Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12.

M. Gnant, B.
08 june 2008--Background: Zoledronic acid (ZOL) has demonstrated antitumor and antimetastatic activity in preclinical and early clinical studies. The Austrian Breast and Colorectal Cancer Study Group Trial 12 (ABCSG-12) examined the efficacy of ovarian suppression using the gonadotropin-releasing hormone analogue goserelin in combination with anastrozole (ANA) or tamoxifen (TAM) ± ZOL in premenopausal women with endocrine-responsive breast cancer (BC). Methods: 1,801 premenopausal women with endocrine-responsive BC were randomized to goserelin (3.6 mg q 28 d SC) and TAM (20 mg/d PO) ± ZOL (4 mg IV q 6 mo) or goserelin and ANA (1 mg/d PO) ± ZOL for 3 yr. Primary endpoint was disease-free survival (DFS) for both the comparison of TAM vs ANA and ZOL vs no ZOL, respectively. Relapse-free survival (RFS) and overall survival (OS) were secondary endpoints. Exploratory endpoints included bone-metastases-free survival and safety. Results: With median follow-up of 60 mo (March 31, 2008), 137 (7.6%) DFS events and 42 (2.3%) deaths have occurred. There was no significant difference in DFS between patients who received TAM alone vs ANA alone (HR = 1.10 [95% CI = 0.79, 1.54]; P = 0.59). However, endocrine therapy plus ZOL significantly reduced the risk of DFS events by 36% compared with endocrine therapy alone (HR = 0.64 [0.46, 0.91]; P = 0.01). The addition of ZOL significantly reduced the risk of RFS events by 35% (HR = 0.65 [0.46, 0.92]; P = 0.015) compared with endocrine therapy alone. For OS, there was a nonsignificant trend favoring ZOL treatment (HR = 0.60 [0.32, 1.11]; P = 0.10). Treatment was generally well tolerated among the 4 groups and consistent with known safety profiles of the drugs. Conclusions: There was no significant difference in DFS between TAM and ANA. The addition of ZOL (4 mg q 6 mo) to adjuvant endocrine therapy significantly prolonged DFS and RFS compared with adjuvant endocrine therapy alone in premenopausal women with endocrine-responsive BC. This large clinical trial demonstrates that the antitumor activity of adjuvant ZOL improves outcomes beyond the effect of endocrine therapy alone.

Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG).

C. J. Punt
08 june 2008--Background: Cetuximab, a chimaeric monoclonal antibody against the epidermal growth factor receptor (EGFR) has shown efficacy in patients (pts) with ACC. Preclinical and early clinical studies suggest a benefit for combining VEGF and EGFR targeting agents in ACC. The CAIRO2 study was designed to investigate the effect of adding cetuximab to capecitabine and oxaliplatin (CapOx) and bevacizumab in ACC. Methods: Previously untreated pts were randomized between capecitabine 1,000 mg/m² orally b.i.d. day 1-14, oxaliplatin 130 mg/m² i.v. day 1, and bevacizumab 7.5 mg/kg i.v. day 1 (arm A) or the same schedule plus cetuximab 400 mg/m² i.v. in week 1, cycle 1, and 250 mg/m² i.v. weekly thereafter (arm B). All cycles were given q 3 weeks. The primary endpoint was progression-free survival (PFS). Response was assessed q 3 cycles (RECIST). The study was designed to detect an increase in the median PFS of 3 months from 11 to 14 months (21% reduction in the hazard ratio of progression, HR=0.79). Results: A total of 755 patients, WHO PS 0-1 and median age 62 yrs (range 27-83), were randomized between June 2005 and December 2006. Of 736 eligible pts, 730 patients started protocol treatment with a median number of cycles of 10 (range 1-39) in arm A and 9 (range 1-40) in arm B. At the time of this analysis, median follow-up is 14.7 months (range 4-28 months) with 140 patients (19%) still receiving treatment. Reasons for end of treatment did not differ between treatment arms, and 28% of pts in arm A and 30% of pts in arm B discontinued treatment for reasons of toxicity. Grade 3-4 toxicity occurred in 71.8% (arm A) and 81.9% (arm B, p=0.0012). Excluding cetuximab-related skin toxicity resulted in similar rates: 71.8% (arm A) and 74.5% (arm B, p=0.40). Most frequent grade 3-4 toxicities in arm A vs B were diarrhea (19.2 vs 25.8%), fatigue (12.6% vs 15.3%), hypertension (13.7% vs 8.8%), nausea (8.5 vs 6.3%), sensory neuropathy (9.6% vs 7.9%), acneiform rash (0.5% vs 25.2%) and hand-foot skin reaction (18.4% vs 18.1%). A total of 554 progressions or deaths were observed: 264 in arm A and 290 in arm B. Median PFS was 10.7 months (CI: 9.7;12.5) in arm A and 9.8 months (CI: 8.6;10.7) in arm B (p=0.019, HR 1.22 (1.03;1.44). Response rates (PR + CR) were 40.6% (CI: 34.5;46.9) vs 43.9% (CI: 37.8;50.1, p=0.44 ), median OS 20.4 (CI: 18.1;26.1) months vs 20.3 months (CI: 17.9;21.6, p=0.21), and 60-day mortality 1.9% vs 2.4%. Conclusions: The combination of both antibodies, cetuximab and bevacizumab, to CapOx results in a significant decrease in PFS compared to bevacizumab and CapOx. Besides skin toxicity, cetuximab did not add additional toxicity to CapOx and bevacizumab. Updated results will be presented at the meeting, including data on KRAS in relation to outcome of treatment.

Pfizer Defends Beleaguered Varenicline (Chantix)

By Todd Neale
NEW YORK, 08 june 2008-- With its antismoking drug varenicline (Chantix) under a cloud for allegedly sparking suicidal behavior and ideation, Pfizer took its case to the press today, defending the agent as contributing far more benefit than potential harm.
Apparently stung by an FDA warning, followed by a ban of use of the drug by pilots and flight controllers issued by the Federal Aviation Administration, the company invited journalists to what it called a roundtable discussion to set the record straight.
At the session, three of Pfizer's senior officers sought to explain the occurrence of the adverse events, compare them with the benefits of quitting smoking, and explain how Pfizer is responding. Also attending was a clinical investigator who took part in a phase III trial of varenicline.
In February, the FDA warned of mood swings and suicidal behavior in patients taking varenicline, but maintained that it was effective as a medication for quitting smoking. (See: FDA Warns of Mood Swings and Suicides With Smoking-Cessation Drug)
The drug works by partially blocking the alpha4-beta2 nicotinic acetylcholine receptor, which releases dopamine when nicotine binds to it. Small amounts of dopamine are released when varenicline binds to the receptor, but substantially less than with nicotine.
The company officers insisted that the drug, approved by the FDA in 2006, is not only effective but safe. "The question is, 'Do we believe that the benefit-risk profile of Chantix is positive,' and I would say absolutely it is," Gretchen Dieck, Ph.D., Pfizer's senior vice president of safety and risk management, said.
"It is far better to get patients off cigarettes," she continued. "We can manage some of the risks that we are seeing that are either due to nicotine withdrawal, underlying disease, or perhaps Chantix."
Ponni Subbiah, M.D., a vice president of Pfizer Medical, said that some of the ongoing studies Pfizer is conducting involved adolescents, pregnant women, and patients with schizophrenia, emphysema and chronic obstructive pulmonary disease, and heart disease. Results from these studies will be published, or at least posted on the company's Web site, within the next few years.
A detailed analysis of neuropsychiatric adverse events linked to use of varenicline will be published later this year, she said.
The FAA ban last month was based on a report released by the Institute for Safe Medication Practices detailing a high number of serious injuries in patients taking the drug. (See: Varenicline (Chantix) Off the Table for Pilots and Controllers)
"The fact that the FAA has done this is not that unexpected," Joseph Feczko, M.D., chief medical officer of Pfizer, said, citing the wide range of drugs the agency also bans, including antidepressants, anxiolytics, diabetes medications, and some antihistamines.
Dr. Dieck pointed out that the institute's report was not peer-reviewed or published in a peer-reviewed journal.
She added that the report listed tallies of adverse events, but without knowing what counts were expected. "The expected number could be far greater than the observed reporting rate," she said.
David Gonzales, Ph.D., of the Oregon Health & Science University in Portland, and lead author for one of the pivotal phase III trials considered during FDA approval of varenicline, said that none of the neuropsychiatric adverse events he observed raised any red flags. He attended the roundtable discussion but not as a panelist.
"We see depressed mood and depression as being very common," he said, "so we didn't see anything in the trials that would cause us to think there was something unique going on with Chantix."
He noted, however, that his group screened patients entering the trial for serious psychiatric disorders and excluded them so they could determine the effect of the drug independent from the history of the patient.
He added that it is difficult to tease out whether the adverse events in trials are caused by the drug or by the withdrawal from nicotine. Many individuals use cigarettes, he asserted, to self-regulate mood, he said, and removing their drug of choice will likely cause some psychiatric symptoms.
Furthermore, he said, events reported outside the clinical trial setting do not have the detailed follow-up that a controlled regimen allows.
"With psychiatric issues, often times with the patient who's making the report you don't have it confirmed by psychiatrists or psychologists," he said.
In closing remarks, Dr. Fecsko reiterated what he believes to be a benefit for quitting smoking with varenicline. "We feel in Chantix we've discovered and developed a significant treatment option for those individuals who need it," he said.

