Metformin May Be Key to Preventing Colorectal, Other Cancers

The first human trial of metformin for precancerous colorectal lesions hints that the diabetes drug may be poised for a second incarnation – this time as a chemopreventive agent for several cancers, including lung, colon, and prostate cancers, and even breast malignancies.

The small study, published in the September issue of Cancer Prevention Research, found that after 1 month of oral metformin, nondiabetic patients who already had at least one colorectal adenoma removed experienced a significant reduction in their number of colorectal aberrant crypt foci – an endoscopic finding that some consider a precursor of adenomatous colon polyps.

A second study, published in the same issue of the journal, found that mice who received the drug after exposure to a potent lung carcinogen developed significantly fewer lung tumors than did those who received a placebo.

In light of these data, physicians may want to look closely at metformin when choosing an oral antidiabetic agent for their patients, Dr. Phillip Dennis of the National Cancer Institute said during a press briefing Sept. 1.

“It’s true that we don’t have an indication for metformin as a cancer chemopreventive,” said Dr. Dennis, lead author of the mouse study. “But a clinician who has four different oral agents for diabetes has to make a choice for his patients, and in that process, this early evidence that metformin may have an oncologic benefit will certainly play a role.”

A growing body of data suggests that metformin reduces the risk of several types of cancer, but thus far the only human evidence had come from observational studies of patients with diabetes. Three epidemiologic studies suggest that metformin decreases the incidence of cancer and cancer-related deaths in diabetic patients by 15%-77% (Euro. J. Cancer 2010;46:2369-2380). In vitro and animal studies suggest similar reductions.

The study released today shows the drug’s potential not only to reduce the number of precancerous lesions, but also to decrease the level of proliferating cell nuclear antigen (PCNA), a marker of tumor virulence, wrote Dr. Kunihiro Hosono of the Yokohama City University School of Medicine, Japan, and colleagues: “This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal aberrant crypt foci, suggesting its promise for the chemoprevention of colorectal cancer” (Cancer Prev. Res. 2010;3:1077-83).

The murine study examined metformin’s potential to prevent lung cancers. Mice that had been exposed to tobacco carcinogens and consumed or were injected with metformin had up to 72% fewer lung tumors than did placebo-treated mice, reported Dr. Dennis and his colleagues (Cancer Prev. Res. 2010;3:1066-76).

Although the new data are exciting, metformin is not ready to grab the spotlight, Dr. Ernest Hawk cautioned in an interview.

“The story is quite compelling, suggesting that metformin may have a role in therapy or in maintenance treatment for cancer survivors,” said Dr. Hawk, division head of Cancer Prevention and Population Sciences at the University of Texas M.D. Anderson Cancer Center, Houston. “Before we make any assumptions, though, we need many more trials to figure out if it will live up to the potential it seems to have.”

The Japanese study included 23 nondiabetic patients who had an average of five adenomas removed during a screening colonoscopy. Nine of the patients were treated with 250 mg/day of metformin for 1 month; the remaining 14 did not receive any treatment.

At baseline, the 23 patients had a mean of eight aberrant cryptal foci (ACF). “ACF are tiny lesions that develop in the earliest stage of colorectal carcinogenesis and consist of large, thick crypts,” Dr. Hosono and his team wrote. “ACF have been shown to be precursor lesions of the adenoma-carcinoma sequence in humans, and have been suggested as a suitable surrogate end point for colorectal chemoprevention.”

After the treatment period, patients were examined again; ACF were detected by methylene blue staining of rectal mucosa. The number of lesions decreased significantly in the active group, from a mean of nine per patient to six (P = .007). There was no change in the untreated group (mean of seven at each exam). The mean number of ACF considered dysplastic also decreased significantly in the treated group, while again, there was no change in the untreated group. The drug also proved safe, with no patient experiencing hypoglycemia.

The researchers also examined rectal epithelial proliferation by proliferative cell nuclear antigen (PCNA) immunoassay. The PCNA index decreased significantly in the treated group but remained steady in the untreated group. However, the drug did not affect the percentage of cells undergoing apoptosis.

Dr. Hawk, who is also the T. Boone Pickens Distinguished Chair for Early Prevention of Cancer at M.D. Anderson, cautioned against overinterpreting the results. The short duration and small study size should temper enthusiasm somewhat – as should the debate about whether ACF are indeed precursors of colorectal cancer and whether affecting them in any way eventually affects cancer risk.

