alerts, “Prostate Cancer: Why You May be at High Risk for Osteoporosis,” Sept. 29th, 2011; and, “FDA Expands Approval for Denosumab”, NewsPulse from the Prostate Cancer Foundation, Sept. 30th, 2011;

Bone Scans for Metastatic Prostate Cancer

Sanibel, FL; photo BJ Gabrielsen

The most troubling thought for prostate cancer patients whose cancer has recurred after an initial radicalprostatectomy is the fact that there are PSA-producing cells located somewhere in our bodies. While subsequent treatments such as androgen deprivation (hormonal) therapy may keep these cells under control, there are undoubtedly micro-metastases somewhere in our bodies. When the controlling therapies are discontinued, the cells begin to multiply and PSA rises. Bone scans are generally prescribed to identify sites of metastases. The scans involve the injection of a small amount of a radioactive element, technetium-99 (as technetium Tc 99m medronate). Greater than 90% of the mild radiation produced is eliminated from the body in 24 hours. It is generally accepted that technetium Tc 99m medronate is deposited on the surface of hydroxyapatite crystals, a mineral form of calcium, which comprises up to 50% of bone. Rapidly dividing tumor cells require enhanced blood flow (a process called angiogenesis) in order to grow.  Enhanced blood flow and / or blood concentration is most important in the delivery of the technetium-99 reagent to sites of uptake. Therefore, actively dividing cancer cells in bone would be specifically targeted. In addition to areas of abnormal osteogenesis (bone formation) such as those that occur with metastatic bone disease, other non-cancerous conditions such as Paget’s disease, arthritic disease, osteomyelitis (bone infection), and fractures can also be identified in a bone scan. Bone scans may not always be recommended as long as a patient’s PSA levels are not increasing. In my own case, even though my PSA had remained at very low or at undetectable levels, my Johns Hopkins urologist recommended a bone scan since I had not had one in seven years. His rationale was that even though the likelihood of seeing bone metastases is small, nonetheless, the disease can progress on hormonal deprivation therapy even if the PSA is low. Small quiet progression, if it is found, is something to be noted and followed. Thank God, my bone scan showed no evidence of metastatic cancer but it “lit up like a Christmas tree” since it revealed areas of formerly-broken bones (ankle, wrist, ribs) and arthritis in my lower spine and right hip which had been replaced in 1991. Physicians may differ in their prescriptions for bone scans. Therefore this website commentary is for information purposes only and should be utilized only after discussion with your personal health care provider.  Since this blog was initially written, an excellent review article entitled “Imaging Studies for Prostate Cancer: What to Expect” was published in the October 20th, 2011 edition of the Johns Hopkins Prostate Disorders Health Alert. The article goes into more detail about when bone scans should be prescribed, ProstaScint scans for metastases to lymph nodes or small organs and the uses of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) scans.

NewsPulse, a Medical Resource from the Prostate Cancer Foundation. Biomarkers in Urine for the Detection of Prostate Cancer.

Sources of current medical information concerning prostate cancer are listed on this website under the section Medical Resources.  Recently, a new August 2011 electronic newsletter entitled NewsPulse was received from the Prostate Cancer Foundation. The issue contained very current information on specific diagnostic methods, biomarkers for cancer detection, targeted therapies and drugs under development, nutrition and genetics. One example follows below. Their e mail address is info@pcf.org. I would strongly recommend a subscription.

Biomarkers in Urine for the Detection of Prostate Cancer.

Biomarkers are usually genes, gene products or proteins and are found in various body fluids (blood, urine, cerebrospinal fluid). Their presence, absence and quantities are measured and used to diagnose various diseases and their stages. An example is prostate-specific antigen or PSA used to detect prostate conditions. The availability of an easy-to-use urine test that is specific in identifying the presence of cancer has the potential to eliminate thousands of unnecessary prostate biopsies in the U.S. each year. Thus the benefits of such biomarker tests below include identifying which patients actually require biopsies.

