Laser Eye Surgery for High Myopia works well in Long Term

A ten year follow up study carried out by researchers in Spain and Turkey on patients who had laser surgery to treat high myopia (short or near sightedness) found the treatment was safe and effective in the long term, with a retreatment rate of under 30 per cent.

The study is published in the January 2008 issue of the American Journal of Ophthalmology and is the work of researchers from Miguel Hernandez University, Medical School, Alicante, Spain, and from Ankara University School of Medicine, Ankara, Turkey.

Laser surgery for eye problems has been around since the early 1990s. There are two main types for correcting myopia: PRK, Photorefractive Keratotomy, for low to moderate myopia; and LASIK, laser in situ keratomileusis, for high myopia.

In that time there have been over 18 million LASIK operations worldwide, with controversial evidence about the maximum correction possible and the long term effects of the technique.

This new study found that in the long term, LASIK was a safe and effective procedure for patients with preoperative myopia of over -10 D.

The researchers evaluated 196 eyes of 118 patients that needed at least 10 diopter (10 D) corrections to achieve 20/20 vision before receiving laser surgery. The extent of the preoperative myopia was a mean of -13.95 plus or minus 2.79 D.

The patients all received LASIK surgery at the Instituto Oftalmologico de Alicante, in Spain, between April 1992 and December 1995. They came back for check ups after 3 months, 1, 2, 5 and 10 years.

The results showed that:

· After 10 years, 42 per cent of eyes were within plus or minus 1.00 D.

· 61 per cent of eyes were within plus or minus 2.00 D.

· 27.5 per cent of eyes were retreated because of under correction or regression, or both.

· Myopic regression in eyes that were not retreated occurred at a mean rate of -0.25 plus or minus 0.18 D per year.

· 5 per cent of eyes lost more than 2 lines of best spectacle corrected visual acuity (BSCVA).

· 40 per cent of eyes showed a postoperatively uncorrected visual acuity of 20/40 or better.

· 1 per cent of eyes with more than 15 D myopic correction developed corneal ectasia (bulging).

· The retreatment rate was 27 per cent.

The researchers concluded that:

"LASIK for myopia over -10 D is a safe procedure with myopic regression that slows down with time and a high rate of BSCVA increase in the long term."

Lead investigator, Jorge L. Alio, said that:

"These results are extremely encouraging considering that this refractive correction implies the maximum limit of application of this technique."

"This study has allowed us to demonstrate that, in spite of the prejudices about the limits of LASIK technique, the results regarding predictability, efficacy and safety for high myopic patients are very good in the long term," he added.

He stressed that the optimum limit of predicatability for this type of surgery appears to be around 10 D of myopia.

In an editorial in the same issue of the journal, Dr. George O. Waring, of Emory University and Inview in Atlanta, generally supported the findings, and said that LASIK and other vision correction procedures have improved significantly in the last ten years, with some recent studies on LASIK reporting correction to plus or minus 0.5 D in more than 90 per cent of eyes.

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Oral Anti Diabetic Substance Discovered

Research in the Department of Biology at the Faculty of Science and Science Education of the University of Haifa has discovered a substance that may become an oral treatment for diabetes and its complications. The substance, which is derived from yeast, is called Glucose Tolerance Factor (GTF). "The research is now at the stage where the substance has been successfully tested on diabetic rats and was found to reduce sugar and lipids in the blood of the treated animals. The next stage of the research is to evaluate GTF efficacy in humans," said Dr. Nitsa Mirsky, who is conducting the research.

Diabetes is recognized as a major global health problem. Diabetes affects 5%-10% of the population in developed countries, while in developing countries the disease has been recently declared an "epidemic". Diabetics suffer from lack of insulin or a deficiency in the body's ability to respond to insulin. Diabetes is a chronic illness with no cure and can lead to kidney failure, heart problems, strokes or blindness, as well as other complications. Approximately 50% of diabetics are treated with insulin, which has to be injected, while the rest are treated with oral medications which tend to be more difficult to regulate and often have side effects.

According to Dr. Mirsky, there are a number of problems with insulin treatment; the main one being that insulin is not always an effective treatment, due to gradual development of resistance to the hormone. An additional problem is that insulin doses are not necessarily synchronized with the patient's physical activities or eating intervals. A large dose of insulin injected before a diabetic patient eats, for example, can cause a sudden drop in blood sugar (hypoglycemia) that can result in a diabetic coma and ultimately death. In addition, the fact that insulin must be injected is in and of itself difficult for many patients.

This current research was conducted on two levels: on diabetic rats and on the molecular-cell level. The results indicate that GTF acts similarly to insulin in the rats, lowering the level of glucose, and of LDL-cholesterol, (the "bad" cholesterol), and raising the level of HDL-cholesterol (the "good" cholesterol). GTF inhibited oxidation processes that can cause atherosclerosis and result in further complications of the disease like strokes and heart attacks. Moreover, when GTF is given at early stage of the disease, it could prevent or delay renal complications. GTF also helped to prevent cataracts and retinal damage. It was also found that GTF improves the effectiveness of injected insulin. Further research is needed in order to find a combined regimen of insulin and GTF as a potential treatment for diabetes.

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Cornell Researcher seeks clues to how Tuberculosis infects Cells

Cornell researchers are using advanced genetic techniques to better understand the relationship between the bacteria that cause tuberculosis and the human immune system defense cells that engulf them.

The researchers have discovered that unlike many bacterial pathogens, Mycobacterium tuberculosis does not react when immune system cells called macrophages initially make contact; but the bacterium's genes become activated minutes after the pathogen is enveloped by a macrophage and contained in one of its membrane-bound compartments called vacuoles.

David Russell, professor of molecular microbiology at Cornell's College of Veterinary Medicine, and colleagues reported in a November issue of the journal Cell Host and Microbe, that increased acidity inside the vacuoles containing the bacteria serves as the trigger for M. tuberculosis genes to express proteins.

The study also compared the responses of M. tuberculosis to a live bacterial vaccine against tuberculosis known as Bacillus Calmette-Guerin (BCG). It found that the two bacteria may each respond differently to the same stimuli and that BCG appears less capable of protecting itself once inside a macrophage. The findings are consistent with the reduced virulence of BCG, which is key to its safety as a vaccine.

The study is a small part of a larger plan to understand the processes that allow the bacteria to survive within macrophages and then to use that knowledge to develop more effective drugs to fight tuberculosis, which currently kills 2 million people worldwide each year. Existing drugs require six to nine months to treat the active disease that invades and replicates within the lungs.

"What we propose is the exploitation of the data obtained from these basic science studies to develop a comprehensive program of drug development that targets bacterial processes critical to survival inside the human host," said Russell.

Russell's lab used gene chips, or microarrays, to identify genes activated under specific environmental conditions. This allowed them to generate real-time readouts of bacterial health and their response to stress. The researchers have also created real-time readouts that measure conditions within the tuberculosis-containing vacuole at any time during the immune system's process.

"Our goal is to develop these bacterial fitness readouts to screen small molecule libraries for compounds that will kill M. tuberculosis inside the macrophage," said Russell. "Unfortunately, Cornell does not have either the instrumentation or the chemical libraries necessary to do this work, so I am trying different, private funding agencies to get the support to purchase equipment and libraries."

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Pain Killer Skin Patch gets Second FDA Safety Warning

The Fentanyl transdermal system, a skin patch that provides powerful pain relief is the source of a second safety warning by the Food and Drug Administration (FDA). The first warning was issued in 2005, explaining that the product label directions and patient package insert should be followed precisely in order to prevent overdosing - the warning was sent to health care professionals.

Despite the 2005 warning, reports of deaths and life-threatening side effects have still come in to the FDA - in most cases patients have incorrectly used the patch, or doctors have inappropriately prescribed it.

The FDA wants all fentanyl patch manufacturers to update their product information immediately and develop a patients' medication guide.

The Fentanyl patch has a potent narcotic, the opioid fentanyl. It was approved in 1990 for people who had become opioid tolerant and experienced persistent moderate-to-severe pain. A person who is opioid tolerant has been using an opioid narcotic pain medication 24 hours a day for at least one week. Cancer patients make up the majority of Fentanyl patch users.

The FDA has received reports of doctors and other health care professionals prescribing fentanyl patch for post-surgical pain, headaches, and for mild pain - for patients who are not opioid tolerant. The reports explain that patients did not use the patch correctly - they replaced it more often than they should, used more patches than the prescription indicated, and/or applied heat to the patch. All these incorrect usages resulted in dangerously elevated blood levels of fentanyl.

Bob Rappaport, M.D., FDA's Director, Division of Anesthesia, Analgesia and Rheumatology Products, FDA, said "There is an unmet need to provide patients suffering from chronic pain with safe and effective products that will not only alleviate their pain, but that will also be tolerable when used chronically. While these products fill an important need, improper use and misuse can be life-threatening. Therefore, it is crucial that doctors prescribe these products appropriately and that patients use them correctly."

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Merged with nurseako.com

Nursing Gazette has merged with another website http://nurseako.com, a Filipino moderated site that functions as a forum. It also caters international visitors with the same medical interests. We have done this move to provide an effective means of communication among nurses, whether they be Registered Nurses, Student Nurses, or casual visitors.

All this to help everybody who are fond of nursing.

Nonhospital Health-Care Workers at substantial risk of exposure to Bloodborne Pathogens

In one of the largest studies of its kind, researchers from the Columbia University Mailman School of Public Health assessed the risk of exposure to bloodborne pathogens among non-hospital based registered nurses (RNs), and found that nearly one out of 10 of the more than 1100 nurse participants reported at least one needlestick injury in the previous 12 months. Findings of the study are published in the December issue of Industrial Health.

According to Robyn Gershon, DrPH, principal investigator and professor of Sociomedical Sciences at the Mailman School of Public Health, "These rates of exposure are surprising since they are similar to rates reported for hospital-based nurses, even though hospitalized patients generally have high levels of acuity of patient care (i.e., more procedures, including more invasive procedures), than are typically performed in community healthcare settings." But, as Dr. Gershon and colleagues point out, these findings are not completely unexpected since patient care, including more complex types of care, is increasingly delivered at non-hospital based healthcare facilities, including out-patient clinics, nursing homes, doctor's offices, patients' homes, and public health clinics.