“Frankly, the Japanese are very good at these ACF studies. And while they have been very reproducible in animal models, human results have been much more difficult to confirm. A number of American investigators have tried to replicate earlier Japanese ACF studies using aspirin, a known colorectal cancer chemopreventive agent, and have not been able to get the same results.”

It’s unclear whether the difference lies in the treatment time, study design, or even the basic differences between a homogeneous Japanese population and the typical heterogeneous American study group, Dr. Hawk said. “Whatever it is, whether the results can be reproduced is the most important question.”

While larger studies are necessary to discover the unknowns of metformin, he said, the drug already has a lot going for it terms of the known. “We have so much data on metformin, and it has such a strong track record of safety, that I believe it’s an agent worth exploring.”

A review co-released with the studies suggested that metformin may be a more effective chemopreventive agent in patients with hyperinsulinemia. “There is evidence indicating that the growth of untransformed epithelial cells and a subset of cancers is stimulated by insulin, and that the systemic insulin-lowering action of metformin might inhibit the proliferation of these cancers,” wrote Dr. Michael Pollak of McGill University and Jewish General Hospital, Montreal. Cancers stimulated by insulin include endometrial, cervical, breast, and prostate cancers, as well as lung and colorectal malignancies. “This action of metformin shares mechanistic features with the manner by which caloric restriction inhibits the growth of certain cancers,” he said (Cancer Prev. Res. 2010;3:1060-5).

If Dr. Pollak’s theory is correct, Dr. Hawk said, metformin or other biguanides may help stem the flood of obesity- and diabetes-related cancers that researchers have predicted for several years. A recent study concluded that obesity could soon become the leading cause of cancer in women – possibly overtaking smoking as the leading cause (Int. J. Cancer 2010;126:692-702).

“The rise of diabetes-related cancer speaks to the importance of pursuing this investigation vigorously,” Dr. Hawk said. “We know that this is a problem of enormous impact for our future.”

Two Combination Therapies Work Equally Well to Reduce Acne

Combination topical tretinoin and clindamycin was as effective as combination salicylic acid and clindamycin for reducing lesions in patients with mild to moderate acne, based on data from a 12-week randomized trial.

The findings were published online July 28 in the Journal of the European Academy of Dermatology and Venereology.

Several types of combination treatments allow clinicians to target different causes of acne vulgaris, but the safety and efficacy of tretinoin/clindamycin phosphate and salicylic acid/clindamycin phosphate have not previously been compared, according to Dr. A. Babayeva of Dokuz Eyll University in Izmir, Turkey, and colleagues.

Researchers randomized 46 acne patients aged 18-31 years to one of the two combination therapies: 3% salicylic acid plus clindamycin phosphate 1% lotion (SA/CDP) or all trans retinoic acid 0.05% cream plus clindamycin phosphate 1% lotion (all-TRA/CDP). The average lesion count at baseline was 67 in both groups, and the proportion of inflammatory and noninflammatory lesions was similar between the groups (J. Eur. Acad. Dermatol. Venerol. 2010 July 28 [doi:10.1111/j.1468-3083.2010.03793.x]).

After 12 weeks, the average total lesion count was 13 in the SA/CDP group and 10 in the all-TRA/CDP group; the difference was not statistically significant. The average inflammatory and noninflammatory lesion counts were not significantly different between the two groups (5 vs. 4 and 8 vs. 6, respectively).

After 2 weeks of treatment, significantly more patients in the all-TRA/CDP group showed a 50% reduction in total lesion counts, compared with the SA/CDP group, but there were no significant differences in lesion counts between the groups when patients were assessed after 4, 8, and 12 weeks of treatment, according to the investigators.

All reported side effects were mild to moderate, and most occurred during the first 2 weeks of treatment. The most common reported side effects were dryness, peeling, erythema, burning, and itching. The proportion of patients reporting at least one side effect was similar between the SA/CDP and all-TRA/CDP groups (83% vs. 74%).

Although the efficacy of the all-TRA/CDP was higher in the first 2 weeks, the end results were similar, suggesting SA/CDP can be an effective alternative to all-TRA/CDP, the researchers found. The results support data from previous studies, and they suggest that CDP can help reduce the irritation associated with all-TRA.

Serotonin a Possible Marker for Decompensated Heart Failure

SAN DIEGO – Plasma levels of serotonin were significantly elevated in patients with decompensated systolic heart failure, compared with patients in the compensated state and with normal controls, according to a single-center study.