Primary Hyperaldosteronism Not as Common as Previously Thought

By Todd Neale
THESSALONIKI, 08 june 2008-- Primary hyperaldosteronism, thought to be prevalent in patients with resistant hypertension, is not as common in hypertensive patients as previous studies have suggested, researchers found.Of 1,616 patients with resistant hypertension, 11.3% had confirmed primary hyperaldosteronism, Michael Doumas, M.D., of Hippokration Hospital here, and colleagues reported in the June 7 issue of The Lancet."If we take into account that resistant hypertension is seen in 10% to 30% of people with hypertension and primary hyperaldosteronism is less prevalent in milder forms of hypertension," the researchers said, "we could rationally assume that primary hyperaldosteronism is substantially less common in patients with hypertension than currently thought."
To test that assumption, Dr. Doumas and colleagues did a retrospective analysis of 1,616 patients (mean age 55.8; 51% male) with resistant hypertension -- a blood pressure greater than 140/90 mm Hg that did not respond to a three-drug treatment including a diuretic -- who were evaluated at a clinic in Thessaloniki over 20 years.
Serum aldosterone and plasma renin activity were measured in all patients and the ratio of the two was calculated to screen for primary hyperaldosteronism.
Patients with a ratio greater than 65.16 and a serum aldosterone level of 416 pmol/L or higher -- 338 or 20.9% of the study population -- were considered positive, although further testing was required to verify the diagnosis.
These patients underwent two salt suppression tests, which identified 182 (11.3% of the total patient population) who had primary hyperaldosteronism.
Treatment with spironolactone -- an aldosterone receptor blocker -- significantly lowered the blood pressure in all 182 patients (P<0.0001), href="http://www.thelancet.com/journals/lancet/article/PIIS014067360860834X/abstract" target="_blank">"Prevalence of primary hyperaldosteronism in resistant hypertension: a retrospective observational study" Lancet 2008; 371: 1921-1926. Additional source: The LancetSource reference: Kaplan N, "Déjà vu for primary aldosteronism" Lancet 2008; 371: 1890-1891.

AUA: Acupuncture, Electrical Stimulation Show Promise for Chronic Prostatitis

By Charles Bankhead
ORLANDO, 08 june 2008-- Novel strategies to treat chronic prostatitis and pelvic pain produced mixed results in clinical trials reported here.
Acupuncture and transrectal electrical stimulation of the pelvic floor significantly improved symptoms, but the alpha-blocker alfuzosin (Uroxatral) proved no better than placebo, investigators told attendees at the American Urological Association meeting.
Acupuncture is an attractive option for chronic pelvic pain because of its demonstrated efficacy in other pain syndromes and low risk of adverse events, said Shaun W. Lee, of the University of Science in Penang, Malaysia. In addition, observational evidence has suggested acupuncture efficacy in chronic prostatitis.
Lee reported findings from a multinational trial involving 89 men who had a two-year history of chronic prostatitis and pelvic pain. They were randomized to acupuncture or sham needle insertion.
Acupuncture involved insertion of six needles at four trigger points previously associated with chronic prostatitis and pelvic pain. Needles were inserted to a depth of 1.5 to 2.5 inches. Patients had two 30-minute treatment sessions a week for 10 weeks.
Sham procedures involved insertion of needles to a depth of no more than one-half inch at sites that were a half-inch away from the acupuncture trigger points.
The primary endpoint was the proportion of patients who had at least a six-point decrease in the NIH-Chronic Prostatitis Symptom Index, a threshold response that would permit detection of subtle changes in symptoms, said Lee.
The secondary endpoint was the percentage of patients in each group who had at least 50% improvement in the subjective global assessment.
The median baseline NIH-CPSI score was 25 in both groups. At the end of the treatment period, 32 of 44 (73%) of the acupuncture patients and 21 of 45 (47%) of the sham-treated patients met response criteria (P=0.02).
The symptom index declined by an average of 10.3 points in the acupuncture group compared with 6.0 points in the sham group.
Acupuncture's symptom relief was significantly more durable compared with the sham procedure. One month after the study, 18 acupuncture patients remained symptom-free compared with only one patient in the sham group (P=0.03). Three months after the study ended, 14 acupuncture patients remained symptom-free compared with six in the sham group (P=0.04).
Adverse events in the acupuncture group consisted of hematoma in four patients and pain at the needle insertion site in two. Adverse events in the sham group consisted of one hematoma, three cases of needle-site pain, and one case of acute urinary retention.
"Acupuncture was 50% more effective than the sham procedure," Lee said. "Acupuncture and sham were both safe, as all adverse events were minor and resolved quickly."
Several lines of evidence suggest that pelvic floor dysfunction plays a role in chronic prostatitis and pelvic pain, providing a rationale for evaluating transrectal electrical stimulation of the pelvic floor, said Jordan D. Dimitrakov, M.D., of Harvard.
So he and his colleagues compared electrical stimulation against a sham procedure in a randomized trial involving 77 patients with chronic prostatitis and pelvic pain.
Active treatment consisted of daily transrectal electrical stimulation procedures for one month, followed by twice-weekly sessions for five months. Patients who completed the six months of treatment had the option to continue twice-weekly treatment for an additional six months. Dr. Dimitrakov said the treatment could be self-administered at home.
Patients randomized to sham treatment followed the same treatment schedule as the patients who received active therapy.
The primary endpoint was patient-reported improvement in pain, as reflected in the NIH-CPSI. The secondary endpoint was patient global assessment of pain, disease activity, and response to therapy.
At one month, active therapy was associated with a 3.7-point reduction in the pain score versus 1.6 points in the sham group (P<0.001). After six months, the electrostimulation group had a mean reduction in pain score of 2.9 points compared with 1.1 in the sham group (P<0.001).
Electrostimulation also led to significantly greater improvement in all components of the secondary endpoint compared with sham treatment (P<0.001).
"Future studies should evaluate the optimal duration of this treatment approach," Dr. Dimitrakov concluded.
Observational studies had provided evidence of efficacy for several alpha-blockers in early-stage chronic prostatitis and pelvic pain, said J. Curtis Nickel, M.D., of Queen's University in Kingston, Ontario.
He and his colleagues sought to extend those findings in a randomized clinical trial involving 272 patients whose baseline NIH-CPSI score averaged 24 to 25.
The trial examined the efficacy of alfuzosin when given for more than six weeks to patients with early-stage chronic prostatitis and pelvic pain and no history of treatment with an alpha-blocker.
Patients were randomized to placebo or alfuzosin and followed for 12 weeks. The primary endpoint was the proportion of patients who responded to therapy, defined as a decrease of four points or more in the NIH-CPSI score at 12 weeks.
The secondary endpoint was the percentage of patients who reported moderate or marked improvement in the subjective global assessment.
At the end of the study, the two patient groups had identical response rates of 49%.
Global assessment responses demonstrated 34% to 35% improvement in each group. The treatment arms also did not differ with respect to pain, quality of life, depression, or erectile function.
"This was a great hypothesis ruined by good science," Dr. Nickel said.
Lee and Dr. Dimitrakov had no disclosures. Dr. Nickel reported relationships with multiple pharmaceutical companies, including sanofi-aventis, which provided the active drug for the NIH-sponsored study.
Primary source: American Urological Association meetingSource reference:Lee SW, et al "Randomized, double blind comparison of acupuncture versus sham acupuncture for chronic prostatitis/chronic pelvic pain syndrome" AUA Meeting 2008; Abstract 88. Additional source: American Urological Association meetingSource reference: Dimitrakov JD et al. "Pelvic floor electrical stimulation in the treatment of chronic pelvic pain syndrome: a randomized controlled trial" AUA Meeting 2008; Abstract 91. Additional source: American Urological Association meetingSource reference: Nickel JC, et al "A randomized multicenter double-blind clinical trial to evaluate the efficacy and safety of alfuzosin in the treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in recently diagnosed and/or newly symptomatic alpha-blocker naïve patients" AUA Meeting 2008; Abstract 87.

