To PSA or Not to PSA: That is the Question

The current raucous debate over the commonly used PSA blood test to screen for prostate cancer, the third leading cause of cancer deaths in men in the U.S.(a), stems from the U.S. Preventive Services Task Force’s recommendation to discontinue PSA screening(b). The debate is pitting physician against physician, cancer advocacy groups against health care insurance companies, and leaving men with enormous questions about what to do about their lifetime risk of developing prostate cancer.

The Task Force’s recommendation is based on its review of medical literature that concluded that PSA screening leads to more unnecessary treatment complications than are justified by lives saved because of:

  1. the questionable accuracy of the PSA test to detect cancer,
  2. medical complications caused by unnecessary follow-up procedures because the PSA test has false positives, and
  3. increasing pressures to slow the rate of increase of medical care

However, the well meaning conclusion by the U.S. Task Force to discontinue PSA screening is not likely to be followed by all physicians because of the negative consequences of missing a cancer if PSA screening is not performed.

A large European study has clearly demonstrated, however, that PSA screening reduces deaths from prostate cancer by 20%(c,d). Therefore, until there are better options, PSA screening is unlikely to be abandoned, but the results need to be put in the context of individual prostate cancer risk and other medical indicators in order to minimize unnecessary invasive procedures. New guidelines for follow-up diagnostics and treatment need to be developed, and there is an urgent need for better prostate cancer screening tests, like those being developed for semen specimens by Bedford Research Foundation scientists.

BACKGROUND

PSA is an acronym for “prostate specific antigen,” a protein made specifically by the prostate gland. The biological role of the prostate is to contribute fluids and proteins to semen at ejaculation. The other glands that contribute fluids and proteins to semen are the seminal vesicles. The prostate and seminal vesicles contract at ejaculation; the seminal vesicles contribute proteins that are extremely large, making semen thick, thus concentrating the sperm in the vagina, close to the cervix, the opening to the uterus. PSA is a specific type of protein, an enzyme, that is capable of breaking up the large seminal vesicle proteins, making them shorter and less viscous, allowing the sperm to swim free of the ejaculate, through the cervix into the uterus and fallopian tubes in search of an egg.

Another biological role for the proteins and fluids contributed by the prostate to ejaculated semen is to block negative responses to sperm by cells of the immune system in the vagina to protect the female reproductive organs from bacterial infection. Laboratory studies by Bedford Research scientists have shown that even very small amounts of semen added to cultures of immune cells causes them to die within 24 hours(e). It seems possible that this suppression of immune response to protect sperm has the unwanted side effect of making the prostate gland itself “immune suppressed” and thus less capable of protecting itself from infections and cancer. Some men suffer from low grade infections of the prostate for years, a condition known as “chronic prostatitis.” Other men may also have chronic prostatitis, but without symptoms. Some studies indicate that chronic, low-grade infections can eventually lead to cancer.

Like most cancers, prostate cancer has several forms, many of which are so slow-growing that they are not life threatening — not unlike a wart. Others are highly threatening because they grow very fast and invade surrounding tissues. The various types of prostate cancers are best distinguished by examination of small pieces of the prostate (biopsies) by a trained pathologist. Even then, it is sometimes difficult to distinguish fast growing from slow growing cancers, grouped under the general term “neoplasias” (“new growth”).

Because like other cancers, early prostate cancer can have no symptoms and not be detected during a physical exam of the prostate, the development of the PSA screening test in the late 1980’s was greeted with enthusiasm as an additional tool to protect men from death by prostate cancer. Because it was a blood test, it was initially thought to predict cancer spread, beyond the prostate gland itself, into surrounding tissues, including the spine and the blood stream. It is now known, however, that cancerous prostate cells actually produce less PSA than normal prostate cells, so blood levels of PSA do not necessarily mirror tumor size or spread. A further complication of PSA screening is that many fast growing prostate cancers never lead to elevations in PSA levels. Moreover, chronic, low-grade infections, and the gradual increase in the size of the prostate gland that accompanies aging can also lead to elevated PSA in blood samples. The reason for this is unknown.

STUDIES CAUSING DEBATE

By the mid 1990’s many studies to refine the use of PSA blood tests to predict prostate cancer had appeared. Some suggested following changes in PSA levels over time, some suggested isolating different forms of PSA in blood, e.g. “bound” or “free.” But none of the refinements increased the specificity of the PSA blood test to distinguish prostate cancer from other diseases of the prostate, nor to always detect prostate cancer itself.