The finding suggests that that serotonin has an active role in the progression of heart failure, researchers led by Dr. Ahmed M. Selim reported Sept. 15 during a poster session at the annual meeting of the Heart Failure Society of America.

“More studies should be done to test the sensitivity, specificity, and prognostic value of serotonin as a marker for congestive heart failure and also to investigate the therapeutic benefits of the medications affecting this pathway,” wrote the researchers from the department of cardiology at Albert Einstein College of Medicine, New York.

They noted that, while the relationship between heart failure and the serotoninergic system has been established in previous research, fluctuations in serotonin levels during the course of the disease and its correlation with exacerbation of heart failure have never been tested.

Dr. Selim, a heart failure research fellow, and his associates collected plasma serotonin levels from 29 patients who were admitted with decompensated heart failure, 61 patients with stable heart failure, and 22 normal controls. They excluded patients receiving medications affecting serotonin receptors and those with pulmonary hypertension. All heart failure patients were on stable doses of heart failure medications and had left-ventricular ejections fractions of 40% or less, while normal controls had a mean ejection fraction of 59%.

Overall, the mean age of patients was 55 years, and 62% were male.

The researchers reported that the mean serotonin level in the control group was 2.4 ng/mL, compared with 4.1 ng/mL in the compensated group and 11.8 ng/mL in the decompensated group. This was independent of age, race, renal function, diabetes mellitus, and hypertension. “All results were highly significant,” the researchers wrote.

Dr. Selim and his associates stated that they had no relevant financial disclosures to make.

Male Menopause: Fact or Fiction?

An upsurge in media attention recently regarding the so-called "male menopause" has left many men rushing to their doctor to treat symptoms they believe may be related to low levels of testosterone. The concept behind the concept of male menopause is that the decline in testosterone levels that occurs as men age may produce a characteristic and potentially treatable set of symptoms. Male menopause is also commonly referred to as low-T, andropause, or its medical name, late-onset hypogonadism.

However, some medical experts argue that the analogy to the process in women (with some authors even using terminology like "male PMS") has been carried too far. While it is true that testosterone levels do decline as a man ages, the decline in female hormones occurs to a much greater extent. Moreover, the symptoms in women associated with decreased estrogen levels are clearly understood.

In contrast, symptoms of what is referred to as male menopause are less clearly defined. Sexual dysfunction is a common complaint, but other nonspecific symptoms such as depression, mood changes, weight gain, or fatigue, have been interpreted by some as symptoms of a male midlife change. Although many doctors have treated midlife symptoms in men with testosterone hormone therapy, the value of male hormone therapy remains controversial because there are few long-term studies about the effects or benefits of testosterone supplementation.

Still, prescriptions for testosterone are on the rise, even if doctors don't yet agree on whether or not this therapy should be recommended.

In 2006, the Endocrine Society published evidence-based guidelines for testosterone replacement therapy in men. Specifically, for men who do not have testicular or pituitary disease, these experts recommend testosterone therapy only for men with definite and reproducibly low serum testosterone concentrations (<200 ng/dL) who have symptoms of androgen deficiency (symptoms of deficient blood levels of testosterone hormone).

As with any therapy, doctors will discuss the uncertainty about the risks and benefits of testosterone therapy. Experts further recommend that the therapeutic goal in these men is to reach a testosterone level that is lower than that for younger men, for example, 300 to 400 ng/dL, rather than 500 to 600 ng/dL, to minimize the potential risk of developing any testosterone-dependent diseases.

Magnet Treatment May Help Stroke Patients

 Researchers in Egypt say a non-invasive type of brain stimulation involving magnets could be a useful treatment for patients partially paralyzed by stroke.

Repetitive transcranial magnetic stimulation (rTMS) is mostly used for depression, with some studies finding it to be a beneficial treatment and others showing little benefit.

The technique involves the use of electromagnets positioned strategically on the head to create a magnetic field that sends tiny electric currents into the brain.

The study is among the first to examine rTMS as a treatment for ischemic stroke-related weakness.

Sixty patients with mild to moderate muscle weakness on one side of the body were recruited for the study within one- to 36-months after having strokes.

Twenty patients had high frequency (5-Hz daily) rTMS sessions for 10 consecutive days, while 20 others had 10 daily treatments at a lower frequency (1-Hz daily). An additional 20 patients unknowingly received sham treatments with no brain stimulation. All 60 patients received the same physical therapy, which included rehabilitation sessions developed by the researchers to stimulate hand movement.

