CRYOPRESERVE SEMEN OF MALE CANCER PATIENTS

Cryopreserved Semen From Cancer Patients Often Effective

NEW YORK (Reuters Health) Dec 31 - Cancer patients who have had semen samples cryopreserved because of the possible adverse effects of the malignancy or of its treatment on their subsequent fertility, appear to have about a 50% chance of achieving parenthood, Dutch researchers report in the December issue of Fertility and Sterility.

"Semen cryopreservation should be offered to all male cancer patients," lead investigator Dr. Niels J. van Casteren told Reuters Health, "to offer them some kind of protection against the detrimental effects of chemotherapy, as it is not always clear who will and who will not become permanently infertile."

To determine the usage rate and outcome of assisted reproduction technologies (ART) employing cryopreserved semen, Dr. van Casteren of Erasmus University Medical Center, Rotterdam, and colleagues conducted a retrospective analysis of data on 557 men from whom a total of 749 semen samples were preserved.

Over an average follow-up of 7 years, 91 of the patients died and another 29 requested that their samples be disposed of. However, 42 (7.5%) with post-treatment azoospermia requested that their banked semen be used, and ART data was available for 37 of these men.

A total of 101 ART cycles were performed. Techniques employed were intracytoplasmic sperm injection, in vitro fertilization, cryo-embryo transfer and intrauterine insemination.

In all, 25 children were born, 19 singletons and 3 twins. Two couples were also awaiting a child by the end of the study period, thus achieving a success rate of at least 54%.

Summing up, Dr. van Casteren concluded, "Approximately 9% of those men who survive their malignant disease will use their cryopreserved semen, of whom 50% succeed in achieving fatherhood. These men would not have been able to do this without their stored semen."

LOW DOSE PPI AS EFFECTIVE AS HIGH DOSE

Low-Dose PPI as Effective as High-Dose for Peptic Ulcer Bleeding

NEW YORK (Reuters Health) Jan 01 - Low-doses of proton pump inhibitors (PPIs) are as effective as high-dose PPIs for the prevention of recurrent bleeding after endoscopic hemostasis of peptic ulcer bleeding, according to a report in the December American Journal of Gastroenterology.

"The message is straightforward: use the standard does of PPI in conjunction with a successful endoscopic therapy," Dr. Angelo Andriulli from "Casa Sollievo della Sofferenza" Hospital, San Giovanni, Italy, told Reuters Health.

Dr. Andriulli and colleagues compared low-dose (40 mg bolus daily) and intensive (80 mg bolus followed by 8 mg/h for 72 hours) PPI regimens for the prevention of rebleeding, surgery, and death in 474 patients with high-risk bleeding peptic ulcers in whom successful endoscopic hemostasis was achieved.

Bleeding recurred in 11.8% of patients in the intensive regimen group and in 8.1% of the patients in the standard regimen group (p=0.18), the authors report.

Rebleeding rates did not differ significantly between the two treatment groups or by type of ulcer (gastric or duodenal), the report indicates.

A similar number of units of blood were transfused in the two groups, the researchers note, as were the proportions of patients who required 2 or more units of blood transfused.

Five patients in each group died, including 3 in each group in whom the cause of death was linked to the bleeding event.

"The next study should compare the oral route versus the IV administration of PPI from the start of the bleeding," Dr. Andriulli said. "Moreover, the PPI dose should be the standard one, i.e., two tablets orally."

Although the elimination of the continuous PPI infusion does represent a step forward in terms of limiting resource utilization, "there are far greater potential gains if there were definitive proofs of the equivalence of an oral PPI regimen, which may facilitate earlier discharge of higher risk patients with upper gastrointestinal bleeding," write Dr. Laura E. Targownik and Dr. Peter A. Thomson from University of Manitoba, Winnipeg, in a related editorial.

They conclude, "Perhaps we will soon know whether the benefits provided by IV dosing over oral dosing are also illusionary."

Dr. Andriulli expressed surprise at the difficulty he encountered in publishing these findings. "My personal explanation for the rebuttal was that we were not backed by a pharmaceutical company in the planning, executing, and collecting of the results."