The authors note that increasingly complex procedures, many of which involve needles and other sharp instruments, are being performed, primarily by well-trained registered nurses, in these non-hospital settings, thereby increasing the potential risk of exposure. The population at risk is large, since non-hospital based nurses represent a substantial portion of the overall nursing workforce; approximately 40% of the 2.3 million RNs in the U. S. are employed in non-hospital settings. Extrapolated to the entire non-hospital based RN workforce in the United States, the authors estimate that the annual number of needlesticks in the non-hospital RN workforce may be in excess of 145,000 per year.

Importantly, the researchers found that 70% of the exposed nurses were never seen by a healthcare provider at all, even though appropriate and timely follow-up of these incidents can reduce the risk of infection. Findings from the study also suggest that many of the exposed nurses may be at increased risk of infection with serious bloodborne pathogens, such as the human immunodeficiency virus (HIV), hepatitis C virus and hepatitis B virus, since only 65% of these serious exposures were ever formally reported to the nurse's administrator. Fear of getting into trouble, not having enough time to report, and not knowing how to report an exposure, were the three most common reasons given for not reporting.

According to Dr. Gershon, "These exposures place them at risk of potential infection, therefore efforts to facilitate adequate post-exposure care must be made by administrators; fortunately, rapid access to post-exposure care may significantly help reduce the risk of infection."

The study also provided important information regarding the risk factors associated with these exposures, which have been well categorized for the hospital-based workforce. The researchers found similar risk factors in the non-hospital based nurses, including heavy patient loads, long working hours, poor safety climate, inadequate training and lack of safety devices. "While the risk factors may be similar for both hospital-based and non-hospital based registered nurses, there are numerous barriers to effective infection control and safety programs in non-hospital settings," remarked Dr. Gershon. A large proportion (approximately one-third) of non-hospital RNs work in establishments with fewer than 100 employees, and a sizable percentage (16%) work in establishments with fewer than five employees. "As a result, many of these facilities lack on-site infection control and employee health programs," observed Dr. Gershon and colleagues.

According to Dr. Gershon, "With nearly 900,000 registered nurses employed in a wide range of non-hospital settings, and patient prevalence rates for certain bloodborne pathogens similar or even higher in non-hospital based settings, it is important to develop and implement targeted risk reduction strategies that are tailored to these unique non-hospital settings." As the authors note, "Clearly it is best to eliminate these types of exposures in the first place. In fact, participatory action teams (PAR), which were formed as part of the study, identified several risk reduction strategies, with an emphasis on improved availability of safety devices to help eliminate or reduce the risk of injury."

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Cancer kills over 20 Thousand People a Day says Global Report

A new global cancer report by a leading US health organization estimates that cancer will kill 7.6 million people worldwide this year (about 20,000 cancer deaths a day), and more than 12 million people will find out they have the disease.

The report is called the Global Cancer Facts and Figures 2007, and is published by the American Cancer Society.

Using data from the Globocan 2002 database compiled by the International Agency for Research on Cancer (IARC), report co-author, Dr. Ahmedin Jemal, an epidemiologist with the American Cancer Society, and colleagues, showed there were significant disparities in the cancer rates between the developed and the developing world.

Jemal and colleagues estimate that 5.4 million cancers and 2.9 million cancer related deaths will be in economically developed countries, while in the less developed world there will be 6.7 million cases and 4.7 million deaths.

Infection appears to play a greater part in cancer incidence in the developing world (26 per cent of all cancers) where the incidence of infection-related cancer is some 3 times higher than in the developed world (8 per cent of all cancers).

Also, in the less developed nations, among men, the most commonly diagnosed cancers are those of the stomach, lungs, and liver, and for women, breast, cervical and stomach cancer were the most commonly diagnosed.

In the developed nations, among men, prostate, lung, and colorectal cancers are the most commonly diagnosed, and for women it is breast, colorectal, and lung cancers.

In the developing world, infection with the Helicobacter pylori (H. pylori) bacteria is considered to be the main cause of stomach cancer; infection by the human papillomavirus (HPV) is thought to be the main risk factor for cervical cancer; and hepatitis B and C infections, which the report describes as rampant in Africa and East Asia, are thought to be the main link to liver cancer.

Jemal and colleagues said lack of prevention, early detection and treatment facilities were probably the reason for the less developed world having lower cancer survival rates.

As an example they cited the 5-year survival rate for children with cancer, which is about 75 per cent in Europe and North America, but only 48 to 62 per cent in Central America. This was also based on the IARC figures.

The report estimates that if the growing use of tobacco products persists in developing countries, there will be 2 billion smokers in the world by 2030.

In 2000 there were 5 million deaths linked to smoking, of which 1.42 were from cancer, said the report.

According to the World Health Organization (WHO), over 80 per cent of the 1.3 billion smokers in the world live in developing countries.

There are 350 million smokers in China alone, more than the whole of the US population.

Overall, tobacco was responsible for around 100 million deaths worldwide in the 20th century, and will be responsible for more than 1 billion deaths worldwide in the 21st century, said the report authors. Most of the deaths will be in the developing world, and the authors said stopping the rapid spread of tobacco in developing countries should be a top global health priority.

The cancer burden is on the rise said Jemal, because developing nations are increasingly adopting a western lifestyle, characterized by "cigarette smoking, higher consumption of saturated fat and calorie-dense foods, and reduced physical activity".

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Tykerb reduced Brain Tumors Spread from Breast Cancer

When used in combination with another breast cancer drug, Tykerb (lapatinib) appeared to reduce the size of brain tumors in women whose breast cancer had spread to the brain.

This was the main result of an extended arm of a phase 2 clinical trial, said the drug company GlaxoSmithKline Plc to the 30th Annual San Antonio Breast Cancer Symposium in San Antonio, Texas, on Sunday 16th December. The symposium was sponsored by GlaxoSmithKline and the study was listed as abstract 60761 in the symposium.

The study, which included 49 patients with breast cancer that had spread to other parts of the body (metastatic breast cancer), including the brain, showed that 20 per cent of the ones on Tykerb and Xeloda (capecitabine, another cancer drug) experienced a 50 per cent reduction in measurable volume of brain tumors due to metastasis.

Also, 37 per cent of the patients had a brain tumor volume reduction of at least 20 per cent.

These results are important because nearly one third of women with HER2-positive advanced breast cancer are likely to experience the cancer spreading to the brain and central nervous system.

Dr. Nancy U. Lin, lead study investigator and Instructor in Medicine, Dana-Farber Cancer Institute, in Boston, Massachusetts said:

"As women live longer with advanced breast cancer, some are developing brain metastases that are getting worse despite standard treatments, such as radiation."

"Very few medications have shown activity in the treatment of brain metastases, in particular HER2-positive metastatic breast cancer patients and therefore, these data are quite encouraging," she added.

Tykerb is a small molecule HER2 (ErbB2) kinase inhibitor taken in tablet form, once a day. It was approved by the US Food and Drug Administration in March this year. It is used with Xeloda to treat patients with advanced or metastatic breast cancer whose tumors over express HER2 and who have already been treated with other drugs such as anthracycline, a taxane and trastuzumab (Herceptin).

The drug manufacturer said other studies were under way to discover the full potential of Tykerb for preventing and treating brain metastases.

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Europe wants warnings on Champix Smoking Cessation Drug

The European Medicines Agency (EMEA) said it wants the marketer of the adult smoking cessation prescription drug Champix (varenicline) to update the patient and doctor information to mention that some patients on the drugs have been having suicidal thoughts and made attempts to kill themselves.

The European Commission (EC) authorized Champix, marketed by drug company Pfizer, in September 2006. The EMEA Committee for Medicinal Products for Human Use (CHMP) has been monitoring the drug's safety since then as part of its watching brief. The Committee reviewed reported cases of suicidal ideation and suicide attempts in July, October and November 2007.

At a recent meeting this month, December 2007, the CHMP resolved the product information should be updated to warn doctors and patients about reported cases of depression in patients using Champix to help them stop smoking. Suicidal thoughts (ideation) and attempts are symptoms of depression.

CHMP has asked Pfizer to propose changes to the marketing authorization and product information for Champix, to take into account these post marketing reports, by the day after tomorrow, Wednesday 19th December.

Champix is marketed in the US as Chantix. The active ingredient is varenicline (usually as varenicline tartrate), and is available in tablet form to help adults stop smoking.

In November, the US Food and Drug Administration issued a similar early communication on Chantix, that said it had received a number of post-marketing reports, from the drug company, about patients having suicidal thoughts and behaving erratically while taking the drug.

Both EMEA in Europe and the FDA in the US have stressed the difficulty of finding out if the symptoms are due to varenicline. People can become depressed when they stop smoking, whether they take a drug to help them or not.

Champix is authorized in the following European countries: Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Hungary, Ireland, Luxembourg, the Netherlands, Portugal, Slovenia, Slovakia, Spain, Sweden and the United Kingdom. It is also authorized in Iceland and Norway.

In the meantime, until better scientific information is available, the EMEA advises doctors to tell their patients that depression can be a side effect of giving up smoking, and patients on Champix who start to get suicidal thoughts should stop taking the drug and go see their doctor at once.

The EMEA's CHMP committee has suggested the following changes be made to the information that accompanies the drug:

"Depressed mood may be a symptom of nicotine withdrawal. Depression, including suicidal ideation and suicide attempt, has been reported in patients undergoing a smoking cessation attempt. These symptoms have also been reported while attempting to quit smoking with Champix. Clinicians should be aware of the possible emergence of significant depressive symptomatology in patients undergoing a smoking cessation attempt, and should advise patients accordingly."

The expected next step is Pfizer will resubmit the marketing authorization in the next day or so, this will be reviewed by the CHMP, and then, all being well, patients and doctors will be given the new warning information.

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Molecular Pathway appears crucial in Development of Pulmonary Fibrosis

A study led by Massachusetts General Hospital (MGH) researchers may have found a key mechanism underlying idiopathic pulmonary fibrosis (IPF), a usually fatal lung disease for which transplantation is the only successful treatment. The investigators found that a specific molecular pathway appears responsible for key aspects of the scarring of lung tissue that characterizes IPF, the cause of which is currently unknown. The results will appear in the January issue of Nature Medicine and have received early online release.