FDA Adds Black Box Warning to Diabetic Ulcer Cream

By Peggy Peck
ROCKVILLE, Md., 08 june 2008-- A boxed warning about increased risk of cancer deaths is being added to the label of becaplermin (Regranex Gel 0.1%), a prescription cream used to treat refractory leg and foot ulcers in diabetic patients, the FDA announced.
The agency said it decided the warning was needed after reviewing data from a retrospective study that compared cancer incidence and cancer mortality among 1,622 patients exposed to becaplermin and 2,809 controls.
The study found a five-fold increased risk of cancer mortality in patients exposed to three or more tubes of the cream.
There was no overall increase in cancer incidence based on exposure to becaplermin. No single type of malignancy was involved.
Susan Walker, M.D., director of the FDA's division of dermatological and dental products, said the cream was "not recommended for patients with known malignancies."
The FDA initiated a safety review of becaplermin in late March.
The active ingredient in the cream is a recombinant form of human platelet-derived growth factor, which is applied directly to diabetic foot and leg ulcers that are not healing. The recombinant form of platelet growth factor has a biologic activity that is much like that produced naturally by the body.

Intense diabetes therapy didn't cut heart problems

By STEPHANIE NANO
06 june 2008--Aggressively treating diabetes doesn't prevent heart problems and deaths any better than standard treatment for lowering blood sugar, Australian researchers reported Friday.
It's the second large study, involving thousands of patients, to show no heart benefit from drastically lowering diabetics' blood sugar levels. Experts said doctors should stick to the recommended target levels.
Heart disease is the cause of death for two-thirds of diabetics. Researchers tried pushing blood sugar down to near-normal levels to see if that would protect the hearts of high-risk patients with Type 2 diabetes.
But the Australian study showed no difference in the number of heart attacks, strokes and heart-related deaths between groups who got intensive or standard care. A U.S. study that was stopped earlier this year also showed no benefit and in addition reported an unexplained higher number of deaths among those who were aggressively treated.
The Australian study showed one positive result — a one-fifth reduction in kidney problems, a common complication of diabetes, compared to normal care.
"Both studies are important contributions to the field but do not provide a definitive answer," Dr. William T. Cefalu, of Louisiana State University, wrote in an editorial in the New England Journal of Medicine. He said other ongoing studies should provide clarification.
Both studies were released Friday in the journal and are being presented at an American Diabetes Association meeting in San Francisco. Partial results of the U.S. research were released in February when it was halted.
An estimated 21 million Americans and 250 million people worldwide have diabetes, meaning their bodies can't properly regulate their blood sugar, or glucose. Most have Type 2 diabetes. High levels of blood sugar can cause damage to the heart, blood vessels, kidneys and eyes.
Instead of trying aggressive measures, experts say there should be more focus on other strategies known to lower heart risks — diet, exercise and medications such as aspirin, cholesterol-lowering statins and blood pressure drugs.
In the two studies, researchers used a test that tracks average glucose levels over two to three months. For diabetics in the U.S., the recommended level is below 7. People without diabetes have levels around 5.
Both studies targeted diabetes patients middle-aged or older who had a heart problem or other heart risk factors. Doctors used a variety of diabetes drugs and insulin to try to get blood sugar levels down — to less than 6 in the U.S. study and 6.5 or lower in the international study.
The Australian study had more than 11,000 participants from Asia, Australia, Europe and Canada; the U.S. study had 10,000.
The U.S study was stopped after 3 1/2 years because of more deaths in the aggressively treated group: 257 deaths compared to 203 for standard care. The researchers said they haven't found a reason for the difference. Everyone was switched to standard treatment, and the researchers are continuing to follow them.
In a statement, Dr. Elizabeth G. Nabel, director of the National Heart, Lung, and Blood Institute, said that severely lowering blood sugar appears to be too risky for diabetes patients at higher risk for heart problems. Her institute helped pay for the study.
Dr. Alvin Powers of Vanderbilt University said the Australian study was reassuring because it showed blood sugar levels could be safely lowered below the current targets, in contrast to the U.S. results. He said reducing kidney complications is significant because it would might mean fewer people needing dialysis or a kidney transplant.
"I think this affirms that 7 (blood sugar level) should remain our goal — but most people don't reach that goal," he said.
The Australian study was funded by the government and diabetes drugmaker Servier. The U.S. study was paid for by National Institutes of Health, and various companies provided diabetes drugs. A number of researchers in both studies report receiving grant support or frees from drugmakers.

Osteoporosis drugs little used in nursing homes

06 june 2008--Few nursing home patients at high risk of bone fractures are given medications to strengthen their bones, a new study suggests.
Researchers found that of more than 4,400 older adults admitted to a nursing home after sustaining a fracture, only 11.5 percent were prescribed a medication for the bone-thinning disease osteoporosis.
This, the investigators say, is despite the fact that guidelines recommend "strong consideration" of drug therapy, beyond vitamin D and calcium, for nursing home patients at risk of fractures.
"There is considerable room for improvement in the use of osteoporosis (drug therapy) in this high-risk nursing home population," Dr. Seema Parikh and colleagues at Brigham and Women's Hospital and Harvard Medical School write in the Archives of Internal Medicine.
The researchers based their findings on data from 4,430 elderly adults who sustained a bone fracture and were subsequently admitted to a New Jersey nursing home between 1995 and 2004.
Overall, just 11.5 percent were given an osteoporosis medication, though prescriptions became more common over time. In 1995, less than 2 percent of patients received an osteoporosis medication, compared with 19 percent in 2001. The rate did not continue to increase after 2001, however.
Worries about osteoporosis drug side effects might be one reason for the low prescription rate, Parikh's team speculates. The drug raloxifene (Evista), for example, carries a risk of blood clots, while medications called bisphosphonates (such as Fosamax and Actonel) can cause gastrointestinal irritation.
However, the researchers point out, general guidelines call on doctors to consider drug therapy for nursing home patients at risk of bone breaks -- particularly those who have already suffered a fracture.
Based on the current findings, the researchers write, "Interventions aimed at enhancing osteoporosis treatment in nursing homes are vital."
SOURCE: Archives of Internal Medicine, May 26, 2008.

High cholesterol may up Parkinson's disease risk

06 june 2008--High cholesterol levels are associated with an increased risk of Parkinson's disease, according to findings from a Finnish study.
While it's well established that high cholesterol increases heart disease risk, "the association between serum cholesterol level and neurodegenerative diseases risk has been debated," write Dr. Gang Hu, of the National Public Health Institute, Helsinki, Finland, and colleagues.
The researchers examined this relationship in a cohort of 24,773 Finnish men and 26,153 women between the ages of 25 and 74 years. A total of 321 men and 304 women developed Parkinson's disease during an average follow-up of 18 years, the researchers report in the medical journal Neurology.
Compared to people with the lowest cholesterol, those with the highest had an 86 percent greater likelihood of developing Parkinson's disease.
This increased risk applied to people 24 to 54 years of age. "However, no association was found among subjects aged 55 years or older at baseline," Hu's team explains.
SOURCE: Neurology, May 20, 2008.