However, 11 investigators in Italy have embarked on a multicenter with similar data from previous placebo-controlled trials, and so far contradict current recommendations put forward by consensus guidelines. "This raises several points on the way referees are selecting and judging submissions," the researcher said

GENE MUTATION PREDICTS RELAPSE IN CHILDHOOD ALL

Gene Mutation Predictive of Relapse in Childhood ALL

January 9, 2009 — Although improved therapies have dramatically increased cure rates in children with acute lymphoblastic leukemia (ALL), up to 20% of patients will still relapse after initial treatment. Survival among patients who experience relapse remains poor. However, new research suggests that alteration of IKZFI, a gene that encodes the protein IKAROS, is associated with a poor outcome in B-cell progenitor ALL. The findings were published online January 7 in the New England Journal of Medicine.

"We found a genetic abnormality that predicts a very high risk for relapse," said Charles Mullighan, MD, assistant member in the Department of Pathology at St. Jude Children's Research Hospital, in Memphis, Tennessee, and the paper's first author. "Using these genetic approaches, we are gaining new insight into the disease and developing new therapeutic approaches."

The study was conducted as part of the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to use modern genomic technologies to identify therapeutic targets in childhood cancers. The researchers found that, in multivariate analysis, the association between IKZFI status and outcome was independent of confounders that included age, leukocyte count at presentation, cytogenetic subtype, and level of minimal residual disease.

Overall, 66.5% of the cohort with high-risk ALL had at least 1 mutation of genes regulating B lymphoid development, the authors note and, of this group, deletion of IKZFI was detected in 28.6% of patients. Deletion or mutation of IKZF1 was significantly associated with an increased risk for relapse, adverse events among low- and high-risk patients, and elevated levels of minimal residual disease.

"The key message is that this is a new predictor of poor outcomes and provides additional information over the existing testing panel," Dr. Mullighan said in an interview.

These findings, the authors note, indicate that detecting IKZFI alterations at the time of diagnosis might be useful in identifying patients who are at a high risk for treatment failure.

But there are no immediate plans to change therapy based on these findings, coauthor Gregory H. Reaman, MD, chair of the Children's Oncology Group, told Medscape Oncology. "These and similar observations are expected to drive the development of targeted agents, based on specific gene alterations, for children with ALL, with the goal to both improve outcome with such specific therapy and to minimize the risk of serious late effects of conventional therapy approaches."

Before making treatment decisions based on these findings early in the planned treatment, Dr. Reaman explained, a prospective evaluation of the impact of early treatment interventions is required. "At present, we have insufficient information to know whether existing therapy approaches will improve outcome," he said. "Further research is needed. It is expected that as this and other specific genetic alterations are defined, using this information to develop specific molecularly targeted therapy approaches is the required next step."

Dr. Mullighan agreed that their results need to be validated by other groups, and it is difficult to speculate at this time how these findings will affect therapeutic decisions. "We need to tailor the intensity of therapy appropriately, as we want it to cure the disease but not cause too much toxicity," he said.

Association with Increased Risk for Relapse

Genetic data were analyzed in a cohort of 221 children with high-risk B-cell progenitor ALL, using single-nucleotide polymorphism microarrays, transcriptional profiling, and resequencing of samples that were obtained at diagnosis. The patients had all been previously treated in the Children's Oncology Group P9906 study, and were enrolled from May 2000 to April 2003. The median follow-up time was 3.94 years (range, 0.16 to 6.20).

To confirm that specific genetic changes were associated with relapse, the researchers tested their hypothesis in an independent validation cohort of 258 patients with B-cell progenitor ALL. The children in the validation cohort were treated at St. Jude Children's Hospital, and the cohort included both standard- and high-risk patients.

In the primary cohort, the researchers identified a mean of 8.36 copy-number abnormalities per patient, with more than 50 recurring copy-number abnormalities in which the minimal common region of change involved 1 or a few genes. Of these, the most common deletions involved CDKN2A/B (45.7%), the lymphoid transcription-factor genes PAX5 (31.7%) and IKZF1 (28.6%), ETV6 (also known as TEL) (12.7%), RB1 (11.3%), and BTG1 (10.4%).

Among patients in both cohorts, deletion or mutation of IKZF1 was significantly associated with an increased risk for relapse and adverse events, and IKZF1 deletions were also associated with a poor outcome among patients in the validation cohort with BCR-ABL1-negative ALL.