"Identifying the key role of this pathway in the development of fibrosis gives us an exciting new target for devising treatments," says Andrew Tager, MD, of the MGH Pulmonary and Critical Care Unit, who led the study. "An agent that blocks this pathway is already being developed as a potential cancer treatment, and we're hoping to be able to test it in our animal model of IPF to determine whether it might be a candidate for trials in patients."

About 50,000 new cases of IPF are diagnosed in the U.S. each year, primarily in people aged 50 to 75. While some patients may survive for extended periods, in others the diseases progresses rapidly, leading to death in an average of 3 to 5 years. Theories about the cause of IPF previously focused on chronic inflammation of the lungs, but recent evidence has suggested that an abnormal healing response to some sort of lung injury may be responsible.

The primary characteristic of IPF is scarring (fibrosis) of the lung surface, rendering it unable to transmit oxygen into the bloodstream. In any part of the body, scarring occurs when cells called fibroblasts, an important part of normal wound healing, make collagen to reinforce the healing matrix that forms over damaged tissue. Normally scarring is limited, but if too many fibroblasts travel to the site of an injury, large amounts of collagen can be deposited, producing excessive, fibrotic scarring. Fibroblasts are known to be present in affected lung tissue in IPF, and previous studies showed that the activity of factors that attract fibroblasts to the site of an injury rises with the severity of the disease. The current study was designed to determine which specific "chemoattractants" were associated with IPF, something not previously known.

Analysis of fluid from the lung surfaces of a mouse model of pulmonary fibrosis suggested that the activity of lysoposphatidic acid (LPA), acting through its receptor LPA1, was responsible for attracting fibroblasts in the disorder. This association was supported by the fact that a strain of mice lacking the gene for LPA1 did not develop pulmonary fibrosis when treated with a compound that usually causes the disease in the animals. Lung fluid samples from human IPF patients not only had significantly higher levels of LPA than control samples, laboratory tests showed that patient samples attracted fibroblasts while fluid from controls did not. In addition, an agent that blocks the LPA1 receptor eliminated the ability of fluid from IPF patients to attract fibroblasts.

"These results indicate that the LPA-LPA1 pathway is responsible for the abnormal migration of fibroblasts into the lungs in IPF, an absolutely crucial step in the development of fibrosis," says Andrew Luster, MD, PhD, senior author of the study. "This pathway appears to be involved in several steps in the development of fibrosis, including the leaking of blood vessels, which is why the LPA1 knockout mice are so dramatically protected. If we're right, then targeting this pathway should be a very exciting new therapeutic strategy for IPF." Luster is director of the MGH Center for Immunology and Inflammatory Disease (CIID) and a professor of Medicine at Harvard Medical School (HMS). Tager is also associated with the MGH CIID and has opened a clinic focused on pulmonary fibrosis and related lung diseases. He is an assistant professor of Medicine at HMS.

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Prostate Cancer

Prostate cancer is a disease in which cancer develops in the prostate, a gland in the male reproductive system. It occurs when cells of the prostate mutate and begin to multiply out of control. These cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, erectile dysfunction and other symptoms.

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States. According to the American Cancer Society, prostate cancer is least common among Asian men and most common among black men, with figures for white men in-between. However, these high rates may be affected by increasing rates of detection.

Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is the most common type of cancer in men in the United States, where it is responsible for more male deaths than any other cancer, except lung cancer. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.

Prostate cancer is most often discovered by physical examination or by screening blood tests, such as the PSA (prostate specific antigen) test. There is some current concern about the accuracy of the PSA test and its usefulness. Suspected prostate cancer is typically confirmed by removing a piece of the prostate (biopsy) and examining it under a microscope. Further tests, such as X-rays and bone scans, may be performed to determine whether prostate cancer has spread.

Signs and Symptoms

Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for an elevated PSA noticed during a routine checkup. Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hypertrophy. These include frequent urination, increased urination at night, difficulty starting and maintaining a steady stream of urine, blood in the urine, and painful urination. Prostate cancer may also cause problems with sexual function, such as difficulty achieving erection or painful ejaculation.

Advanced prostate cancer may cause additional symptoms as the disease spreads to other parts of the body. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis or ribs, from cancer which has spread to these bones. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.

Causes

The cause of prostate cancer isn't fully understood at present. But there are certain factors that make prostate cancer more likely, which are listed below.

* The risk of prostate cancer increases steadily with age and it is rare in men under 50.
* Your risk is higher if you have close relatives (a father, uncle or brother) who have had prostate cancer.
* If several women in your family have had breast cancer (especially if they were diagnosed at under 40 years of age) an inherited faulty gene may be present. The gene may also increase the risk of the men in that family getting prostate cancer.
* If you are African-Caribbean or African-American you are at highest risk whereas if you are Asian, you are at lower risk.
* A high fat diet may increase your risk.

Diagnosis

When a man has symptoms of prostate cancer, or a screening test indicates an increased risk for cancer, more invasive evaluation is offered.

The only test which can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of small pieces of the prostate for microscopic examination. However, prior to a biopsy, several other tools may be used to gather more information about the prostate and the urinary tract. Cystoscopy shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down the urethra. Transrectal ultrasonography creates a picture of the prostate using sound waves from a probe in the rectum.

Biopsy

If cancer is suspected, a biopsy is offered. During a biopsy a urologist obtains tissue samples from the prostate via the rectum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate) in less than a second. Prostate biopsies are routinely done on an outpatient basis and rarely require hospitalization. Fifty-five percent of men report discomfort during prostate biopsy.

Gleason score

The tissue samples are then examined under a microscope to determine whether cancer cells are present, and to evaluate the microscopic features (or Gleason score) of any cancer found.

Tumor markers

Tissue samples can be stained for the presence of PSA and other tumor markers in order to determine the origin of malignant cells that have metastasized.

New tests being investigated

Currently, an active area of research involves non-invasive methods of prostate tumor detection. Adenoviruses modified to transfect tumor cells with harmless yet distinct genes (such as luciferase) have proven capable of early detection. So far, though, this area of research has only been tested in animal and LNCaP models.

PCA3

Another potential non-invasive methods of early prostate tumor detection is through a molecular test that detects the presence of cell-associated PCA3 mRNA in urine. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. PCA3 is not a replacement for PSA but an additional tool to help decide if, in men suspected of having prostate cancer, a biopsy is really needed. The higher the expression of PCA3 in urine, the greater the likelihood of a positive biopsy, i.e. the presence of cancer cells in the prostate. Company Diagnocure has an exclusive worldwide license for all diagnostic and therapeutic applications related to PCA3

Early prostate cancer

It was reported in April 2007 that a new blood test for early prostate cancer antigen-2 (EPCA-2) is being researched that may alert men if they have prostate cancer and how aggressive it will be.

Pathogenesis/Pathophysiolgy

Genetics play some role in risk of prostate cancer. Specifically, around 9% of prostate cancers appear to be familial.

The male hormone, testosterone, and its analogues are definitely involved in the pathogenesis of prostate cancer. The National Cancer Institute lists the following as support for the role of male sex hormones in prostate cancer.

· Neither benign prostatic hypertrophy (BPH) nor prostate cancer have been reported in men castrated prior to puberty.

· Many studies have shown that populations with higher levels of testosterone and most importantly dihydrotestosterone have higher incidences of prostate cancer. For example the highest levels are found in blacks males, intermediate levels in white males, and lowest levels in native Japanese. The incidence of prostate cancer parallels the levels.

· Deprivation of androgens (males sex hormones) leads to decreased levels of PSA, and death of prostate cancer cells.

Dietary fat appears to play a role in prostate cancer but studies are conflicting. If dietary fat is a risk factor, it appears that saturated fat from animal origins is a greater risk factor than unsaturated fat from vegetable origin. The mechanism by which fat may be involved in prostate cancer has been hypothesized. First, dietary fat increases serum levels of male sex hormones (androgens). Some studies indicate that omega 3 oils (fish oil, flaxseed oil) may actually prevent prostate cancer. Finally, many studies have found that there is a relationship between the amount of fat eaten by the mother during pregnancy and the later development of prostate cancer in her male offspring.

Previous articles have outlined the benefits of eating a Mediterranean style diet, consisting of plenty of fresh fruits and vegetables, fish, and olive oil. This type of diet has benefits for cardiovascular health, and appears to be advisable for prevention of cancers of all types.

Finally, there is some evidence that exposure to pesticides and heavy metals may be a risk factor for prostate cancer. Specifically there may be a relationship between dioxin (a contaminant of herbicides) and prostate cancer. Likewise, the metal cadmium found in NiCad batteries is suspect. Workers in plants that manufacture or recycle these batteries should take extreme precautions to prevent exposure.

Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most prostate cancers are adenocarcinomas (95%).

Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Few cases have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.

Of cases of prostate cancer, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Natural history

The natural history is still relatively unknown, and many aspects of progression are poorly understood. Symptoms or abnormal DRE findings in the pre-PSA era only brought 40-50% of patients with prostate cancer to medical attention, and these patients usually had locally advanced disease. The advent of PSA testing has helped identify patients with less-advanced, organ-confined disease.

Evidence suggests that most prostate cancers are multifocal and heterogeneous. Cancers can start in the transitional zone or, more commonly, the peripheral zone. When these cancers are locally invasive, the transitional zone tumors spread to the bladder neck, while the peripheral zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces is a relatively late event.

The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, occasionally without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread, the mechanical theory and the seed-and-soil theory.

* The mechanical theory involves direct spread through the lymphatics and venous spaces into the lower lumbar spine.

* Advocates of the seed-and-soil theory believe tissue factors must be present that allow for preferential growth in certain tissues, such as the bone. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples.

The doubling time in early-stage disease is as slow as 2-4 years, but this changes as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.

Natural history by stage

* T1a - Progression over 10 years (uncommon)

* T1b - Tumor-related death rate of 10% in 10 years

* T2 - Ten-year metastasis-free survival rate of 81% with grade 1, 58% with grade 2, and 26% with grade 3

* T3 - Lymph node metastasis at presentation in 50% and approximately 25% rate of 10-year disease-free survival

The natural history of clinically localized disease is variable, with lower-grade tumors having a more indolent course, while some high-grade lesions progress to metastatic disease with relative rapidity. Several studies have examined the cancer-specific and quality-of-life outcomes associated with a watchful waiting approach to localized disease.