Diabetes Boosts Liver Cancer Risk in Hepatitis, Cirrhosis Cases

06 june 21008 -- Diabetes doubles the risk of liver cancer in patients with chronic hepatitis C with advanced fibrosis, or cirrhosis, a Dutch study reports.
Researchers at the Erasmus MC University Medical Center in Rotterdam analyzed data on 541 European and Canadian patients with chronic hepatitis C with advanced cirrhosis. Of those patients, 85 had diabetes. Patients with more severe fibrosis were more likely to have diabetes.
"The prevalence of diabetes mellitus was 10.5 percent for patients with Ishak fibrosis score 4, 12.5 percent for Ishak-score 5 and 19.1 percent for Ishak-score 6," the researchers wrote.
The patients were followed for a median of four years. During that time, 11 patients with diabetes and 27 patients without diabetes developed liver cancer. The five-year liver cancer occurrence rate was 11.4 percent and 5.0 percent, respectively. The study also found that being male and older were significantly associated with increased risk of liver cancer.
Among patients with diabetes, there was a trend toward higher liver cancer risk as fasting glucose levels increased, which suggests that hyperinsulinemia might explain the increased liver cancer risk among diabetic patients, the study authors suggested.
Whatever the mechanism, it's clear that diabetes increases the risk of liver cancer in patients with chronic hepatitis C and advanced cirrhosis, the researchers concluded.
The study was published in the June issue of the journal Hepatology.

Pfizer Defends Beleaguered Varenicline (Chantix)

By Todd Neale
NEW YORK, 06 jun 2008-- With its antismoking drug varenicline (Chantix) under a cloud for allegedly sparking suicidal behavior and ideation, Pfizer took its case to the press today, defending the agent as contributing far more benefit than potential harm.
Apparently stung by an FDA warning, followed by a ban of use of the drug by pilots and flight controllers issued by the Federal Aviation Administration, the company invited journalists to what it called a roundtable discussion to set the record straight.
At the session, three of Pfizer's senior officers sought to explain the occurrence of the adverse events, compare them with the benefits of quitting smoking, and explain how Pfizer is responding. Also attending was a clinical investigator who took part in a phase III trial of varenicline.
In February, the FDA warned of mood swings and suicidal behavior in patients taking varenicline, but maintained that it was effective as a medication for quitting smoking.The drug works by partially blocking the alpha4-beta2 nicotinic acetylcholine receptor, which releases dopamine when nicotine binds to it. Small amounts of dopamine are released when varenicline binds to the receptor, but substantially less than with nicotine.
The company officers insisted that the drug, approved by the FDA in 2006, is not only effective but safe. "The question is, 'Do we believe that the benefit-risk profile of Chantix is positive,' and I would say absolutely it is," Gretchen Dieck, Ph.D., Pfizer's senior vice president of safety and risk management, said.
"It is far better to get patients off cigarettes," she continued. "We can manage some of the risks that we are seeing that are either due to nicotine withdrawal, underlying disease, or perhaps Chantix."
Ponni Subbiah, M.D., a vice president of Pfizer Medical, said that some of the ongoing studies Pfizer is conducting involved adolescents, pregnant women, and patients with schizophrenia, emphysema and chronic obstructive pulmonary disease, and heart disease. Results from these studies will be published, or at least posted on the company's Web site, within the next few years.
A detailed analysis of neuropsychiatric adverse events linked to use of varenicline will be published later this year, she said.
The FAA ban last month was based on a report released by the Institute for Safe Medication Practices detailing a high number of serious injuries in patients taking the drug."The fact that the FAA has done this is not that unexpected," Joseph Feczko, M.D., chief medical officer of Pfizer, said, citing the wide range of drugs the agency also bans, including antidepressants, anxiolytics, diabetes medications, and some antihistamines.
Dr. Dieck pointed out that the institute's report was not peer-reviewed or published in a peer-reviewed journal.
She added that the report listed tallies of adverse events, but without knowing what counts were expected. "The expected number could be far greater than the observed reporting rate," she said.
David Gonzales, Ph.D., of the Oregon Health & Science University in Portland, and lead author for one of the pivotal phase III trials considered during FDA approval of varenicline, said that none of the neuropsychiatric adverse events he observed raised any red flags. He attended the roundtable discussion but not as a panelist.
"We see depressed mood and depression as being very common," he said, "so we didn't see anything in the trials that would cause us to think there was something unique going on with Chantix."
He noted, however, that his group screened patients entering the trial for serious psychiatric disorders and excluded them so they could determine the effect of the drug independent from the history of the patient.
He added that it is difficult to tease out whether the adverse events in trials are caused by the drug or by the withdrawal from nicotine. Many individuals use cigarettes, he asserted, to self-regulate mood, he said, and removing their drug of choice will likely cause some psychiatric symptoms.
Furthermore, he said, events reported outside the clinical trial setting do not have the detailed follow-up that a controlled regimen allows.
"With psychiatric issues, often times with the patient who's making the report you don't have it confirmed by psychiatrists or psychologists," he said.
In closing remarks, Dr. Fecsko reiterated what he believes to be a benefit for quitting smoking with varenicline. "We feel in Chantix we've discovered and developed a significant treatment option for those individuals who need it," he said.

Bladder and dementia therapy may be incompatible

By David Douglas
05 june 2008--In a study of elderly nursing home patients, those who took medications for dementia called cholinesterase inhibitors and medications for incontinence called anticholinergics at the same time had a 50 percent faster decline in function than those who were being treated only for dementia.
"Over a year's time, the decline would represent a resident going from requiring only limited assistance in an activity to being completely dependent, or from requiring only supervision to requiring extensive assistance in an activity," study chief Dr. Kaycee M. Sink, of Wake Forest University, Winston-Salem, North Carolina said in a university-issued statement.
These two drug classes "cancel each other out should not be used in combination," Sink added in comments to Reuters Health.
The researchers report the finding in the Journal of the American Geriatrics Society.
Sink and colleagues studied data on more than 3,500 elderly nursing home residents who were taking cholinesterase inhibitors, drugs that increase levels of acetylcholine, a chemical that enhances communication between nerve cells in the brain. Examples of cholinesterase inhibitors include donepezil (Aricept), galantamine (Razadyne), rivastigmine (Exelon), and tacrine (Cognex).
About 10 percent of the residents were also taking either oxybutynin (Ditropan) or tolterodine (Detrol), the two most often prescribed drugs for urinary incontinence. These drugs are known as anticholinergics and are designed to block acetylcholine.
According to the researchers, the combination of drugs affected older adults who started out with higher levels of function in routine activities of daily living such as dressing, personal hygiene, going to the bathroom, getting out of bed, eating and being able to get around the nursing home.
Specifically, they found that, in people who initially were most capable of performing routine activities of daily living and were not taking the bladder drug, functioning declined by an average of 1.08 points per quarter, while in those who were taking both types of drugs, the decline in functioning was 1.62 points per quarter -- a significant 50 percent greater decrease.
In patients who started out with lower functional ability, there was no excess decline attributable to dual therapy. There also were no between-group differences overall in cognitive function in patients taking or not taking both types of drugs.
Sink thinks it is "important for physicians and patients to work together to decide which symptom they would rather treat with a medication: the dementia -- Alzheimer's -- or the overactive bladder."
"If it is the dementia," he concluded, "then the overactive bladder symptoms can be managed by non-medication approaches."
SOURCE: Journal of the American Journal of Geriatrics, May 2008.