The June 1st, 2011 issue of the Johns Hopkins Health Alerts and the August issue of NewsPulse both describe two new biomarkers found in urine which may potentially be useful in detecting prostate cancer as opposed to other non-cancerous prostate conditions such as BPH (benign prostatic hyperplasia or enlarged prostate). The two specific biomarkers are: a) prostate cancer antigen or PCA3, which is expressed at high levels in 95 percent of prostate cancer patients; and, b) the DNA marker TMPRSS2:ERG gene fusion, a hybrid gene made from two previously separate genes, specifically the ERG and TMPRSS2 genes. This DNA marker is present in 50 percent of prostate cancer patients. The presence of this gene fusion is “thought to promote the development of prostate cancer and possibly a more aggressive form of the disease.”

PCA3 is made by a specific gene that produces the protein in 60-100 times more abundance in prostate cancer cells as compared to non-cancerous ones. According to Johns Hopkins, in order to be most predictive, the test for PCA3 should be done in conjunction with a digital rectal examination. PCA3 testing would not replace the usual PSA blood test but would help to either confirm or rule out the prospect of cancer in men with elevated PSA levels.

Patients with high levels of these biomarkers have been shown to have a 70 percent chance of having cancer with a 40 percent of it being a high grade cancer. There is also an association between test results and the size of the tumor in patients who do have cancer. It will take some time before the combined urine-based assay is widely introduced into practice. However, NewsPulse reports that the “University of Michigan has been offering the PCA3 test alone since earlier this year. They expect to be offering it in combination with TMPRSS2:ERG by the end of this year under a license agreement with GenProbe. Another trial using the combined assay will soon be conducted in cooperation with the Early Detection Research Network (EDRN). EDRN, an initiative of the National Cancer Institute (NCI), brings together dozens of institutions to help accelerate the translation of biomarker information into clinical applications and to evaluate new ways of testing cancer in its earliest stages and for cancer risk.”

“Once the University of Michigan begins offering the combined TMPRSS2:ERG/PCA3 test, physicians can send urine samples for analysis until the combined test is more widely available. For more information on this, men with questions about prostate cancer screening should speak to their doctors or call the U-M Cancer AnswerLine at 800-865-1125.”

As previously stated, the contents of this website are intended solely for information and encouragement. All medical decisions and actions should be made in consultation with a physician or appropriate medical personnel.

Information from Johns Hopkins: a) Use of Immunotherapies (Provenge, Prostvac) Against Prostate Cancer; and, b) Gleason Scores.

Broad Run-Middletown, MD; bj gabrielsen photo

Provenge (sipuleucel-T) was the first approved prostate cancer therapy which uses a person’s immune system to fight the disease.  Its approval was limited to men with advanced prostate cancer who have not responded to other treatments like hormonal (androgen deprivation) therapy and are experiencing few or no symptoms. Cost and supply remain significant issues hindering its widespread use. A recent article in the Johns Hopkins Health Alerts (September 8th, 2011) describes on-going studies involving the administration of Provenge under differing conditions. These include: a) combining Provenge with hormonal therapy in patients with earlier stage disease; b) combining Provenge with radiation therapy in hopes that the combination will have a greater effect than either of the two therapies alone (synergism); and, c) Phase 3 studies in men with early-stage, non-metastatic prostate cancer. Other immunotherapies in clinical trials include Prostvac (from the National Cancer Institute, National Institutes of Health) which may be less costly.

In another earlier issue of the Johns Hopkins Health Alerts (August 24th, 2011), the concept of the Gleason score is described. It is defined as a grade assigned to biopsied tumor cells to indicate a tumor’s potential aggressiveness. This tumor grade “reflects how far the cancer cells deviate from normal, healthy cells.” Gleason scores of 5 and 6 are generally classified as low-grade tumors, a Gleason score of 7 as intermediate and Gleason scores of 8, 9 and 10 as high grade, with the least favorable outlook.

 These Johns Hopkins Health Alerts and additional Bulletins written by Dr. Jacek Mostwin and colleagues are invaluable sources of current information for prostate cancer patients.