* Albertsen et al followed patients who received no initial treatment for prostate cancer. As disease progression occurred, many received antiandrogens. Men with poorly differentiated tumors lost 6-8 years of life, while those with moderately differentiated tumors lost 4-5 years. Of all men followed for 10 years, 40% died of causes other than prostate cancer. This study was performed prior to PSA screening.

* Graversen et al compared watchful waiting with radical prostatectomy. They found no overall difference in survival, but they did find that a high Gleason score was associated with poor survival in both groups.

* Chodak et al confirmed this finding by analyzing 6 studies and finding a 34% survival rate with grade 3 tumors versus an 87% disease-specific survival rate for grade 1 and 2 tumors. The metastasis-free survival rate also significantly dropped as the grade progressed from 1 to 3.

* Johansson reported their recent update on a population-based cohort study with a mean observation period of 21 years. In this study, 223 patients with early-stage, initially untreated prostatic cancer were observed. Patients with tumor progression received hormonal treatment (orchiectomy or estrogens) if they had symptoms. Thirty-nine (17%) experienced metastatic disease, with most cancers having an indolent course during the first 10-15 years. However, further follow-up at 15-20 years revealed a substantial decrease in cumulative progression-free survival (from 45% to 36%), survival without metastases (from 76.9% to 51.2%), and prostate cancer–specific survival (from 78.7% to 54.4%). Prostate cancer mortality increased from 15 deaths per 1000 person-years during the first 15 years to 44 deaths per 1000 person-years beyond 15 years of follow-up.

Taken together, these data suggest that although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. In addition, these findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.

Prevention

Several medications and vitamins may also help prevent prostate cancer. Two dietary supplements, vitamin E and selenium, may help prevent prostate cancer when taken daily. Estrogens from fermented soybeans and other plant sources (called phytoestrogens) may also help prevent prostate cancer. The selective estrogen receptor modulator drug toremifene has shown promise in early trials. Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride, and dutasteride, have also shown some promise. The use of these medications for primary prevention is still in the testing phase, and they are not widely used for this purpose. The problem with these medications is that they may preferentially block the development of lower-grade prostate tumors, leading to a relatively greater chance of higher grade cancers, and negating any overall survival improvement. Green tea may be protective (due to its polyphenol content), though the data is mixed. A 2006 study of green tea derivatives demonstrated promising prostate cancer prevention in patients at high risk for the disease. In 2003, an Australian research team led by Graham Giles of The Cancer Council Australia concluded that frequent masturbation by males appears to help prevent the development of prostate cancer. Recent research published in the Journal of the National Cancer Institute suggests that taking multivitamins more than seven times a week can increase the risks of contracting the disease. This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label. Scientists recommend a healthy, well balanced diet rich in fiber, and to reduce intake of meat. A 2007 study published in the Journal of the National Cancer Institute found that men eating cauliflower, broccoli, or one of the other cruciferous vegetables, more than once a week were 40% less likely to develop prostate cancer than men who rarely ate those vegetables. Scientists believe the reason for this phenomenon has to do with a phytochemical called Diindolylmethane in these vegetables that has anti-androgenic and immune modulating properties. This compound is currently under investigation by the National Cancer Institute as a natural therapeutic for prostate cancer.

Capsaicin

Capsaicin, the chemical found in peppers, has been shown to cause 80% of cancerous prostate cells to undergo apoptosis in mice. For prostate cancer cells whose growth is dependent upon testosterone, Capsaicin curbed the proliferation of such cells by freezing the cells in a non-proliferate state, and cancerous prostate cells that are androgen independent "suicided" as well.

"Capsaicin had a profound anti-proliferative effect on human prostate cancer cells in culture," said Sören Lehmann, M.D., Ph.D., visiting scientist at the Cedars-Sinai Medical Center and the UCLA School of Medicine. "It also dramatically slowed the development of prostate tumors formed by those human cell lines grown in mouse models."

Peppers which rank higher on the Scoville scale and thus have a higher piquancy contain a higher amount of Capsaicin. Habaneros, for example, have a Scoville rating of over 300,000, while red chili peppers have a rating of 5,000. While the UCLA and Samuel Oschin Comprehensive Cancer Institute studies show promising implications, the same effects have not yet been duplicated in men.

Treatment

Treatment for prostate cancer may involve watchful waiting, surgery, radiation therapy, High Intensity Focused Ultrasound (HIFU), chemotherapy, cryosurgery, hormonal therapy, or some combination. Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are the man's age, his general health, and his feelings about potential treatments and their possible side effects. Because all treatments can have significant side effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations.

The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option. This may enter into the treatment decision.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors who treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting, HIFU, radiation therapy, cryosurgery, and surgery are generally offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease which has spread beyond the prostate. However, there are exceptions: radiation therapy may be used for some advanced tumors, and hormonal therapy is used for some early stage tumors. Cryotherapy, hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.

Complications

The list of complications that have been mentioned in various sources for Prostate Cancer includes:

* Metastatic cancer
* Bone pain

Complications and sequelae of Prostate Cancer include:

* Red cell production reduced
* Osteosclerosis
* Prostate specific antigen levels raised (plasma or serum)
* Back pain
* Bone pain
* Hematospermia
* Bone metastases
* Incontinence, urine
* Urethral stricture
* Hematuria
* Pathological fracture
* Acid phosphatase levels raised (plasma or serum)

References

http://www.wikipedia.org
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http://www.alternative-cancer-treatments.com
Provided additional information.

http://hcd2.bupa.co.uk
Provided extra reference.

http://www.emedicine.com
Provided complete information and extra reference.

http://www.wrongdiagnosis.com
Provided extra references.

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New Avandia Study finds higher risk of Heart Problems and Death

A new Canadian study on older patients who took diabetes medications known as thiazolidinediones (which include rosiglitazone or Avandia), concluded they ran a significantly higher risk of congestive heart failure, heart attack, and death compared with patients on other diabetes drugs.

The researchers said their study provides further evidence that thiazolidinediones (TZDs) do more harm than good. GlaxoSmithKline, who market Avandia said the study was misleading and conflicted with more robust clinical studies.

The study is published today, 12th December, in the early online issue of the Journal of the American Medical Association (JAMA) and is the work of Dr. Lorraine L. Lipscombe of the Institute for Clinical Evaluative Sciences, Toronto, Canada, and colleagues.

The TZDs rosiglitazone (brand name Avandia, marketed by Glaxosmithkline) and pioglitazone (brand name Actos, marketed by Takeda), are oral medications taken by patients with type 2 diabetes to help control blood sugar (glycemic control).

Lipscombe and colleagues wrote:

"While improved glycemic control has been linked to better clinical outcomes in diabetes and TZDs have been suggested as having potential cardiovascular benefits, recent concerns have arisen regarding adverse cardiac effects of these drugs."

Other studies have shown that both rosiglitazone and pioglitazone may raise the risk of congestive heart failure, and that rosiglitazone may be liked with an increased risk of acute myocardial infarction (heart attack) and death.

However, after reviewing the evidence on Avandia, the US Food and Drug Administration concluded last month that it was inconclusive, and allowed the drug to stay on the market. But the agency imposed the strongest warning, the so-called "black box" label, on the drug.

In this latest study, Lipscombe and colleagues evaluated the risk of congestive heart failure, heart attack and death from all causes linked to the use of TZDs compared with other oral hypoglycemic drugs among diabetic patients aged 66 years and above.

The authors said this group of older patients was often under-represented in TZD trials, despite having a higher rate of diabetes and being at higher risk of harm from medication.

The researchers used health care records from databases in Ontario, Canada, which covered 159,026 diabetics on oral oral hypoglycemic drugs who were monitored for a median period of 3.8 years, up to March 2006.

During the monitoring period, 7.9 per cent (12,491) of the patients visited the hospital for congestive heart failure, 7.9 per cent (12,578) for a heart attack, and 19 per cent (30,265) died.

After analyzing the records, the researchers showed that compared to patients on oral hypoglycemic agent combination treatments, the ones taking only a TZD had a 60 per cent higher risk of congestive heart failure, 40 per cent higher risk of heart attack, and 28 per cent higher risk of death. The increased risks appeared to be limited only to rosiglitazone (Avandia).

They concluded that:

"In this population-based study of older patients with diabetes, TZD treatment, primarily with rosiglitazone, was associated with an increased risk of congestive heart failure, acute myocardial infarction, and mortality when compared with other combination oral hypoglycemic agent treatments."

The authors were of the view that these findings argued against the current labeling policy of TZDs which warns against use only in patients at high risk of congestive heart failure. They said their study did not find any subgroup of older patients who were protected against the adverse effects of TZDs.

"These findings provide evidence from a real-world setting and support data from clinical trials that the harms of TZDs may outweigh their benefits, even in patients without obvious baseline cardiovascular disease," they added.

Until further studies quantify the risks versus the benefits of TZDs, and whether the hazards identified are restricted to rosiglitazone (Avandia), the authors recommended that treatment decisions be made on a patient by patient basis, with doctors weighing up the risk versus benefits according to the individual's situation, especially in the case of high risk elderly patients.

GlaxoSmithKline gave several examples of where the study was limited and misleading. For instance, the Ontario (ODB) database comprised a select group of patients:

"Rosiglitazone [Avandia] is only prescribed for those patients who fail treatment on metformin and sulfonylurea, or for whom sulfonylurea or metformin are contraindicated."

The patients on Avandia were therefore already at a higher baseline cardiovascular disease risk, said the drug company.

They also stressed another limitation of the study:

"Patients prescribed rosiglitazone alone suffered from more chronic diseases compared with those prescribed pioglitazone alone; therefore they were sicker patients."

GlaxoSmithKline said the authors did not correct for this in their analysis and that their conclusions were "inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies".

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Highmark presents work on MRSA Prevention at National Health Care Quality Conference

At a national forum on quality in health care, Highmark officials presented information on one aspect of their pay-for-performance program designed to deal with Methicillin Resistant Staphylococcus Aureus (MRSA). Highmark's program, called QualityBLUE, has been extremely successful for hospitals in western Pennsylvania in identifying patients that have been infected with the disease.

"By identifying patients who are carriers of MRSA earlier than in the past, hospitals are reducing the spread of the disease and reducing mortality, decreasing length of stay and use of antibiotics, and ultimately having significantly improved outcomes for patients," said Deborah Donovan, director, Provider Quality Performance Management at Highmark. "Highmark is working collaboratively with 30 hospitals in Pennsylvania. It is in great part because of this cooperation that the program has been so successful."