New Hints Seen That Red Wine May Slow Aging

By NICHOLAS WADE
05 june 2008--Red wine may be much more potent than was thought in extending human lifespan, researchers say in a new report that is likely to give impetus to the rapidly growing search for longevity drugs.
The study is based on dosing mice with resveratrol, an ingredient of some red wines. Some scientists are already taking resveratrol in capsule form, but others believe it is far too early to take the drug, especially using wine as its source, until there is better data on its safety and effectiveness.
The report is part of a new wave of interest in drugs that may enhance longevity. On Monday, Sirtris, a startup founded in 2004 to develop drugs with the same effects as resveratrol, completed its sale to GlaxoSmithKline for $720 million.
Sirtris is seeking to develop drugs that activate protein agents known in people as sirtuins.
“The upside is so huge that if we are right, the company that dominates the sirtuin space could dominate the pharmaceutical industry and change medicine,” Dr. David Sinclair of the Harvard Medical School, a co-founder of the company, said Tuesday.
Serious scientists have long derided the idea of life-extending elixirs, but the door has now been opened to drugs that exploit an ancient biological survival mechanism, that of switching the body’s resources from fertility to tissue maintenance. The improved tissue maintenance seems to extend life by cutting down on the degenerative diseases of aging.
The reflex can be prompted by a faminelike diet, known as caloric restriction, which extends the life of laboratory rodents by up to 30 percent but is far too hard for most people to keep to and in any case has not been proven to work in humans.
Research started nearly 20 years ago by Dr. Leonard Guarente of the Massachusetts Institute of Technology showed recently that the famine-induced switch to tissue preservation might be triggered by activating the body’s sirtuins. Dr. Sinclair, a former student of Dr. Guarente, then found in 2003 that sirtuins could be activated by some natural compounds, including resveratrol, previously known as just an ingredient of certain red wines.
Dr. Sinclair’s finding led in several directions. He and others have tested resveratrol’s effects in mice, mostly at doses far higher than the minuscule amounts in red wine. One of the more spectacular results was obtained last year by Dr. John Auwerx of the Institute of Genetics and Molecular and Cellular Biology in Illkirch, France. He showed that resveratrol could turn plain vanilla, couch-potato mice into champion athletes, making them run twice as far on a treadmill before collapsing.
The company Sirtris, meanwhile, has been testing resveratrol and other drugs that activate sirtuin. These drugs are small molecules, more stable than resveratrol, and can be given in smaller doses. In April, Sirtris reported that its formulation of resveratrol, called SRT501, reduced glucose levels in diabetic patients.
The company plans to start clinical trials of its resveratrol mimic soon. Sirtris’s value to GlaxoSmithKline is presumably that its sirtuin-activating drugs could be used to treat a spectrum of degenerative diseases, like cancer and Alzheimer’s, if the underlying theory is correct.
Separately from Sirtris’s investigations, a research team led by Tomas A. Prolla and Richard Weindruch, of the University of Wisconsin, reports in the journal PLoS One on Wednesday that resveratrol may be effective in mice and people in much lower doses than previously thought necessary. In earlier studies, like Dr. Auwerx’s of mice on treadmills, the animals were fed such large amounts of resveratrol that to gain equivalent dosages people would have to drink more than 100 bottles of red wine a day.
The Wisconsin scientists used a dose on mice equivalent to just 35 bottles a day. But red wine contains many other resveratrol-like compounds that may also be beneficial. Taking these into account, as well as mice’s higher metabolic rate, a mere four, five-ounce glasses of wine “starts getting close” to the amount of resveratrol they found effective, Dr. Weindruch said.
Resveratrol can also be obtained in the form of capsules marketed by several companies. Those made by one company, Longevinex, include extracts of red wine and of a Chinese plant called giant knotweed. The Wisconsin researchers conclude that resveratrol can mimic many of the effects of a caloric-restricted diet “at doses that can readily be achieved in humans.”
The effectiveness of the low doses was not tested directly, however, but with a DNA chip that measures changes in the activity of genes. The Wisconsin team first defined the pattern of gene activity established in mice on caloric restriction, and then showed that very low doses of resveratrol produced just the same pattern.
Dr. Auwerx, who used doses almost 100 times greater in his treadmill experiments, expressed reservations about the new result. “I would be really cautious, as we never saw significant effects with such low amounts,” he said Tuesday in an e-mail message.
Another researcher in the sirtuin field, Dr. Matthew Kaeberlein of the University of Washington in Seattle, said, “There’s no way of knowing from this data, or from the prior work, if something similar would happen in humans at either low or high doses.”
A critical link in establishing whether or not caloric restriction works the same wonders in people as it does in mice rests on the outcome of two monkey trials. Since rhesus monkeys live for up to 40 years, the trials have taken a long time to show results. Experts said that one of the two trials, being conducted by Dr. Weindruch, was at last showing clear evidence that calorically restricted monkeys were outliving the control animals.
But no such effect is apparent in the other trial, being conducted at the National Institutes of Health.
The Wisconsin report underlined another unresolved link in the theory, that of whether resveratrol actually works by activating sirtuins. The issue is clouded because resveratrol is a powerful drug that has many different effects in the cell. The Wisconsin researchers report that they saw no change in the mouse equivalent of sirtuin during caloric restriction, a finding that if true could undercut Sirtris’s strategy of looking for drugs that activate sirtuin.
Dr. Guarente, a scientific adviser to Sirtris, said the Wisconsin team only measured the amount of sirtuin present in mouse tissues, and not the more important factor of whether it had been activated.
Dr. Sinclair said the definitive answer would emerge from experiments, now under way, with mice whose sirtuin genes had been knocked out. “The question of how resveratrol is working is an ongoing debate and it will take more studies to get the answer,” he said.
Dr. Robert E. Hughes of the Buck Institute for Age Research said there could be no guarantee of success given that most new drug projects fail. But, he said, testing the therapeutic uses of drugs that mimic caloric restriction is a good idea, based on substantial evidence.

ASCO: Blood Test Shows Promise for Early Lung Cancer Detection

By Peggy Peck
CHICAGO, 05 june 2008-- A blood test for early detection of lung cancer demonstrated almost 90% accuracy in a preliminary clinical evaluation reported here.
The RNA-fingerprint analysis identified a group of patients who developed lung cancer during two years of follow-up with 86% sensitivity and specificity, Thomas Zander, M.D., of the University of Cologne in Germany, told attendees at the American Society of Clinical Oncology meeting.
The results could form the basis for a blood test capable of identifying lung cancer perhaps years before the disease becomes clinically manifest.
"We are convinced that this test warrants further investigation in prospective studies," Dr. Zander said at a press briefing.
Evaluation of the blood test began with the generation of a lung cancer-associated RNA fingerprint from peripheral blood samples of 13 smokers with lung cancer and 11 controls. The fingerprint was validated in an additional 22 smokers with lung cancer and 15 controls.
Dr. Zander and colleagues then examined records on 25,000 participants in the Prospective Investigation on Cancer and Nutrition (EPIC) trial and identified 12 smokers who had developed lung cancer within two years of enrolling in EPIC.
Using archived specimens, the researchers applied the RNA fingerprint to the cancer patients and to a matched control group without cancer.
The test identified the lung cancer patients with 88% accuracy (P<0.0001).
The investigators then evaluated the test in blood samples collected before the cancer became clinically manifest. Dr. Zander and colleagues predicted impending development of lung cancer with 80% accuracy (P<0.05).
Although preliminary, the findings are very promising, said Julie Gralow, M.D., of the University of Washington in Seattle, who moderated a press briefing at which the results were presented.
"We know early detection of many cancers has been shown to lead to better outcomes, including fewer relapses and less death and also less need for aggressive treatment," said Dr. Gralow. "This is a very promising lead that may lead to early detection of lung cancer."
Dr. Zander reported no significant disclosures.
Primary source: American Society of Clinical OncologySource reference:Zander T, et al "Predictive value of transcriptional changes inperipheral blood for future clinical onset of lung cancer in asymptomatic smokers" ASCO Meeting 2008; Abstract 1509.