In March, 2009, the results of two large studies to determine the usefulness of testing blood samples for PSA were reported in the New England Journal of Medicine. The U.S. study(f) enrolled 76,693 men from 1993 to 2001: 38,343 to receive annual PSA screening and 38,350 to receive “usual care” to serve as the control group. Eighty six percent of the “annual PSA screening” group actually received annual screening for six years, and up to 52% of those in the “control group” also received annual PSA screening, markedly decreasing the power of the study to distinguish the long term effects of annual PSA screening after 7 to 10 years of follow-up. In contrast, the larger European study(c) enrolled 182,000 men in seven European countries (Netherlands, Belgium, Sweden, Finland, Italy, Spain and Switzerland) who were randomly assigned to receive PSA screening at an average of once every four years, or to receive no PSA screening. After an average of 9 years of follow-up, the death from prostate cancer in the screening group was 20% lower than in the control group. A more recent two-year follow-up to the original 9 years(d) confirmed that death from prostate cancer was 21% lower in the screening group at 11 years of follow up than in the control group.

Importantly, both the U. S and European study teams noted the high rate of complications and unnecessary surgeries resulting from both false-positive PSA screens, and highly invasive surgeries for slow-growing cancers that were in all likelihood not life threatening.

GOING FORWARD

That PSA screening prevents death from prostate cancer has been clearly demonstrated by the large European study. They are careful to note, however, that preventing death from prostate cancer did not influence “all cause mortality,” suggesting no over-all lengthening of life span.

One way to prevent the complications and unnecessary surgeries that result from PSA screening is to not do it anymore, as has been recommended by the U.S. Task Force. Another way to prevent such problems is to adjust the responses of physicians and patients to the results of PSA screening. The panic that sets in at the mere thought of a cancer diagnosis needs to be treated first, before further diagnostics are initiated. Patients need to be able to keep in perspective the difference between a diagnosis of prostate cancer and the risk of dying from prostate cancer. The table illustrates the difference in the rates of death of the top five(a) cancers in men:

Estimated New Cancer Cases and Deaths in U.S. Men for 2012, All Races

Primary Site Estimated New Cases in 2012 Estimated Deaths in 2012 Ratio of Deaths/New Cases
Prostate
241,740
28,170
0.12
Digestive System
(esophagus to rectum, liver and pancreas)
156,760
80,560
0.51
Respiratory System
130,270
91,110
0.70
Urinary System
(bladder and kidney)
97,610
19,670
0.20
Lymphoma and Leukemia
69,950
24,490
0.35

Cancer Facts & Figures, 2012, American Cancer Society; excludes basal and squamous cell skin

Having by far the lowest ratio of Deaths to New Cases emphasizes the slow growing nature of most prostate cancers. The aggressive U.S. campaigns to encourage people to get tested for cancer as a life-saving measure have been very successful, with many cancers detected at early enough stages for successful treatment. Bedford Research Foundation scientists are laying the groundwork for additional screening tools for early detection of prostate cancer in semen specimens.

But until new prostate cancer screening tools are developed and tested, it is time to launch a campaign about prostate cancer that emphasizes most are not life threatening, and overly-aggressive treatment of an elevated PSA screening test may cause life altering side effects far worse than living with the cancer itself.

  1. National Cancer Institute, National Institutes of Health, American Cancer Society Cancer Facts and Figures, pdf
  2. Screening for prostate cancer. U.S. Preventive Services Task Force, 2008 (http://www.uspreventiveservicestaskforce.org/uspstf/uspsprca.htm).
  3. Screening and prostate-cancer mortality in a randomized European Study. N Engl J Med 2009;360:1320-8.
  4. Prostate-Cancer Mortality at 11 Years of Follow-up. N Engl J Med 2012;366:981-990.
  5. Seminal Plasma Induces Programmed Cell Death in Cultured Peripheral Blood Mononuclear Cells. Aids Res and Human Retroviruses, 2002,18:797-803. .pdf attached
  6. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360:1310-1319.

 

 

Over-Regulation of Parthenotes Stifles Valuable Scientific Research

Sean Kealy, UPenn Law RegBlog

A recent article in Scientific American questioned whether research on stem cell lines derived from unfertilized eggs was too tightly regulated by the federal government. Now that technology allows the creation of stem cells without fertilization, there is no question that federal laws and guidelines are overly restrictive, causing a detrimental effect on valuable scientific inquiry.