The poster presentation was made at the 19th Annual National Forum on Quality Improvement for Health Care in Orlando, Fla. and sponsored by the Institute for Healthcare Improvement (IHI). In December 2006, the IHI added the reduction of MRSA infections to its new 5 Million Lives campaign. Participating hospitals submit such data as the percentage of patients who were tested for MRSA on admission and compliance with prevention techniques.

Highmark's pay-for-performance program began targeting MRSA testing and prevention initiatives in July 2005. "We have made it easier for participating hospitals to work with IHI and Highmark," said Donovan.

Results from Highmark's fiscal year 2007 review show that during the past year, 8.4 percent of patients admitted to hospitals' high-risk areas such as the intensive care unit were identified as carriers of MRSA. With the thorough screening program, the spread of MRSA has been reduced. Measures that participating hospitals use to reduce the spread once the patient is identified as a carrier include placing the patient in isolation, using dedicated equipment, and strict adherence to appropriate hand hygiene.

Donovan says the QualityBLUE program has expanded for fiscal year 2008 for the participating hospitals in western and central Pennsylvania. Each hospital identified three units within its facility for intense activities designed to reduce MRSA transmission.

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Soliris(R) Therapy provided clinical improvements in PNH Patients regardless of disease severity

Soliris(R) (eculizumab) therapy reduced hemolysis, fatigue, thromboses (blood clots) and transfusion requirements in patients with a rare blood disorder called paroxysmal nocturnal hemoglobinuria (PNH), including those who might have been expected to have less severe disease, according to data from an ongoing open-label clinical study presented at the 49th Annual Meeting of the American Society of Hematology Meeting in Atlanta.

The data were highlighted in an oral presentation titled, "High Incidence of Progression to Significant Disease Burden in Paroxysmal Nocturnal Hemoglobinuria Patients with Lower Levels of Hemolysis, Mild Anemia and Minimal Transfusion: Clinical Improvement with Eculizumab Therapy."

In the study, Soliris was associated with significant long-term clinical improvements in patients with PNH, regardless of baseline degree of hemolysis, anemia or transfusion requirements. The study also demonstrated that patients who might have been expected to have less severe disease, considering their baseline clinical characteristics, suffered from significant disease burden.

"PNH patients once thought to have less severe disease based on their clinical characteristics actually face significant disease burden from anemia, fatigue, impaired quality of life, blood transfusion requirements and blood clot risk," said Monica Bessler, MD, PhD, lead author of the study and Professor of Medicine, Professor of Pharmacology and Molecular Biology, Washington University in St. Louis School of Medicine. "The results presented today show that, in this study group, regardless of disease severity, long- term Soliris treatment provides important clinical improvements in their disease signs, symptoms and complications."

"We continue to observe that the PNH patient population includes a wide range of patients with a broad clinical profile," said Leonard Bell, MD, Chief Executive Officer of Alexion Pharmaceuticals. "The results presented today provide further evidence for the utility of Soliris therapy in patients with diverse manifestations of PNH. We remain committed to our goal that all patients who can benefit from Soliris will have access to it."

Soliris, developed by Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN), is the first therapy approved for the treatment of patients with PNH, a rare, debilitating and life-threatening blood disorder defined by the destruction of red blood cells, or hemolysis. Soliris is a complement inhibitor indicated for the treatment of patients with PNH to reduce hemolysis. In patients with PNH, hemolysis can cause thromboses, kidney disease, liver dysfunction, disabling fatigue, impaired quality of life, recurrent pain, shortness of breath, pulmonary hypertension, intermittent episodes of dark colored urine (hemoglobinuria), and anemia.

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Scientists discover how BRCA1 Gene Variant helps Breast Cancer grow

A new international study has discovered how a variant of the BRCA1 gene helps breast cancer to grow by knocking out a tumor suppressor gene called PTEN. The researchers believe their discovery could lead to new ways to treat this aggressive type of breast cancer.

The study is published in the early online edition of the journal Nature Genetics and is the work of researchers at Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center in the US, and Lund University in Sweden.

Study co-author, Dr. Ramon Parsons, who is director of the Avon Foundation Breast Cancer Research Laboratory and also director of the Breast Cancer Program of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and New York Presbyterian Hospital, said in a prepared statement:

"These findings are exciting because ever since the link was established between BRCA1 and breast cancer more than 10 years ago, we have been frustrated by our lack of understanding about how mutations in this gene cause breast cancer."

"We have been stymied by our limited resources to treat these cancers, which are associated with very poor prognoses. Now that we know that PTEN is involved, we finally have a target for therapy for these cancers," he added.

Parsons led one of the two teams in 1997 that independently revealed that PTEN, a key tumor suppressor gene, was knocked out in breast, brain and prostate cancers.

Scientists now know that PTEN mutations are second only to p53 as being the most frequently present in all cancers, affecting about 30 per cent of them.

Disabling PTEN switches on a strong signal that encourages tumor growth. This is different to the direct effect of the BRCA1 mutation itself, which causes cells to be more vulnerable to genetic damage and indirectly sends out cell growth signals. As Parsons explained:

"Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer."

PTEN mutations increase the activity of various proteins via the PTEN/PI3K pathway to promote tumor growth. Phase I clinical trials investigating the effect of shutting down proteins in this pathway as a way to stop tumor growth are already under way, said the researchers.

Parsons and colleagues used a new technique to find the link between BRCA1 and PTEN; more conventional ways of searching for mutations had failed. The new method looks for physical breaks in chromosomes.

They examined 34 biopsies from women with BRCA1 tumors and found in about one third of them that the PTEN gene was incomplete. In some cases large sections of the gene were missing, and in others one half of the gene had come away and was reattached to other parts of the chromosome.

The researchers said that lack of BRCA1 in tumors can lead to this type of chromosome damage because BRCA1 is involved in PTEN repair. Women with breast cancer who have normal BRCA1 rarely have such large mutations in PTEN, they said.

Parsons and colleagues estimate that PTEN mutations affect about 50 per cent of BRCA1 breast cancers.

BRCA1 causes a type of breast cancer called basal-like or triple negative, because the tumors are missing receptors for estrogen, progesterone, and HER2, which are needed for treatment to work.

The study showed that PTEN is also damaged in most tumors from basal-like cancer, which occurs in 10 to 20 per cent of women with breast cancer not caused by inheriting a faulty BRCA1 gene.

Lead author Dr. Lao Saal, who at the time of the research was a fellow in Parsons' Avon Foundation Breast Cancer Research Laboratory and is now finishing his medical degree at Columbia University College of Physicians and Surgeons, said that:

"Our results point to PTEN as a major player in both hereditary and non-hereditary basal-like breast cancer, a finding that may now be exploited to develop new therapeutic strategies to improve outcomes for women with these aggressive tumors."

Parsons, Saal, and colleagues suggest BRCA1 also affects other cancer genes, and there may be similar links between another breast cancer gene, BRCA2 and mutations in other genes. They hope to use the new chromosome scanning technique to track down other mutated genes involved in the development of breast cancer:

"These kinds of mutations that break tumor suppressors in half may turn out to be common in many kinds of carcinomas, particularly those with deficiencies in DNA repair pathways similar to BRCA1, a question that only a systematic search can answer," explained Saal.

Dr. Åke Borg, professor of oncology at Lund University and study co-author said:

"Similar research is underway in tumors from carriers of germline mutations in BRCA2, the other known major breast cancer susceptibility gene."

"BRCA2 has a role downstream in the same DNA double strand break repair pathway as BRCA1, but tumors from BRCA2 mutation carriers have a quite different phenotype compared to BRCA1 tumors, less often involving PTEN loss. However, like BRCA1, BRCA2 tumors have an instable genome with massive chromosomal aberrations, suggesting that other genes may be targeted," explained Borg.

Basal-like breast cancer tumors are among the most aggressive tumors, they grow fast and spread quickly, are resistant to standard breast cancer treatments such as Tamoxifen or Herceptin, and are more likely to be fatal than other cancers.

Between 60 and 80 per cent of women carrying a BRCA1 mutation will have breast cancer. BRCA1 mutations are more common among African-American women and women of Ashkenazi Jewish descent.

Women who inherit BRCA1 and BRCA2 mutations are also more likely to get ovarian cancer, a disease that is often undetected in the early stages so currently the prognosis is very poor for most women who eventually discover they have it.

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Evaluation of Stem Cells' potential for new ways to treat disease - Aided by PET and Bioluminescent Imaging

Using positron emission tomography (PET) imaging with bioluminescence - the light produced by a chemical reaction within an organism - researchers are starting to understand the behavior of transplanted or implanted stem cells that may one day be used to develop new treatments for disease.

According to a study in the December Journal of Nuclear Medicine, scientists have found that using the unique combination of noninvasive PET imaging and optical (bioluminescent) imaging is "an ideal method for tracking stem cell transplantation in small animal models," said Zhenghong Lee, an associate professor of nuclear medicine/radiology and biomedical engineering departments at Case Western Reserve University in Cleveland, Ohio. Researchers were able to use these two imaging techniques to "follow" stem cells for a longer time than previously had been achieved to determine their "fate," explained Lee.

Human mesenchymal stems cells or multipotent marrow stromal cells (hMSCs) are self-renewing adult stem cells that are found in adult donor bone marrow. These stem cells, the body's blank or "master" cells, may differentiate (or change) into bone, fat tissue and cartilage, said Lee. "The promise of MSC therapies - derived from adult bone marrow and used as a viable and renewable source of stem cells - mandates research leading to a better understanding of the long-term fate and trafficking of transplanted MSCs in animal and human subjects," said the investigator at Case Western's Center for Stem Cell and Regenerative Medicine. These progenitor cells may have great potential in providing future treatments for heart diseases, brain disorders and cancer and greatly reduce the need to use embryonic stem cells or other fetal tissues.

Specifically, this imaging research could help optimize treatments for individuals with graft-versus-host disease, a life-threatening condition where immune cells from donated marrow or cord blood attack the body of a bone marrow transplant patient, said Lee. Additionally, bone marrow stem cells may help regenerate cells in individuals with heart disease (heart attacks) or brain disorders (strokes, multiple sclerosis) or bone fractures. They could act as a drug delivery vehicle for cancer patients, he added. Much research in these areas still needs to be done "since there are many things that we don't know about stem cell biology," noted Lee.