ASCO: Triple-Drug Therapy Not a Winner for Metastatic Kidney Cancer

By Crystal Phend
CHICAGO, 05 june 2008A triple-drug treatment regimen may hold little meaningful advantage over standard interferon alfa alone for treatment of metastatic renal cell carcinoma or recurrence after nephrectomy, results of two studies indicate.
Despite the fact that the combination of interleukin-2 (IL-2), interferon alfa, and fluorouracil (Adrucil) increased response rates (24% versus 16%, P=0.004) compared with interferon alfa alone, the combination failed to prevent disease progression or improve survival, results of a large randomized trial presented at the American Society of Clinical Oncology meeting showed.
This "puts the nail in the coffin of this triple combination regimen," commented Mario Sznol, M.D., of the Yale Cancer Center in New Haven, Connecticut, who was a discussant for the study.
Following promising results in several phase II studies, Martin Gore, Ph.D., of the Royal Marsden Hospital in London, and colleagues tested the regimen in one of the largest phase III studies ever done in this patient population.
Their European Organization for Research and Treatment of Cancer (EORTC) RE04 trial included 1,006 patients with metastatic kidney cancer randomized to receive single agent interferon 10 MU three times a week until progression or toxicity or a combination of interferon alfa, IL-2, and fluorouracil for two cycles.
The median age of patients was 57 and 57% were WHO performance status 0. Nearly all (90%) had undergone nephrectomy.
After a median follow-up of 27.8 months, the triple-drug regimen was associated with no improvement in progression-free survival compared with interferon alone (median 5.3 months versus 5.5, hazard ratio 1.04, P=0.56).
Nor was there an advantage to the three-drug treatment for the primary outcome of overall survival (median 18.5 months versus 18.7, HR 1.05, P=0.57).
However, for the secondary outcomes of response, the advantage was significant for combination therapy with an 8% absolute improvement (24% versus 16%, P=0.004).
Among the findings for individual best response rates, the researchers reported:
Complete response in 2% of patients in both groups.
Partial response in 22% of combination-group patients versus 14% of control-group patients.
Stable disease in 46% versus 52% of patients, respectively.
Progression in 30% of patients treated with the combination regimen versus 32% of those treated with interferon alfa alone.
Michael Aitchison, M.D., of Nuffield Hospital in Glasgow, Scotland, and colleagues also looked at the same three-drug combination.
They randomized 154 patients post-nephrectomy for renal cell carcinoma without macroscopic residual disease with stage T3b-c,T4 or any pT and pN 1 or pN 2 or positive microscopic margins or microscopic vascular invasion, and no metastases to the combination therapy or to observation alone.
Patients receiving treatment showed no real benefit for disease-free survival (HR 0.86, P=0.353) or overall survival (HR 0.91, P=0.631) in the preliminary analysis.
The researchers also found that the regimen showed significant toxicity, with 92% of the patients randomized to combination therapy reporting grade 3-4 adverse events.
"The chances that this study will meet its endpoints are low," Dr. Sznol said.
And it's not clear that an increase in response rate alone justifies an adjuvant trial in metastatic disease, he added. Better predictors of outcome are needed, Dr. Sznol said.
Furthermore, he said, "I'm a little worried about adjuvant studies even now with the agents that we have because again, if biology is important it may be just as effective and much more efficient to treat the patients when they develop metastatic disease."
Dr. Gore's group reported conflicts of interest in the form of honoraria and other renumeration from Roche and Schering-Plough as well as research support from Chiron, Roche, and Schering-Plough.
Dr. Aitchison's group reported no conflicts of interest. Dr. Sznol reported serving in a consulting or advisory role for Bristol-Myers Squibb, Medarex, Pfizer, Lpath, Eisai, and Anaeropharma.
Primary source: American Society of Clinical Oncology meetingSource reference:Gore ME, et al "Interferon-α (IFN), interleukin-2 (IL2) and 5-fluorouracil (5FU) vs IFN alone in patients with metastatic renal cell carcinoma (mRCC): Results of the randomized MRC/EORTC RE04 trial" ASCO Meeting 2008; Abstract 5039. Additional source: American Society of Clinical Oncology meetingSource reference: Aitchison M "Preliminary results from a randomized phase III trial of adjuvant interleukin-2, interferon alpha and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC)" ASCO Meeting 2008; Abstract 5040.

ASCO: Intraperitoneal Chemotherapy May Boost Advanced Gastric Cancer Survival

By Crystal Phend
CHICAGO, 05 jun 2008-- Advanced gastric cancer penetrating the serosa membrane may respond well to intraperitoneal chemotherapy during surgery, Korean researchers found.Intraperitoneal plus intravenous chemotherapy increased the absolute rate of recurrence-free survival and overall survival about 10% at three and five years of follow-up compared with intravenous chemotherapy alone, reported Yoon-Koo Kang, M.D., Ph.D., of Asan Medical Center in Seoul, and colleagues at the American Society of Clinical Oncology meeting here.These randomized trial results "are very provocative" but not practice changing, commented David H. Ilson, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center in New York, who was a discussant for the study.
Confirmation is needed in a trial with fewer variables, he said. "The experimental arm in addition to adding intraperitoneal chemotherapy made several other modifications to the chemotherapy." The researchers suggested that the primary reason for the survival and recurrence advantages to their regimen was the use of intraperitoneal chemotherapy and the early start of chemotherapy.
Their results showed no link between dose of doxifluridine administered and overall or recurrence-free survival. A prior trial showed no benefit from adding cisplatin (Platinol) and prolonged doxifluridine (the oral prodrug of 5-fluorouracil [Adrucil]) in curatively resected advanced gastric cancer, Dr. Kang noted.
Dr. Ilson agreed that intraperitoneal chemotherapy was likely a major contributor. Peritoneal recurrence is common after gastric resection, but administering cytotoxic drugs directly to the peritoneum increases exposure 10- to 100-fold, he said.
Intraperitoneal chemotherapy is a standard of care for ovarian cancer but rarely used in gastric cancer, Dr. Ilson said. U.S. oncologists typically use 5-fluorouracil and radiation as adjuvant treatment for gastric cancer, he said.
On the basis of a Spanish study showing improved disease-free and overall survival with intravenous mitomycin-C (Mutamycin) plus short-term oral fluoropyrimidine chemotherapy, the researchers tested an even more aggressive approach in the randomized AMC 0101 study.
Compared with the control treatment, the experimental regimen added:
A course of 100 mg of intraperitoneal chemotherapy during surgery.
Earlier initiation of mitocycin-C (15 mg/m2 on day one after surgery versus 20 mg/m2 three to six weeks after surgery).
Six months of cisplatin at a dose of 60 mg/m2 on day one every four weeks.
Twelve versus three months of doxifluridine at a dose of 460 to 600 mg/m2 per day.
The study included 521 patients with completely resected, histologically proven, nonmetastatic gastric adenocarcinoma and gross serosa involvement.
After a median 3.5 years of follow-up, 229 progression or death events had occurred.
For the primary endpoint, the experimental strategy improved the rate of recurrence-free survival by about 10% at both three (60.2% versus 50.0%, hazard ratio 0.695, P=0.006) and five years (50.5% versus 43.8%).
Subgroup analyses showed a similar pattern of benefit with the exception of patients without total resection and those with stage IV disease, for whom results were equivocal.
The recurrence rate was significantly reduced overall with the experimental regimen (P=0.02), and tended to be lower for both peritoneal and distant recurrence.
Overall survival likewise was significantly improved with the more aggressive regimen by about an absolute 10% at three (71.2% versus 59.6%, HR 0.710, P=0.02) and five years (56.2% versus 47.0%).
The experimental regimen caused substantially more grade 3-4 neutropenia than seen with the control treatment (34.2% versus 11.6%). Higher-grade anemia and vomiting were also more common with the peritoneal chemotherapy-containing regimen.
However, intraperitoneal chemotherapy administered during surgery did not increase surgical complications.
"Gastric cancer is an area where we've had very little progress," Dr. Ilson concluded. "The currently available standards of care have limited benefit and we clearly need to look for other ways to improve outcome."
Dr. Kang disclosed no conflicts of interest. Dr. Ilson reported receiving research funding from sanofi-aventis, Genentech, and Bristol-Myers Squibb/Imclone.
Primary source: American Society of Clinical Oncology meetingSource reference:Kang Y-K, et al "Postoperative adjuvant chemotherapy for grossly serosa-positive advanced gastric cancer: A randomized phase III trial of intraperitoneal cisplatin and early mitomycin-C plus long-term doxifluridine plus cisplatin (iceMFP) versus mitomycin-C plus short- term doxifluridine (Mf) (AMC 0101) (NCT00296322)" ASCO meeting 2008; Abstract LBA4511.