Patient improvement was recorded over 12 weeks. The researchers used several accepted measures of stroke improvement, including a standardized test known as the thumb-index finger-tapping test.

Both of the rTMS treatment groups showed statistically significant improvement in finger-tapping ability over the course of the observation period, but no improvement was seen in the sham-treatment group.

Researcher Anwar Etribi, who is emeritus professor of neurology at Cairo's Ain Shams University, says the treatment may work by restoring balance to the brain.

"We believe that people develop partial paralysis down one side after they have a stroke because the hemispheres of the brain become unbalanced," Etribi explains in a news release. "The hemisphere that has not been affected can become overactive, while the damaged hemisphere can become inhibited."

Close to 800,000 people in the U.S. have strokes each year. Nine out of 10 of these are ischemic strokes, which occur when blood vessels become blocked and deprive the brain of blood and oxygen.

Weakness is common on one or both sides of the body in people who survive strokes, and useful therapeutic approaches to help patients regain motor function are badly needed, says American Heart Association spokesman Daniel Lackland, MD.

Lackland is a professor in the department of neurosciences at the Medical University of South Carolina in Charleston.

He tells WebMD the study failed to convince him that rTMS has a place in the rehabilitation of stroke patients.

"This is a small, pilot study and the outcomes they reported were minimal," he says. "I'm not sure too many people in the field will be excited about such a complex treatment with minimal effects."

The study appears in the September issue of the European Journal of Neurology. In an email to WebMD, Etribi said the research was paid for by Ain Shams University, with no public grants or industry funding.

Anemia Drugs Could Pose Threat to Some Kidney Patients

 When people with chronic kidney disease and type 2 diabetes take certain anemia drugs, the level of hemoglobin cells in their blood should go up.

Reporting in the Sept. 16 issue of the New England Journal of Medicine, a team of international researchers says that those who had the worst response to erythropoiesis-stimulating agents (ESAs) -- drugs that include Aranesp, Epogen and Procrit -- had a 31% rise in the risk of cardiovascular complications and a 41% increased risk of death.But a new study finds that if those levels don't increase by much, these "poor responders" experience a significantly increased risk of heart problems and death.

"For people who have chronic kidney disease, I think this is further evidence that we have to be extremely cautious when we use ESAs. There is a potential for harm. The patients who respond poorly are the ones who get the most drug, and we may be putting them at increased risk," said the study's lead author, Dr. Scott Solomon, director of noninvasive cardiology at Brigham and Women's Hospital and an associate professor of medicine at Harvard Medical School in Boston.

"What we can't determine from this study is if these patients had worse outcomes because they were sicker to begin with, or because they got more of the drug, or some combination of the two," added Solomon.

When someone has kidney disease, the kidneys may not produce enough of the hormone erythropoietin to prevent anemia, a deficiency in red blood cells. Symptoms of anemia include fatigue and pale skin, and it can even contribute to heart disease, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases.

ESAs were developed to replace the missing erythropoietin in kidney patients and stimulate red blood cell production. But these drugs can cause serious, even life-threatening complications in some patients. Because of this, the U.S. Food and Drug Administration requires manufacturers to include a warning about the risks.

The current study is a secondary analysis of a randomized, double-blind, placebo-controlled study done in 24 countries from 2004 to 2009. All of the study volunteers -- 1,872 in all -- had type 2 diabetes and chronic kidney disease.

The study volunteers were randomly assigned to receive either 0.75 micrograms of darbepoietin alfa (Aranesp) per kilogram of body weight or a placebo. In people who didn't respond well to the initial dose of the drug, the dose was repeated after two weeks. After that, hemoglobin levels were monitored and doses adjusted based on an individual's hemoglobin levels, reported the study.

In the initial analysis of these study volunteers, the researchers found no reduction in the risk of death or of cardiovascular or kidney problems in those taking the drug compared to those on placebo. But they did see a significant increase in the risk of stroke. Solomon said there was only a slight, "unimpressive" increase in quality of life for those taking the ESA.

At the same time, other studies have been finding an increased risk of heart problems in people taking ESAs. Solomon's team wanted to know why some people might be at greater risk than others.

In a sub-analysis of the initial study, they divided the group into four smaller groups based on their response to darbepoietin alfa, which is how they found the increased risk of death and cardiovascular events in people who responded poorly to the drug.

Solomon said he thinks this effect would likely be seen in other ESAs, not just darbepoietin alfa. Amgen, the maker of Aranesp, provided funding for the study.