For this study, researchers used a fusion protein combining firefly luciferase (a light-emitting substance) for optical imaging, a red fluorescent protein for cell separation and a virus enzyme thymidine kinase for PET imaging in mice to visualize biological processes at the molecular level. "The triple-fusion reporter approach resulted in a reliable method of labeling stem cells for investigation by use of both small-animal PET imaging and bioluminescent imaging," said Lee. PET is a powerful molecular imaging procedure that noninvasively demonstrates the function of genes, cells and organs/tissues, providing information about the biochemistry processes, metabolic activities and body functions. PET scans use very small amounts of radioactive pharmaceuticals that are detected or "traced" by a special type of camera that works with computers to provide quantitative pictures of the area of the body being imaged. To image dim light from bioluminescence - the process of light emission in living organisms - researchers use an ultra-sensitive camera from an external vantage point. This research is detailed in "Imaging of Mesenchymal Stem Cell Transplant by Bioluminescence and PET."

In a related Journal of Nuclear Medicine article, the growing number of exciting animal and preclinical studies are explored, revealing the "immense potential in stem cell-based therapies, particularly in the area of treating cardiovascular diseases," said Joseph C. Wu, assistant professor of cardiovascular medicine and radiology at Stanford University School of Medicine in Stanford, Calif. Wu and co-author Sarah J. Zhang review the basic principles of current techniques for cardiac stem cell tracking, compare the relative advantages and disadvantages of these imaging modalities and discuss the future prospect of cardiac stem cell trafficking. "Comparison of Imaging Techniques for Tracking Cardiac Stem Cell Therapy" is the first article in the journal's new monthly feature called "Focus on Molecular Imaging."

"The unique information obtained from molecular imaging techniques is particularly helpful in evaluating cell engraftment and may shed light on the mixed findings regarding stem cell-based therapy," said Wu. "The current noninvasive imaging approaches for tracking stem cells in vivo include imaging with magnetic particles, radionuclides, quantum dots, reporter genes, and fluorescence and bioluminescence imaging," he added. "It is possible that a tailored combination of two or more techniques may provide the most ideal information profile for clinical applications," concluded Wu.

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Broccoli three times a month can significantly reduce Cancer Risk

If you are not keen on broccoli or cabbage be comforted with the news that you do not have to eat too much of it to reduce your chances of developing cancer. In fact, if you eat broccoli or cabbage just three times each month you could well be reducing your chances of developing bladder cancer by up to 40%, say scientists from the Roswell Park Cancer Institute in Buffalo, USA. They presented their findings at the American Association of Cancer Research Conference, Philadelphia.

In this study, the researchers looked at 1,000 people. 275 of them had bladder cancer while the rest (825) were cancer free. They were all asked about their eating habits, in particular, their consumption of such vegetables as cabbage or broccoli (cruciferous vegetables). Cruciferous vegetables are known to have large amounts of isothiocyanates (ITCs), which experts say can help reduce your risk of developing cancer.

They found that a smoker who consumes less than three servings of cruciferous vegetables per month has the highest risk of developing bladder cancer. They also found that those who ate raw cruciferous vegetables at least three times a month had a 40% lower risk than those who consumed the raw veggies less often. The difference was also 40% when smokers who ate raw cruciferous vegetables at least three times a month were compared to smokers who ate them less often.

However, the scientists stressed that they only observed this significant difference in bladder cancer risk with raw vegetables, not cooked vegetables. This is probably because cooking lowers the ITC content by 60-90%, they explained.

In another study, carried out on rats by researchers also from Roswell Park Cancer Institute, the animals were induced to develop bladder cancer. They were then given freeze-dried broccoli sprout extract. The chances of developing bladder cancer were much lower if the rats ate larger quantities of the freeze dried extract.

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Sickle Cell Anemia treated using Reprogrammed Skin Cells in Mice

Scientists in the US have used a recently proven stem cell technology based on reprogramming skin cells to make them act like embryonic stem cells to treat sickle cell anemia in mice. Although proved in principle, the technique is not safe to use in humans and there are some significant hurdles to overcome before it is.

The study is published in the December 6th online issue of the journal Science and was carried out by Tim Townes of the University of Alabama, Birmingham, and colleagues.

Last month, another group of scientists showed it was possible to reprogram human fibroblast skin cells into an induced pluripotent (iPS) or embryonic stem-cell like state by inserting four transcription factors. This opened a new avenue for obtaining the benefits of customized embryonic stem cells without the ethical problems of creating and destroying embryos.

However, the therapeutic potential of such iPS technology had not yet been tested.

In this new study, Townes and colleagues used mice with sickle cell anemia, a type of blood disorder caused by one faulty gene.

Blood cells is a good place to start because they are easier to replace than tissue cells. Sickle cell anemia causes red blood cells to curve which impedes their transit in blood vessels.

Stem cell researcher and co-author of the paper, Rudolf Jaenisch of the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology, both in Cambridge, said that mice with sickle cell anemia show many of the human symptoms which makes them good subjects to test the potential therapeutic value of iPS cells.

Townes, Jaenisch and colleagues took skin cells from the tails of mice with sickle cell anemia and inserted the four transcription factors to convert them into iPS cells. Then they inserted a corrected hemoglobin gene into the iPS cells and encouraged them to develop into a type of stem cell that produces blood cells.

After exposing the mice to radiation to kill their own blood stem cells, the researchers injected them with the new blood stem cells containing the corrected hemoglobin gene. Within a few weeks the new stem cells were producing new mature blood cells and the symptoms of sickle cell anemia were significantly reduced.

Townes said he and Jaenisch had previously tried to use a cloning method to make corrected stem cells, also called nuclear transfer, where the nucleus of an egg is destroyed and replaced with the desired DNA, but the experiments failed because the method was not efficient enough. He said the iPS method was "amazingly efficient".

An article in ScienceNOW reported that Jose Cibelli of Michigan State University in East Lansing called this study an "important step forward". The results are impressive, said Cibelli but:

"If they do not have therapeutic value, they will be far from getting to the point of replacing the whole idea of therapeutic cloning."

What needs to happen next, said Cibelli, is for scientists to find reliable ways to make a range of useful cell types from these cells and to overcome the problem posed by undifferentiated cells that can cause tumors.

Other experiments have shown that if some of the cells do not differentiate, they can start to produce undesired cells and cause cancer. But in this study the mice did not show signs of this after 12 weeks. However, this is not long enough to prove the method is safe, said Townes, and much longer term experiments are needed before iPS techniques can be trialled in humans.

Townes and colleagues concluded that:

"Our results provide proof of principle for using transcription factor-induced reprogramming combined with gene and cell therapy for disease treatment in mice. The problems associated with using retroviruses and oncogenes for reprogramming need to be resolved before iPS cells can be considered for human therapy."

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Breast Cancer

Compiled and Summarized by Anthony
Worldwide, breast cancer is the fifth most common cause of cancer death (after lung cancer, stomach cancer, liver cancer, and colon cancer). In 2005, breast cancer caused 502,000 deaths (7% of cancer deaths; almost 1% of all deaths) worldwide. Among women worldwide, breast cancer is the most common cause of cancer death.

In the United States, breast cancer is the third most common cause of cancer death (after lung cancer and colon cancer). In 2007, breast cancer is expected to cause 40,910 deaths (7% of cancer deaths; almost 2% of all deaths) in the U.S. Among women in the U.S., breast cancer is the most common cancer and the second-most common cause of cancer death (after lung cancer). Women in the U.S. have a 1 in 8 lifetime chance of developing invasive breast cancer and a 1 in 33 chance of breast cancer causing their death. In the U.S., both incidence and death rates for breast cancer have been declining in the last few years. Nevertheless, a U.S. study conducted in 2005 by the Society for Women's Health Research indicated that breast cancer remains the most feared disease, even though heart disease is a much more common cause of death among women.

The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly blamed on modern lifestyles in the Western world. Because the breast is composed of identical tissues in males and females, breast cancer also occurs in males, though it is less common.

Signs and Symptoms

Early breast cancer can, in some cases, present as breast pain (mastodynia) or a painful lump. Since the advent of breast mammography, breast cancer is most frequently discovered as an asymptomatic nodule on a mammogram, before any symptoms are present. A lump under the arm or above the collarbone that does not go away may be present.

When breast cancer has invaded the dermal lymphatics - small lymph vessels of the skin, its presentation can resemble skin inflammation and thus is known as inflammatory breast cancer. In inflammatory breast cancer, the breast cancer is blocking lymphatic vessels and this can cause pain, swelling, warmth, and redness throughout the breast, as well as an orange peel texture to the skin referred to as peau d'orange. Although there may have been no previous signs of breast cancer and the cancer might be missed in screening mammograms, Inflammatory Breast Cancer is at least locally advanced at presentation (LABC) and Stage IIIB. Immediate staging tests are required to rule out distant metastes which might already be present making it Stage IV.

Changes in the appearance or shape of the breast can raise suspicions of breast cancer.

Another reported symptom complex of breast cancer is Paget's disease of the breast. This syndrome presents as eczematoid skin changes at the nipple, and is a late manifestation of an underlying breast cancer.

Most breast symptoms do not turn out to represent underlying breast cancer. Benign breast diseases such as fibrocystic mastopathy, mastitis, functional mastodynia, and fibroadenoma of the breast are more common causes of breast symptoms. The appearance of a new breast symptom should be taken seriously by both patients and their doctors, because of the possibility of an underlying breast cancer at almost any age.

Occasionally, breast cancer presents as metastatic disease, that is, cancer that has spread beyond the original organ. Metastatic breast cancer will cause symptoms that depend on the location of metastasis. More common sites of metastasis include bone, liver, lung, and brain. Unexplained weight loss can occasionally herald an occult breast cancer, as can symptoms of fevers or chills. Bone or joint pains can sometimes be manifestations of metastatic breast cancer, as can jaundice or neurological symptoms. Pleural effusions are not uncommon with metastatic breast cancer. Obviously, these symptoms are "non-specific," meaning they can also be manifestations of many other illnesses.

Causes

Many women who develop breast cancer have no risk factors other than age and sex.