Failure to Quit Smoking Attributed to Genetics

By Michael Smith
BALTIMORE, 04 jun 2008-- Smokers who can't seem to quit no matter how hard they try may look to their genomes for 99 reasons, researchers here said.
Ninety-nine autosomal genes are differently expressed in those who successfully quit smoking in clinical trials than in those who couldn't do it, according to George Uhl, M.D., Ph.D., of the NIH's molecular neurobiology branch, and colleagues.
The findings are based on genome-wide association studies of 550 smokers taking part in trials that tested either nicotine replacement therapy or bupropion (Zyban), Dr. Uhl and colleagues reported in the June issue of Archives of General Psychiatry.
The study "helps us understand why some people are able to quit smoking more easily than others," Dr. Uhl said. It may one day allow clinicians to match smokers with particular cessation treatments.
The researchers analyzed blood samples from three cohorts:
Participants in a double-blind placebo-controlled trial of bupropion or an open-label trial of a nicotine nasal spray versus a nicotine patch. The 126 volunteers who were biochemically confirmed to have abstained from smoking for at least seven days before the end of treatment and at a 24-week assessment were contrasted with the 140 smokers who were not abstinent at either time.
Those in a placebo-controlled trial of nicotine skin patches. Fifty-five participants were confirmed by carbon monoxide levels to be abstinent six weeks after the quit date and 79 were not.
Individuals in a second double-blind placebo-controlled trial of bupropion, in which smoking cessation was assessed using point abstinence, defined by self-reporting and saliva cotinine levels. The 60 participants with biochemically confirmed abstinence for at least seven days before the end of treatment and at a 24-week assessment were contrasted with the 90 individuals who were not abstinent at either time.
Dr. Uhl and colleagues looked for clusters of single-nucleotide polymorphisms (SNPs) in more than two independent samples that had significant P-values based on Monte Carlo simulation trials.
The 99 genes they identified are likely to alter cell adhesion, enzymatic, transcriptional, structural, and DNA, RNA, or protein-handling functions, Dr. Uhl and colleagues reported.
Among those, 41 were specific for bupropion and 26 for nicotine replacement therapy, the researchers found. The finding makes sense because the two cessation approaches have different biochemical mechanisms, Dr. Uhl and colleagues said.
"This takes us a big step forward in being able to tailor treatment to individual smokers to provide the therapies that are most likely to benefit them," said co-author Jed Rose, Ph.D., director of Duke's Center for Nicotine and Smoking Cessation Research.
"In a few years, a simple blood test may provide physicians with enough information to recommend one treatment over another," Dr. Rose said.
The genes identified in the study overlapped -- but weren't identical -- with genes found in studies looking at who develops an addiction in the first place, Dr. Uhl and colleagues found. In fact, the authors reported less overlap for smokers than other substances to which dependency develops.
For instance, cadherin 13, a cell adhesion molecule, is expressed in neurons in several brain regions, can inhibit neurite extension, and can activate several signaling pathways, "rendering it a strong candidate for roles in brain mechanisms important for both developing and quitting addictions," the researchers said.
The study may be limited by its relatively small sample size, Dr. Uhl and colleagues said, and by its focus on autosomal genes, which may miss sex-related differences. Also, participants were in "demanding" clinical trials, indicating they may not be representative of all smokers.
The study was supported by the NIH, the Pennsylvania Department of Health, and GlaxoSmithKline, Inc. Dr. Uhl reported that several authors may have proprietary interests in a provisional patent filed (after the study was accepted) by Duke University related to the use of genetic markers to predict smoking cessation success.
Primary source: Archives of General PsychiatrySource reference:Uhl GR, et al "Molecular genetics of successful smoking cessation: convergent genome-wide association study results" Arch Gen Psychiatry 2008; 65(6): 683-693.

Exposure Therapy Tops Cognitive Restructuring in Preventing PTSD

By John Gever
SYDNEY, 04 jun 2008-- Accident and assault victims suffering acute stress should receive prolonged-exposure therapy to prevent posttraumatic stress disorder, researchers here said.
In a randomized trial, only 37% of patients who began prolonged-exposure therapy shortly after a traumatic event had developed PTSD six months later, compared with 63% of those treated with cognitive restructuring (P=0.05), reported Richard A. Bryant, Ph.D., of the University of New South Wales, and colleagues in the June issue of Archives of General Psychiatry.
It's the first head-to-head comparison of the two major treatment approaches for patients with acute stress disorder, the researchers said.
Some 47% of those receiving prolonged-exposure therapy had full remission of acute stress disorder symptoms, compared with only 13% of patients treated with cognitive restructuring (P=0.005).
"Despite some concerns that patients may not be able to manage the distress elicited by [prolonged-exposure therapy], there was no difference in dropout rates," Dr. Bryant and colleagues said. In fact, mean distress ratings for each session were significantly lower among those receiving prolonged-exposure therapy.
"Exposure should be used in early intervention for people who are at high risk for developing PTSD," the researchers concluded.
In prolonged-exposure therapy, patients are encouraged to relive the traumatic event over and over. They may describe it verbally in detail in sessions with a therapist and do daily homework assignments that force patients to go over the event in their minds.
Dr. Bryant and colleagues said many clinicians have resisted using exposure therapy because they worry the distress it creates may drive patients away from therapy altogether.
Cognitive restructuring involves identifying unhealthy thoughts and emotional responses to the trauma and tries to modify them by having patients apply rational analysis. The unhealthy thoughts typically revolve around guilt about behavior during the trauma and excessive worry about future harm and their reactions to the stress.
The researchers recruited 90 patients who had been involved in motor vehicle accidents or non-sexual assaults and who met criteria for acute stress disorder -- 30 patients were assigned to prolonged-exposure therapy, 30 to cognitive restructuring, and 30 were assigned to a wait list. Patients on the wait list were reassessed six weeks later and then offered unspecified active treatment.
For both treatment types, patients received five 90-minute sessions at weekly intervals. They were assessed primarily with the Clinician-Administered PTSD Scale-2, as well as with other standard psychological checklists and questionnaires.
Five patients in the prolonged-exposure group and seven in the cognitive restructuring group did not complete the treatment, including two in each group who had adverse reactions to the therapies.
At the six-week evaluation, 71% of the wait-listed patients met standard criteria for PTSD, compared with 52% of those assigned to cognitive restructuring and 12% of those receiving prolonged-exposure therapy (P<0.001).
Dr. Bryant and colleagues pointed out that cognitive restructuring "achieved a modest effect size for most assessments relative to the wait-list group" after treatment. That's an indication that cognitive restructuring also is effective, if somewhat less so than prolonged-exposure therapy.
"We recognize that it does provide an alternate early intervention for patients who are unsuitable for prolonged-exposure [therapy] or unwilling to participate," they said.
The researchers said that most of the earlier research on exposure therapy had combined it with cognitive restructuring. "Prolonged-exposure [therapy] probably accounted for many of the therapy gains in previous studies," they said, but acknowledged that their head-to-head study did not allow for a comparison with the additive effects of the two approaches.
In fact, they suggested, adding cognitive restructuring later in treatment, following initial therapy with prolonged exposure, may provide the best results.
Dr. Bryant and colleagues noted several limitations to their study. Because it focused on accident and non-sexual assault victims, their results may not be generalizable to other populations such as war veterans or victims of sexual assault, they said.
The researchers also noted that they did not assess for all psychiatric disorders known to affect trauma survivors, nor did they assess functioning.
Exposure therapy supported by virtual reality technology was recently reported to be effective against PTSD in soldiers returning from Iraq (See: Virtual Reality PTSD Therapy Shows Promise in Iraq Veterans).
The study was funded by the National Health and Medical Research Council Program. No potential conflicts of interest were reported.
Primary source: Archives of General PsychiatrySource reference:Bryant R, et al "Treatment of acute stress disorder: a randomized controlled trial" Arch Gen Psychiatry 2008; 65: 659-67.