Do you feel like you’re not your old self anymore? Has your cancer recurred? THERE IS HOPE!

In the last few weeks, I received word that prostate cancer had unexpectedly recurred in two men I know. Both men understandably expressed discouragement, apprehension and fear. What now??? I experienced a similar recurrence in 2003 (see My Story, 1994-2003,    “December, 2002 – January 11th, 2004. The cancer recurs. What do I do now?”.) In addition to the emotions experienced by the two afore-mentioned men, I experienced anger at God for allowing His seemingly curative surgical process to fail. But looking at this situation now eight years later, I see not only how God can allow us to experience many years of normal life through the use of existing and newly-approved medical treatments, but how He can use such seemingly negative outcomes in our lives to glorify Himself to people around us.

Anne Graham Lotz, the daughter of Billy Graham, tells a story about receiving a gift from her aging mother. The gift came wrapped in a plain brown paper bag packed with lots of decorative wrapping paper. After examining the contents of the bag and finding nothing of value, Anne Graham Lotz was about to discard the package as a mistake when her aging mother informed her that the package contained a small yet very valuable and historical ring. Anne Graham Lotz had nearly missed a very valuable gift simply because it had come packaged in a common, un-appealing, brown paper bag. The moral of her story was as follows: what “gift” have we been given by God wrapped in an un-assuming package and can He use such a “gift” to bring honor and glory to Himself and fulfillment to our lives if we choose to use it as such? Amazingly, recurring prostate cancer could be such a gift.

Following the recurrence of my own aggressive prostate cancer (my PSA was doubling every three months) in 2002-3 after a very promising and successful radical prostatectomy surgery in 1995, I received an unsolicited, encouraging letter from a friend. The letter writer pointed out to me that every time an angel appeared to someone in the Bible, usually the first words spoken by the heavenly being were “do not fear” or “don’t be afraid.” Familiar Biblical recipients of such angelic messages include Hagar, Gideon, Mary, Joseph, the shepherds in the field, and the two Marys at the tomb of Jesus. I was informed that the phrase “do not fear” is cited 365 times in the Bible, once for each day. This is because God knows how prone we are to fear, anxiety, apprehension and mis-trust when we encounter something we do not understand or expect. But when the phrase “do not fear” is stated, it is invariably linked with a specific characteristic about God or Jesus, such as their presence, power, past performance or promises. Words such as “do not fear for I am……” or “do not fear for I have…..” appear countless times. For example, Isaiah 41:10 states “do not fear for I am with you. Do not be dismayed for I am your God. I will strengthen you and help you. I will uphold you with my righteous right hand.” Such personal knowledge of and trust in the natures, characteristics and promises of God and His Son Jesus are the antidotes to fear and apprehension.

What can the Lord do with your unexpected, un-welcome “gift” of recurrent prostate cancer? Psalm 90:10 states that “as for the days of our lives, they contain seventy years, or if due to strength, eighty years.” I turn 70 next month. Our biological clocks are running. In our cells, our telomeres are shortening. We have the remainder of our earthly life to look forward to followed by our eternal destiny which depends on our relationship with God through Jesus. Instead of our disease, our focus should now be on actions which will benefit our family, friends and acquaintances in this life and especially actions which will have eternal significance for ourselves and those around us. Let all we do glorify God and Christ. Examples of this abound in the Bible. In John 11, Jesus was urgently summoned to the house of his close friends, Lazarus, Martha and Mary. Jesus delayed and meanwhile his friend Lazarus died. After the crowd accused Jesus of arriving too late to help, Jesus said in John 11:4 that Lazarus’ sickness was not intended for “death, but for the glory of God, that the Son of God (Jesus) might be glorified thereby.” Lazarus was raised from the dead and went on to fulfill his life. Likewise, the man born blind from birth in John 9:1-3 was healed so that the works of God might be glorified in him. If that were not enough evidence, look what Jesus could do with five loaves of bread and two fish which were used to feed over 5,000 men in addition to women and children. So what can He do with your “brown bag gift”?