Since 1996, Congress has included the Dickey-Wicker Amendment in the annual federal budget. This amendment was a conservative reaction to what some considered to be scientific research that showed little respect toward life.

Read more: Over-Regulation of Parthenotes Stifles Valuable Scientific Research

Why I Support Stem Cell Research

Victoria Staebler

 

My support for stem cell research has its foundation in my deep-seeded belief in reproductive rights for women. Since I came of age in the 1970’s, women’s reproductive rights and freedom have been continually eroded by federal and state legislation. That has been coupled with diminished government support and funding – ranging from access to abortion services to stem cell research. Because of that, I have volunteered time and donated money to help preserve these rights.

But last summer, my support for stem cell research became personal. During a mugging on the Cape, my stepson was shot by the assailant, resulting in a severed spinal cord at T-5. He’s now a parapalegic. The stem cell research that BRF is doing is laying the foundation for regenerative cell therapy that could potentially cure not only spinal cord injury victims like him, but an incredible range of diseases, from Parkinson’s to bone marrow cancer.

In our current divisive political environment, I don’t believe we will see any support from either the federal government or the National Institute of Health for years to come. So it’s up to us as individuals to move this initiative forward. I’ll bet there’s a personal connection for many of you as well. Please donate, volunteer and spread the word.

Victoria StaeblerVictoria Staebler is a member of the Bedford Stem Cell Research Foundation’s Board of Trustees. She is a Financial Advisor at Merrill Lynch and serves on the board of the Boston Club.

 

 

Testis Stem Cell Project Update

Thanks to private donations, BSCRF scientists have launched the testis stem cell project.

Phase 1 is the isolation of a new line of testis stem cells from the Per2Luc mouse to study the role of circadian genes in testis stem cells. Phase 2 is to improve the efficiency of deriving testis stem cells from cryopreserved (frozen to stay alive) Per2Luc testis tissues. Phases 1 and 2 are underway.

Phase 3, starting in early 2012, will be to collaborate with Dr. Martin Dym, Georgetown University, in deriving human testis stem cells from cryopreserved biopsies archived in his laboratory. We will compare the efficiency of testis stem cell derivation using our newly developed circadian culture conditions with the efficiency previously reported by Dr. Dym.

Phase 4 will derive patient-specific stem cells from the male volunteers for our study

Progress in Circadian Rhythms And Stem Cells

Circadian Rhythms in Early Embryos

BSCRF’s new mouse embryonic stem cells, PL034 (learn about the first incubator videomicroscope).

BSCRF scientists have derived two unique lines of stem cells that may lead to a breakthrough in the efficiency of stem cell derivation and expansion.

BSCRF scientists are following up their discovery that the genes that regulate the rhythms of daily life, circadian rhythm genes, may play important roles in stem cell derivation and stability in culture. Circadian rhythm genes regulate cells in the body by turning “on” and “off” over a 24-hour cycle in response to signals such as light/dark cycles, hormone pulses, and body temperature variations.

Currently, stem cells are cultured in constant temperature in the dark. If BSCRF’s research proves that circadian rhythm genes play important roles in stem cell division and stability, it could markedly improve the efficiency of stem cell derivation and expansion, urgently needed to produce major advances in stem cell therapy.

 Circadian Rhythm Genes: turn “on” and “off” in response to the rhythm of daily life.

To conduct this research, foundation scientists are using a genetic technology that links the circadian genes of a mouse with a gene from a firefly. When the circadian gene is “on”, the mouse cells glow like a firefly; when the circadian gene is “off”, the cells go dark. This mouse, “PER2Luc,” was derived by a circadian gene scientist several years ago and has been used by Dr. Fred Davis of Northeastern University, to study circadian gene expression in mouse tissues.

BSCRF scientists have derived two new lines of embryonic stem cells from PER2Luc embryos. Light emitted by the stem cells is detectable in Dr. Davis’s luminometer, but BSCRF scientists are developing microscope equipment to record light emitted by individual cells in order to compare standard stem cell culture conditions with new culture conditions that support circadian rhythm such as the temperature variations of a mouse. These new stem cells will also be useful to all scientists seeking to understand the relationship between circadian rhythm and cell functions

The 2011 Fall / Winter Newsletter

Newsletter

Download the 2011 BSCRF Fall / Winter Newsletter

In This Issue:

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You Say Embryo, I Say Parthenote

Julia Galef, Scientific American

 

 

Scientific American November 2011

You Say Embryo, I Say Parthenote“, BSCRF and the importance of parthenote stem cells reported in the November, 2011 Scientific American byJulia Galef.
embryos and parthenotes Scientific America
Parthenogenetic stem cells Image: 
From “Derivation of High-Purity Definitive Endoderm from Human Parthenogenetic Stem Cells using an in vitro Analog of the Primitive Streak,” by Nikolay Turovets et al., in Cell Transplantation, Vol. 20, No. 6; June 2011

Check out the Scientific American article, then for more information, see the BSCRF article, “The History of the Dickey-Wicker Amendment” on the ban on federal funding of non-embryonic, parthenote stem cell research.