* Gender is the biggest risk because breast cancer occurs mostly in women.

* Age is another critical factor. Breast cancer may occur at any age, though the risk of breast cancer increases with age. The average woman at age 30 years has one chance in 280 of developing breast cancer in the next 10 years. This chance increases to one in 70 for a woman aged 40 years, and to one in 40 at age 50 years. A 60-year-old woman has a one in 30 chance of developing breast cancer in the next 10 years.

* White women are slightly more likely to develop breast cancer than African American women in the U.S.

* A woman with a personal history of cancer in one breast has a three- to fourfold greater risk of developing a new cancer in the other breast or in another part of the same breast. This refers to the risk for developing a new tumor and not a recurrence (return) of the first cancer.

Genetic Causes

Family history has long been known to be a risk factor for breast cancer. Both maternal and paternal relatives are important. The risk is highest if the affected relative developed breast cancer at a young age, had cancer in both breasts, or if she is a close relative. First-degree relatives, (mother, sister, daughter) are most important in estimating risk. Several second-degree relatives (grandmother, aunt) with breast cancer may also increase risk. Breast cancer in a male increases the risk for all his close female relatives. Having relatives with both breast and ovarian cancer also increases a woman's risk of developing breast cancer.

There is great interest in genes linked to breast cancer. About 5-10% of breast cancers are believed to be hereditary, as a result of mutations, or changes, in certain genes that are passed along in families.

* BRCA1 and BRCA2 are abnormal genes that, when inherited, markedly increase the risk of breast cancer to a lifetime risk estimated between 40 and 85%. Women with these abnormal genes also have an increased likelihood of developing ovarian cancer. Women who have the BRCA1 gene tend to develop breast cancer at an early age.

* Testing for these genes is expensive and may not be covered by insurance.

* The issues around testing are complicated, and women who are interested in testing should discuss this with their health-care providers.

Hormonal Causes

Hormonal influences play a role in the development of breast cancer.

* Women who start their periods at an early age (11 or younger) or experience a late menopause (55 or older) have a slightly higher risk of developing breast cancer. Conversely, being older at the time of the first menstrual period and early menopause tend to protect one from breast cancer.

* Having a child before age 30 years may provide some protection, and having no children may increase the risk for developing breast cancer.

* Oral contraceptives have not been shown to definitively increase or decrease a woman's lifetime risk of breast cancer.

* A large study conducted by the Women's Health Initiative showed an increased risk of breast cancer in postmenopausal women who were on a combination of estrogen and progesterone for several years. Therefore, women who are considering hormone therapy for menopausal symptoms need to discuss the risk versus the benefit with their health-care providers.

Lifestyle and Dietary Causes

Breast cancer seems to occur more frequently in countries with high dietary intake of fat, and being overweight or obese is a known risk factor for breast cancer, particularly in postmenopausal women.

* This link is thought to be an environmental influence rather than genetic. For example, Japanese women, at low risk for breast cancer while in Japan, increase their risk of developing breast cancer after coming to the United States.

* Several studies comparing groups of women with high- and low-fat diets, however, have failed to show a difference in breast cancer rates.

The use of alcohol is also an established risk factor for the development of breast cancer. The risk increases with the amount of alcohol consumed. Women who consume two to five alcoholic beverages per day have a risk about one and a half times that of nondrinkers for the development of breast cancer. Consumption of one alcoholic drink per day results in a slightly elevated risk.

Studies are also showing that regular exercise may actually reduce a woman's risk of developing breast cancer. Studies have not definitively established how much activity is needed for a significant reduction in risk. One study from the Women's Health Initiative (WHI) showed that as little as one and a quarter to two and a half hours per week of brisk walking reduced a woman's breast cancer risk by 18%.

Benign Breast Disease

* Fibrocystic breast changes are very common. Fibrocystic breasts are lumpy with some thickened tissue and are frequently associated with breast discomfort, especially right before the menstrual period. This condition does not lead to breast cancer.

* However, certain other types of benign breast changes, such as those diagnosed on biopsy as proliferative or hyperplastic, do predispose women to the later development of breast cancer.

Environmental Causes

Radiation treatment increases the likelihood of developing breast cancer but only after a long delay. For example, women who received radiation therapy to the upper body for treatment of Hodgkin disease before 30 years of age have a significantly higher rate of breast cancer than the general population.

Diagnosis

An abnormal area on a mammogram, a lump, or other changes in the breast can be caused by cancer or by other, less serious problems. To find out the cause of any of these signs or symptoms, a woman's doctor does a careful physical exam and asks about her personal and family medical history. In addition to checking general signs of health, the doctor may do one or more of the breast exams described below.

* Palpation. The doctor can tell a lot about a lump—its size, its texture, and whether it moves easily—by palpation, carefully feeling the lump and the tissue around it. Benign lumps often feel different from cancerous ones.

* Mammography. X-rays of the breast can give the doctor important information about a breast lump. If an area on the mammogram looks suspicious or is not clear, additional x-rays may be needed.

* Ultrasonography. Using high-frequency sound waves, ultrasonography can often show whether a lump is solid or filled with fluid. This exam may be used along with mammography.

Based on these exams, the doctor may decide that no further tests are needed and no treatment is necessary. In such cases, the doctor may need to check the woman regularly to watch for any changes. Often, however, the doctor must remove fluid or tissue from the breast to make a diagnosis.

Aspiration or needle biopsy. The doctor uses a needle to remove fluid or a small amount of tissue from a breast lump. This procedure may show whether a lump is a fluid-filled cyst (not cancer) or a solid mass (which may or may not be cancer). Using special techniques, tissue can be removed with a needle from an area that is suspicious on a mammogram but cannot be felt.

If tissue is removed in a needle biopsy, it goes to a lab to be checked for cancer cells. Clear fluid removed from a cyst may not need to be checked by a lab.

Surgical biopsy. The surgeon cuts out part or all of a lump or suspicious area. A pathologist examines the tissue under a microscope to check for cancer cells.

Pathogenesis/Pathophysiology

In a normal state, cells proliferate in response to external proliferation-promoting signals to fulfill a function such as replacing lost cells or repairing injured tissues. Once the goal has been reached, a set of proliferation-repressing signals is activated. These signals allow the cells to exit the proliferation cycle (cell cycle) by returning to the dormant state (G0), by differentiating, or by dying (apoptosis). Each of these functions is carried out by a complex system of interacting proteins. Constitutive expression by mutation or another genetic change of any component of the proliferation-promoting system may result in uncontrolled proliferation. The constitutively expressed component is called an oncogene.

Conversely, the loss by mutation or deletion of a proliferation-repressing gene results in an inability to stop the cell cycle and, thereby, continuous proliferation, possibly leading to cancer. The lost gene is called a tumor suppressor gene. Likewise, constitutive expression of antiapoptotic genes may result in immortalization of the cell, paving the way for further genetic changes and eventually cancer formation. Loss of proapoptotic genes may lead to similar results. Thus, autonomous proliferation and immortality shared by all cancers are the final result of successive genetic changes, which may be different from one cancer to another.

Breast cancer is not an exception in that regard. It is the result of multiple genetic changes that are different from those of other malignancies and that confer to this cancer its characteristic phenotype.

Cell-cycle deregulation in breast cancer

Estrogen and progesterone induce cyclin D1 and c-myc expression. Although both sex hormones provide directionality by shifting the CDKI p21 from CDK2 to CDK4, progesterone promotes maturation by inducing p27, while only estrogen allows multiple cycles. Recent studies have reported common amplification of cyclin D1 (a third of breast cancers), inactivation of p16, and mutation of TP53 in breast cancer.

c-myc overexpression is one of the most common genetic alterations encountered in persons with breast cancer (a third of patients). Depending on the availability of its different partners, it may result in proliferation and chromosomal instability (Myc-Max) or differentiation (Myc-Mad), probably by sequestering Myc and reducing its availability. Amplification of the c-myc gene is associated with a poor prognosis and a high S-phase.

Estrogen receptor (ER)–positive breast cancer cells undergo apoptosis after withdrawal of estrogen, suggesting that this hormone functions not only as a mitogen but also as a survival factor. The antiapoptotic factor Bcl-2 is commonly overexpressed in ER-positive breast cancers.

ER negativity is observed in a third of primary breast cancers and a third of recurrences of ER-positive primaries. The ER gene is usually intact with no identifiable deletions or mutations. Although the exact mechanism of this lack of expression is not known, hypermethylation used normally by the genome to silence certain genes is a possible explanation. Methylation of cytosine-rich areas (called CpG islands) of the ER-gene promoter region has been described in the majority of ER-negative breast cancers and in a small fraction of ER-positive breast cancers. Demethylation of these areas with specific agents (eg, 5-azacytidine) restores ER expression and its function in vitro.

A progesterone receptor (PR) is present in approximately 50% of all ER-positive tumors. Its presence depends on the expression of functional ER, which explains its absence in almost all ER-negative breast cancers. The mitogenic effect of progesterone in breast cancer may depend on the induction of local growth hormone production in the hyperplastic mammary epithelium. However, high doses of progestins have proven inhibitory effects on breast cancer growth mediated by the down-regulation of G1-phase CDKs and cyclin D1 leading to cell differentiation.

Regarding adhesion-dependent cell regulation, the transmembrane glycoproteins, ie, epithelial cadherins (E-cadherins), mediate with their extracellular domain cell-to-cell interactions, thus stabilizing the cell in the epithelial tissue. Their intracellular domain interacts with and controls the transcription factors B-catenins. A mutation or the absence of E-cadherins results in cell detachment, increased motility and invasiveness, and release of B-catenins, which up-regulates c-myc expression.

Expression of E-cadherins is down-regulated in breast cancer. Another family of adhesion molecules, the integrins, is involved in cell-to-matrix interactions. Integrins signal through the Fak-Src pathway, which activates PI3K and AKT, resulting in enhanced survival, proliferation, and motility. The main components of this pathway (Fak, PI3K, and AKT) are inhibited by PTEN (ie, phosphatase on chromosome 10 gene product, mutated in Cowden disease), which results in the suppression of survival and apoptosis.

The epidermal growth factor (EGF) receptor family plays a critical role in mammary tumorigenesis. Other than the EGF receptor itself, 3 other members of this family have been described, including c-erb-B2 (HER2, HER2/neu), c-erb-B3, and c-erb-B4; the latter is called a kinase-dead receptor because it does not carry a kinase function on the cytoplasmic domain of the receptor, which is in contrast to the other members of the family.