In Matthew 11:28, Jesus provided the right perspective on life’s happenings that we perceive to be hard to manage. He can handle anything and that’s why He said “come unto Me all you who labor and are heavy laden, and I will give you rest.” Approach the Lord in prayer and cast our burdens upon Him so that He can sustain us. Remember He can use the “gift” you have been given in a brown paper bag to bring glory to Himself and God the Father.

All of us who have received the “gift” of prostate cancer have an assignment. First, we have to make sure our relationship with God through faith in Jesus is intact. If it is, then we should remember to list God’s and Jesus’ characteristics and remember how they have helped us in the past. Finally, we must lay our situations down before the Lord. What’s your brown bag gift and how will you entrust it? Existing medical treatments are available and new ones are progressing through clinical trials. Two treatments have been approved by the FDA this past year alone. God also uses wise, compassionate and knowledgeable physicians to treat and support us. God will sustain you and more than likely, you will be able to outlive this disease with many productive years ahead. Whether our cancer is cured, in remission, under treatment or has recurred, God still loves us so unconditionally that He offered up His Son so that through faith in Jesus, we may have a deeply personal relationship with God, the Father. In addition, He still has a master plan for our earthly life and the promise of eternal life in perfect, cancer-free bodies. You may think you have seen better days, but the best is still to come to those who know God and His Son, Jesus. He can best transform us into men whose lives will be productive, fulfilling and glorifying to God. Don’t give up!!!

Leesburg, VA; bj gabrielsen photo

Good News!

Overlooking Charlotte Harbor from Bokeelia, FL

My prostate-specific antigen (PSA) level was again below detectable limits, 0.01 ng/mL. The prostate cancer is still under control! God’s plan, presence, protection, power and promises again prevailed over my apprehension and fears. Christ’s perfect love truly never fails! The scene above overlooking Charlotte Harbor as it leads to the Gulf of Mexico is from a scenic but rustic area called Bokeelia, on the northern tip of Pine Island off the southwest Florida coast just north of Ft. Myers. The passive scene is not at all indicative of the active and fulfilling retirement life God has given to my wife and I. We are most thankful!!!! May we all keep looking up!!!!

The Next PSA Test; Apprehension and Fear or Trust and Peace?

Overlooking the Gulf of Mexico from Boca Grande, FL

My cancer has been kept under control with the help of hormonal therapy for nearly five (5) years. It is anticipated that at some point, one becomes resistant (refractory) to hormonal therapy. In that case, additional treatments need to be administered. If they are chemotherapies, they have more severe side effects; or, if they are newer treatments such as Provenge® or abiraterone, they may be limited due to their availability and cost. Therefore, every few months when a PSA test is required, the event serves as a marker of disease progression or control. From a medical viewpoint, it is “cut and dry”. From a spiritual viewpoint, the PSA test serves as a test of one’s faith, not simply in God’s healing power but whether or not one trusts God enough to cast this burden upon Him and be able to say with Job 13:15, “though He slay me, yet will I trust Him” or with Jesus Himself, when He prayed in Matthew 26:39 “not My will but Thine be done.”

In the Old Testament, Abraham serves as a shining example of a righteous, godly man. But he himself showed distrust of God on several occasions. Twice he told blatant lies to foreign kings whom he feared might take his life and that of his wife Sarah. He told them that attractive Sarah was not his wife but instead was his sister. Therefore, he put at risk God’s plan that through him and Sarah, a great nation (Israel) would arise. In our case, disease is also part of God’s plan; He is able to be glorified through it as was the case of the man born blind whom Jesus healed in John 9:1-3.  Though apprehension and fear may be normal expected reactions, we need not fear the outcome of a PSA test. Our fears can be conquered through tenacious faith in God’s and Christ’s presence, protection, power and promises. If our fear is putting God’s wonderful plans for us at risk, we must “remember that He will never ask us to do anything He cannot bring to completion, even if it requires miraculous intervention on His part.” (Dr. Joseph Stowell, Our Daily Bread, July 19th, 2011). I’ll know my PSA result on Friday.