"This study helps clarify some of the confusion from previous studies. When you isolate who are the people who got into trouble, it was people who wouldn't respond to ESAs. I think it helps clarify how to use ESAs. If I see that you don't respond, there may be something else going on with you, and I need to give you some special attention because you're at greater risk of having a bad outcome," said Dr. Robert Provenzano, chair of the department of nephrology at St. John Providence Health System in Detroit.

But, if you respond normally to ESAs, he said, the drugs may improve your quality of life when the medication is adjusted to keep your hemoglobin levels between 10 and 12.5 mg/dL.

Solomon said he wasn't sure if the modest benefit seen in patients was worth the potential increase in stroke risk. Provenzano countered that such a decision needs to be individualized based on the effects of the anemia, along with other aspects of the patient's life.

If you take this medication, Provenzano suggested asking your doctor where you fall on the continuum of response and whether you're in a high-risk group.

Research Sheds Light on Why Autism Is More Prevalent in Boys

 A new study is helping unravel an enduring mystery surrounding autism: Why boys are much more likely to be affected by the disorder than girls.

Reporting in the Sept. 16 issue of Science Translational Medicine, the team found that mutations in the PTCHD1 ("patched") gene are linked to inherited forms of autism and intellectual disability in about 1% of affected people in the study. It was not found in any of the controls, however.An international team led by Dr. John Vincent, of the Centre for Addiction and Mental Health in Toronto, examined specific genes in almost 3,000 people with an autism spectrum disorder (ASD) and 246 others with intellectual disability. They then compared that data to genes from more than 10,000 control individuals.

"Our data indicate that mutations at the PTCHD1 locus are ... strongly associated with ASD," the researchers concluded.

They also noted that this gene is typically located on the single X-chromosome in males.

The study "provides further clues as to why ASD affects four times more males than females," said Andy Shih, vice president for scientific affairs at Autism Speaks. "PTCHD1 is part of a neurobiological pathway that determines the development of human embryos. It is one of several genes recently implicated in both ASD and intellectual disabilities."

The finding adds a little more clarity to the murky origins of autism, Shih said.

While each new genetic discovery "may only account for a small fraction of the cases, collectively they are starting to account for a greater percentage of individuals in the autism community, as well as providing insights into possible common pathogenic mechanisms," he said. "Identification of a male-linked genetic mutation begins to address the previously unknown basis for often reported skewed male-to-female ratio in autism."

Why Older People Are Forgetful

Abnormal brain tissue changes called brain lesions may be more at fault than previously thought in forgetfulness in older people, new research shows.

Scientists at Rush University Medical Center in Chicago say the same brain lesions that are associated with dementia in old age may be responsible for mild memory loss.

The researchers studied 350 Catholic nuns, priests, and brothers who were given memory tests annually for up to 13 years, and after death, had their brains examined for lesions.

The study found that memory decline tended to be gradual before speeding up in the last four or five years of life.

Researchers say they found that strokes as well as protein accumulations called tangles and Lewy bodies seemed to be related to memory loss in older people.

They report that minimal gradual memory declines were seen in the absence of tangles, while Lewy bodies and strokes doubled the rate of gradual memory loss.

Tangles and Lewy bodies were found to be associated with rapid memory decline but explained only about a third of the memory loss.

“It appears these brain lesions have a much greater impact on memory function in old age than we previously thought,” study author Robert S. Wilson, PhD, of the Rush University Medical Center, says in a news release. “Our results challenge the concept of normal memory aging and hint at the possibility that these lesions play a role in virtually all late-life memory loss.”

The subjects, for up to 13 years, had memory tests that involved word recall, naming, verbal, number, and reading assignments, and all had agreed to autopsies so that their brains could be studied.

“Understanding how and when these brain lesions affect memory as we age will likely be critical to efforts to develop treatments that delay memory loss in old age,” Wilson says.

The researchers conclude that mild age-related declines in cognitive function are mainly the result of the lesions that traditionally are associated with dementia, but there are other causes as well.

They say their findings indicate that brain lesions associated with dementia are mainly responsible for gradual age-related cognitive decline that precedes dementia,Alzheimer's disease, and related disorders.

The lesions, they write, apparently “have a much greater impact on late-life cognitive functioning than previously recognized.”

The authors say that better understanding of individual differences of memory loss and early changes in the buildup of proteins may offer hope and new strategies for delaying the start of dementia's symptoms.

The study is published in the Sept.15, 2010 online issue of Neurology, the medical journal of the American Academy of Neurology.