These receptors interact with many ligands, including EGF, transforming growth factor (TGF)–alpha, hergulin (or Neu differentiation factor), heparin-binding EGF-like growth factor, beta-cellulin, and epiregulin. Upon binding of a ligand with its cognate receptor, a homodimerization or heterodimerization process occurs, followed by autophosphorylation of the intracellular domain and activation of the intrinsic catalytic domain.

Transmission of the signal is operated via phosphorylation of adaptor proteins (GRB2-SOS, Shc, IRS-1/2, STAT) docked or recruited to the cytoplasmic domain of the receptor, followed by activation of the RAS-GTP protein, then 1 of 3 pathways to the nucleus (ie, Raf/MEK/ERK-1/2, MEKK1/MEK4/7/JNK, PI3K/AKT/GSK).

Transmission of the signal from adaptor proteins to the nucleus without mediation by RAS is possible through Fak/Src or Rho/Rac/CDC42 pathways. In addition, phospholipase C-gamma is activated by direct interaction with the phosphorylated c-erb-B-2; however, its intracellular pathway is not fully known. The final result is the induction of transcription factors (ie, Myc, NF-kB, ATF, Ets, AP-1, EIK, SRF) that drive the cell cycle by up-regulating cyclins and inhibiting CDKIs and proapoptotic signals.

Once the biological message has been executed, the complex ligand receptor is internalized and destroyed in the lysosomes. The pattern of heterodimerization, the intracellular pathway used, and the rate of internalization and destruction of the receptor depend on the specific ligand bound to the receptor.

Although c-erb-B2 does not have a specific ligand, its role in the signal transmission from the epidermal growth factor receptor is crucial. Cell lines lacking c-erb-B2 are resistant to the tumorigenic effect of EGF, while those with a kinase-deficient or carboxyl terminal–truncated EGF receptor with intact c-erb-B2 can still execute all the functions of the wild type.

The discovery of the role of HER2 in breast cancer was one of the landmarks in breast cancer research in the last 2 decades. HER2 is overexpressed in 20-30% of breast cancers. Tumor cells overexpressing HER2/neu may have up to 2 million copies of the receptor on their surface compared with 20,000-50,000 copies in normal breast epithelial cells. Because of this abundance of HER2/neu, many heterodimers contain HER2/neu, resulting in potent intracellular signaling and malignant growth.

Despite persistent controversy regarding certain aspects of its biology, prognostic value, and methods of evaluation, HER2 overexpression or amplification is generally accepted to be correlated with a high histologic grade, the absence of hormone receptor expression, aneuploidy, a high proliferation index, tumor size, and a poor clinical outcome. Its role as a predictor of response to chemotherapy and hormonal therapy (HT) is not clearly defined.

Certain clinical studies using tamoxifen showed not only a lack of response, but also a detrimental effect in the group of patients overexpressing HER2. Retrospectively reviewed chemotherapy data showed longer disease-free survival and overall survival in HER2 overexpressors who received high doses of doxorubicin-containing chemotherapy compared with HER2-negative patients. Available data concerning the interaction between cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy and HER2 overexpression are inconclusive and do not allow the formation of final conclusions. Taxanes seem to have high efficacy in patients overexpressing HER2 (relative risk, 65%) compared with the HER2-negative group (relative risk, 35%).

The IGF family consists of IGF-1, IGF-2, IGF receptor-1, IGF receptor-2, and IGF-binding proteins. The members of this family play an important role in normal mammary development and tumorigenesis. Both IGF-1 and IGF-2 bind to IGF receptor-1, whose strong mutagenic effect is synergistic with estrogen. In breast cancer, IGF receptor-1 and IGF-1 and IGF-2 are overexpressed in epithelial cells and stromal cells, respectively. Paradoxically, this overexpression correlates with a good prognosis, perhaps reflecting simple hormone dependence or association. IGF receptor-2 plays a tumor-suppressing role by down-regulating IGF-2.

The TGF-beta family consists of 3 TGF-beta and 2 interdependent serine-threonine kinase receptors. In normal mammary epithelial cells, TGF-beta blocks the expression of cyclin A, an S-phase–promoting protein and (to a lesser degree) cyclins D and E involved in the G1 phase and induces the expression of the CDKI p15, which results in cell-cycle arrest and, potentially, apoptosis. This explains its role in postlactational mammary gland regression.

Expression of TGF-beta in breast cancer is increased and seems to correlate with disease progression rather than tumor suppression. Mutation of TGF-beta receptors (type I and II) or any of the downstream molecules (Smad4) involved in intracellular signal transduction renders breast cancer cells resistant to its suppressive effects. However, its role in promoting angiogenesis and invasion and in suppressing the immune system becomes advantageous for the cancer cells, which acquire a proliferative advantage by losing sensitivity to TGF-beta and developing a way to escape the host immunosurveillance.

Mutated BRCA1 and BRCA2, breast cancer susceptibility genes, are proven risk factors for breast cancer. More than 500 mutations have been described in the BRCA1 gene (band 17q21), and 250 have been described in the BRCA2 gene (band 13q12-13). The mutations occurring at either end of the BRCA1 gene are associated with more aggressive tumors; those occurring at the 5` extremity are associated with breast and ovarian cancers, while those closer to the 3` end are associated with only breast cancer.

The biological function of the BRCA1 gene product is not well known. Accumulated evidence suggests that BRCA1 is a nuclear protein involved in other genes' expression, in cell cycle progression, and in the response to DNA damage. DNA damage results in activation and interaction of BRCA1, BRCA2, RAD51, and TP53 with subsequent expression of p21, which leads to a cell cycle pause until the damage is repaired. The mutation or absence of BRCA1 results in failure to repair the damaged DNA, and the cell cycle continues to accumulate further mutations, eventually leading to tumorigenesis. BRCA2 seems to play a role similar to that of BRCA1 in the cell cycle, other genes' expression, and DNA damage repair.

Prevention

The most important risk factors for the development of breast cancer are sex, age, and genetics. Because women can do nothing about these risks, regular screening is recommended in order to allow early detection and thus prevent death from breast cancer.

Regular screening includes breast self-examination, clinical breast examination, and mammography.

Breast self-examination (BSE) is cheap and easy. Routine monthly examination may be helpful. Previously considered critical, more recent studies suggest that self breast exam may be less valuable than previously thought, especially for women who are having routine clinical breast examination and/or mammography.

* For women who are menstruating, the best time for examination is immediately after the monthly period.

* For women who are not menstruating or whose periods are extremely irregular, picking a certain date each month seems to work best.

* Instruction in the technique of breast self-examination can be obtained from your health-care provider or from any one of several organizations interested in breast cancer.

Clinical breast examination: The American Cancer Society recommends a breast examination by a trained health-care provider once every three years starting at age 20 years, and then yearly after age 40 years.

Mammograms are recommended every one to two years starting at age 40 years. For women at high risk for the development of breast cancer, mammogram screening may start earlier, generally 10 years prior to the age at which the youngest close relative developed breast cancer.

Obesity after menopause and excessive alcohol intake may increase the risk of breast cancer slightly. Physically active women may have a lower risk. All women are encouraged to maintain normal body weight, especially after menopause and to limit excess alcohol intake. Hormone replacement should be limited in duration if it is medically required.

In women who are genetically at high risk for the development of breast cancer, tamoxifen has been shown to significantly decrease the incidence of the disease. Side effects should be carefully discussed with your health-care provider prior to embarking on therapy. A second drug, raloxifene (Evista), which is now being used for the treatment of osteoporosis, also blocks the effects of estrogen and appears to prevent breast cancer. Initial studies showed that both tamoxifen and raloxifene were able to reduce the risk of invasive breast cancer, but raloxifene did not have this protective effect against noninvasive cancer. Studies are ongoing to further characterize the effectiveness and indications for use of raloxifene as a breast cancer preventive drug.

Occasionally, a woman at very high risk for development of breast cancer will decide to have a preventive or prophylactic mastectomy to avoid developing breast cancer. Additionally, removal of the ovaries has shown to reduce the risk of developing breast cancer in women who have the BRCA1 mutation and who have their ovaries surgically removed before they reach age 40.

Treatment

The mainstay of breast cancer treatment is surgery when the tumor is localized, with possible adjuvant hormonal therapy (with tamoxifen or an aromatase inhibitor), chemotherapy, and/or radiotherapy. At present, the treatment recommendations after surgery (adjuvant therapy) follow a pattern. This pattern is subject to change, as every two years, a worldwide conference takes place in St. Gallen, Switzerland, to discuss the actual results of worldwide multi-center studies. Depending on clinical criteria (age, type of cancer, size, metastasis) patients are roughly divided to high risk and low risk cases, with each risk category following different rules for therapy. Treatment possibilities include radiation therapy, chemotherapy, hormone therapy, and immune therapy.

In planning treatment, doctors can also use PCR tests like Oncotype DX or microarray tests like MammaPrint that predict breast cancer recurrence risk based on gene expression. In February 2007, the MammaPrint test became the first breast cancer predictor to win formal approval from the Food and Drug Administration. This is a new gene test to help predict whether women with early-stage breast cancer will relapse in 5 or 10 years, this could help influence how aggressively the initial tumor is treated.

Also see.

Complications

The list of complications that have been mentioned in various sources for Breast Cancer includes:

Complications and sequelae of Breast Cancer include:

* Cachexia
* Cerebral metastases
* Lymphangitis carcinomatosa
* Breast lump
* Opsoclonus
* Lung metastases
* Brachial plexus neuropathy
* Back pain
* Liver metastases
* Bone metastases
* Prostate specific antigen levels raised (plasma or serum)
* Bone pain
* CEA raised
* Renal metastases
* Mastalgia
* Pleural effusion
* Lymphadenopathy
* Leucoerythroblastic anemia
* Cutaneous metastasis
* Osteosclerosis
* Nipple discharge

References

http://www.wikipedia.org
Served as primary source.

http://www.emedicinehealth.com
Served as secondary source.

http://healthlink.mcw.edu
Served as extra reference.

http://www.emedicine.com
Provided information on Pathogenesis/Pathophysiology.

http://www.wrongdiagnosis.com
Provided extra information and reference.