And also, see the BSCRF one-minute video, What are parthenote stem cellsWhat Are Parthenote Stem Cells?

Thanks to your donations, Bedford Stem Cell Research Foundation is one of the few laboratories able to work on parthenote, non-embryonic, stem cell research.

Donate Now

 

 

Dr. Janet Rossant to be keynote at 2011 Activated Egg Symposium

We’re delighted to report that Dr. Janet Rossant, Professor of Molecular Genetics, Obstetrics and Gynaecology, University of Toronto, and Chief of Research at the Hospital for Sick Children has graciously agreed to be our keynote speaker for the 2011 Activated Egg Symposium to be held Nov 4, 2011, at the Henderson House in Weston, MA.

Dr. Rossant is internationally recognized for her pioneering research in mouse genetics. Her major findings are related to the question of how genetically identical cells adopt distinct characteristics during embryo development.

In 2010, she received the Premeir’s Summit Award, and they made this video:

A little about more about Dr. Rossant:

(from the ISSCR website 2009 | 2010)

Janet Rossant grew up in the UK and trained at the Universities of Oxford and Cambridge. When still a graduate student, she conducted now-classic work defining cell lineages and cell fates in the early mouse embryo. In 1977 Dr. Rossant moved to Canada and joined the faculty at Brock University. From 1985 to 2005, she was a researcher at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital in Toronto. She joined the Hospital for Sick Children in 2005 and became the first female Head of its Research Institute since its founding in 1954. She is also a University Professor in the Department of Molecular Genetics at the University of Toronto.

Throughout her career, she has been a pioneer in manipulating the mouse embryo, deriving novel stem cell lines and interrogating the mouse genome. Most recently, building on her ongoing studies of the mouse blastocyst and the stem cells that arise from it, she is applying her developmental biology skills to derive definitive endoderm lineages from human embryonic stem cells and induced pluripotent stem cells.

As Chair of the Canadian Institutes of Health Research working group on stem cell research and as Deputy Scientific Director of the Canadian Stem Cell Network, Dr. Rossant continues to play a leadership role in setting Canada’s public policy regarding stem cell research.

She has received many accolades for her research, including being elected Fellow of the Royal Society of London (2000), and a Foreign Associate of the National Academies of Science, USA (2008). She was awarded the McLaughlin Medal of the Royal Society of Canada (1998), Eli Lilly/Robert L. Noble Prize from the National Cancer Institute of Canada (2000), Killam Prize for Health Sciences (2004), and FASEB Excellence in Science Award (2004). She received the 2007 March of Dimes Prize in Developmental Biology along with the late Dr Anne McLaren, and the 2007 Conklin Medal of the Society for Developmental Biology, of which she is a Past President.

Here’s another video biography by the Toronto Region Research Alliance in April, 2009:

Bedford presents Post Vasectomy Semen Analysis test kit at Mass Innovation Nights

Foundation Staff | May 24, 2011

 

 

As you may know, Bedford’s laboratory helps cover some of our overhead by offering a couple unique products — GEM and PVSA — that were developed as by-products of our research. PVSA, the newer of the two, was launched just 18 months ago.

PVSA is the first and only post-vasectomy test kit that provides CLIA certified laboratory results from a mail-in kit. This kit was developed using Bedford’s patented specimen fixative and mail-in kits for research.

The kit solves a vital problem for urologists: they are liable for their vasectomy surgeries until their patient’s surgery has been confirmed with two semen specimens.

post vasectomy test kit

At just $30 (plus shipping) the kit is inexpensive, easy to use, and helps doctors solve an almost79% rate of non-compliance from patients. This solution has proven so powerful, we’ve more than tripled our number of clients in the last 10 months.

We are very proud to be presenting this innovative solution at Mass Innovation Nights on June 8, from 6-8:30 PM in Westborough. This event is free and open to the public. Please join us! Also, Mass Innovation Nights will select 4 of the 11 featured products to give a five minute presentation — please vote for us!