Colon Cancer in Family Predicts Better Survival

04 jun 2008--People with a family history of colon cancer carry the emotional burden of knowing they have twice the risk of developing the disease themselves. But now, a new study may ease some of their anxiety. Patients with a family history of colon cancer are also more likely to survive the disease.
The surprising paradox, published in Wednesday’s Journal of the American Medical Association, may ultimately steer researchers toward new treatments and a better understanding of the disease.
An estimated 153,000 cases of colon and rectal cancer will be diagnosed in 2008, according to the American Cancer Society, and about 50,000 people will die from the disease. Studies of twins show that about 35 percent of colon cancers are inherited, and about 11 percent of patients have at least two close relatives with the disease. An individual who has a first-degree relative with colorectal cancer faces about a 1 in 10 chance of being diagnosed with colon cancer, compared to 1 in 20 for those with no family history.
The latest study, conducted by researchers at the Dana-Farber Cancer Institute in Boston, followed 1,087 patients being treated for Stage III colon cancer, which means the cancer had spread to nearby lymph nodes but not to other organs. Of those patients, 195, or about 18 percent, had a parent or sibling with the disease. Those who had at least one close family member with colon cancer were 25 percent less likely to die from the disease during the 5.6 years of patient follow-up than those with no close relatives with colon cancer.
The risk of dying was even lower for those with two or more relatives with the disease. Those patients had a 51 percent lower risk for cancer recurrence or death.
“This news may be reassuring to people with a family history, but our hope is that we can discover what underlies this effect of family history in biological terms,” said the study’s first author, Dr. Jennifer Chan, from Dana-Farber’s Center for Gastrointestinal Oncology.
Why a person has a better prognosis if they have a family history of colon cancer isn’t clear. The scientists ruled out several explanations for the difference, including the possibility that people with a family risk for colon cancer have adopted healthier lifestyles or take part in additional screening. Dr. Chan said the researchers looked at important lifestyle factors like diet, exercise and smoking and found no association with improved survival. And because all the patients had stage III cancers, more frequent screening and an earlier diagnosis also couldn’t explain the difference.
However, there is other evidence that genetic factors play an important role in colon cancer prognosis. It’s known, for example, that colon cancer that develops as a result of a rare inherited condition called Lynch syndrome — also called hereditary nonpolyposis colorectal cancer — is less aggressive than the cancers found in patients with no genetic risk.
The study was paid for with grants from the National Cancer Institute and Pharmacia & Upjohn Co., now Pfizer Oncology.

With a Tiny Bit of Cancer, Debate on How to Proceed

By LAURA BEIL
04 jun 2008--In a cancer patient, lymph nodes are the closest thing to a crystal ball. Gaze into them after removing a tumor. The presence of malignant cells may be a sign that the cancer will recur, leading to more tests and intensive treatment.
As biopsies of the lymph nodes grow more sophisticated and sensitive, oncologists and patients face the unsettling question of what to do with a little bit of cancer. It has become a familiar debate, especially for breast cancer, with no clear answer in sight.
“We can pick up things that we could never pick up before,” said Dr. Minetta Liu, an oncologist at the Georgetown University Medical Center. “But do we need to pick them up?”
Without more data to guide them, doctors worry that some women may be given test results that are actually too good, leading to more medical attention than necessary.
Pathologists have long examined lymph nodes — small grapelike bunches that are part of the immune system — to gain the best sense of whether a tumor, once gone, will reassert itself. If renegade cells become caught in the nodes, the tumor could also be setting up outposts in distant parts of the body.
As recently as the 1990s, doctors took 24 or so nodes to the laboratory for testing, slicing each one and looking for glimpses of cancer. But the more nodes a patient loses, the greater the likelihood of long-term side effects.
In recent years, doctors have tended to focus far more narrowly, on so-called sentinel nodes, the one or two most connected to the internal plumbing of the tumor.
Sentinel node biopsy is growing more and more popular among breast cancer surgeons. The procedure was used in more than 50 percent of patients by 2005, up from about 10 percent in 1998.
Along the way, the field has grown more refined. In one new approach, part of the node is dropped into a high-tech blender, and its genetic material is sifted by computer for signs of cancer.
Now that pathologists have fewer nodes to consider, they have more time to section the tissue. It is as if, after years of skimming a book, doctors could peruse entire chapters. The problem is that the more carefully you read, the less you may know.
“When someone has a very small amount of tumor, what is their actual risk?” asked Dr. Hiram S. Cody III of the Memorial Sloan-Kettering Cancer Center in New York. A tiny bit of cancer could mean that a tumor is going to reignite. Or it could mean very little.
The presence of these so-called micrometastases, and other wisps of tumor too small to count as full-fledged metastases, has been documented in lymph nodes for decades. But only with the popularity of sentinel node testing has the question of micrometastasis entered everyday medical practice.
“Because they are looking at fewer nodes, they can look more carefully,” said Brenda K. Edwards, associate director for surveillance research at the National Cancer Institute.
Dr. Edwards and her colleagues recently found that diagnoses of breast cancer with micrometastatic lymph-node involvement began to increase markedly after 1997 and that it shows no signs of leveling off.
Nowhere are discussions of micrometastases more animated than with breast cancer, where 86 percent of sentinel node biopsies are performed. Scientists are trying to determine whether micrometastases have any effects on survival.
Research is divided, and all the studies have had built-in shortcomings. In The Journal of Clinical Oncology in April, Dr. Cody described a study that looked back at 368 patients from the 1970s. The researchers retrieved stored lymph nodes from the women, examined them for micrometastases and checked to see how the patients had fared.
He and his colleagues found that women with micrometastases did have a slightly worse survival rate than women without any cancer in the nodes. But there are important caveats. Through earlier detection, doctors are diagnosing smaller tumors that are presumably less advanced and less likely to be deadly. Also, none of the subjects received chemotherapy, which has become far more effective in the last 30 years. And the study looked at all nodes, not just the one or two in the sentinel position.
Newer data come from researchers at the John Wayne Cancer Institute in Santa Monica, Calif., home to some of the earliest studies on sentinel node biopsy. Unlike the women in Dr. Cody’s study, these 790 patients underwent chemotherapy and would have received diagnoses on a scale more aligned with modern mammography.
At the annual San Antonio Breast Cancer Symposium in December, researchers reported that women with just micrometastatic cancer in their lymph nodes survived as long, on average, as those with clear nodes.
The problem with that study is that those women and their doctors knew whether micrometastases had been found in their lymph nodes, and that probably influenced the course of treatment.
“We don’t have good answers at this point,” said Dr. Nora Hansen of the Feinberg School of Medicine at Northwestern University, who reported the results.
Other researchers from the John Wayne Institute recently examined breast cancer statistics from 1992 to 2003. They compared how the extent of cancer found in lymph nodes predicted survival.
Writing in December in The Annals of Surgical Oncology, the researchers reported that women with micrometastatic cancer in a sentinel node had a survival rate slightly poorer than women without cancer in the nodes, but better than women with greater node involvement.
Doctors predict that the best insight will come from two national studies involving thousands of participants in which neither the women nor their doctors know about the presence of micrometastases. But those studies are not expected to produce results for years.
So until the issue is settled, oncologists will have to navigate patients through complicated choices. One is whether a node that is positive for micrometastases warrants removing more nodes.
This is no small matter. Women who have been treated for breast cancer often report years of swelling and tightness in the arms just from lymph node removal.
The second dilemma is whether a little cancer is worth a lot of anxiety. Even knowing that its significance is unclear, cancer in a lymph node, no matter how minuscule, can be alarming.
“It’s a hard point for medical oncologists to walk away from,” said Dr. Thomas B. Julian of the Allegheny Cancer Center in Pittsburgh, a leader of one of the two trials that may provide better guidance. “In most centers across the United States, they will treat you for that positive node.”
Dr. Julian and others say that without better answers, micrometastases will continue to affect each doctor and patient differently. Some women, especially younger ones, may want more aggressive treatment, no matter what. Others may decide that the increased risk posed by a micrometastasis is too small and too uncertain to worry about.
And all of them will await the day when medical science does a better job of predicting the future.