The association was weaker for other genetic alterations, the authors observed. Deletions of EBF1 and BTLA/CD200 were associated with a poor outcome only among patients in the primary cohort, not among those in the validation group. An independent association between PAX5 lesions and outcome was also not observed in either cohort.

Increased Risk for Minimal Residual Disease

Elevated levels of minimal residual disease were strongly associated with an increased risk for relapse in both cohorts (at day 8 and day 29 in the original cohort, and at day 19 and day 46 in the validation cohort), which is consistent with previous data, the researchers note. In the original cohort, IKZF1 and EBF1 alterations were strongly associated with elevated levels of minimal residual disease, and high levels of residual disease were detected in patients with an IKZF1 deletion or mutation in the validation cohort.

No Test Available Yet

At present, there are no commercially available assays for detecting mutations in and overexpression of the IKZF1 gene. "This type of test may be somewhat complex, and several tests might be necessary," said Dr. Mullighan. "This might be beyond the reach of some hospital laboratories, and many would have to send the specimens out to a reference laboratory."

However, Dr. Reaman pointed out that in the setting of clinical trials within North America, such testing could be possible within the Children's Oncology Group Reference Laboratory mechanism. "It is likely that there are other genes that have similar predictive ability in identifying patients at increased risk of treatment failure, and ultimately the development of a commercially available laboratory test to make such evaluations generalizable for the entire global pediatric oncology community is a goal," he said. "In North America at the present time, testing would be possible for the overwhelming majority of children with ALL, since most patients are treated in [Children's Oncology Group] clinical trials."

ANTIESTROGENS AND E-CADHERIN

Antiestrogens Can Enhance Cellular Invasion by Certain Breast Cancer Cells

NEW YORK (Reuters Health) Jan 02 - Antiestrogens like tamoxifen can promote an invasive phenotype in estrogen receptor (ER)-positive breast cancer cells with deficient intercellular adhesion, according to a report in the December 4th issue of Breast Cancer Research.

"This is a preclinical study, and its clinical relevance has yet to be proven," Dr. Stephen Hiscox from Cardiff University, Cardiff, UK, told Reuters Health. "Our data, if validated clinically, would add more weight to the use of aromatase inhibitors in breast cancer versus tamoxifen."

Dr. Hiscox and colleagues used Matrigel invasion assays to measure the effect of estrogen, 4-hydroxy-tamoxifen, and estrogen deprivation on the invasive capacity of endocrine-sensitive breast cancer cells in the presence or absence of functional E-cadherin.

In the absence of good intercellular contacts, tamoxifen promoted invasion of breast cancer cells in culture, the authors report, whereas estrogen deprivation had no effect on invasiveness.

Fulvestrant, a steroidal antiestrogen, also enhanced breast cancer cell invasion in the absence of E-cadherin expression, the investigators found.

"Taken together, our preclinical data generate the hypothesis that in patients whose primary breast cancers show reduced or aberrant E-cadherin expression, tamoxifen therapy may promote the development of an adverse cell phenotype that may have an impact on disease relapse, its invasive behavior, and, hence, patient survival," the authors conclude.

"Although our observations may only apply to a relatively small subset of patients, they may account for some of the superiority seen with aromatase inhibitors in the large adjuvant studies," they add.

If these findings are confirmed, the researchers say, endocrine therapy might be guided by E-cadherin expression.

"We are currently addressing levels of E-cadherin in breast tissues from patients who have received tamoxifen," Dr. Hiscox said. "We hope to determine whether low/absent levels of E-cadherin correlate with poor endocrine response."

OVARIAN CANCER AND OBESITY

Link Between Ovarian Cancer, BMI May Vary by HRT Use

January 8, 2009 — There is a "modest positive relation" between body mass index (BMI) and risk for ovarian cancer, but the risk is considerably elevated in women who have never used hormone-replacement therapy (HRT), according to a prospective study of 94,000 mostly postmenopausal women published online January 6 in Cancer.

In the study, the risk for ovarian cancer increased by 80% in obese women, compared with normal-weight women, among those who never used HRT.

"Further studies are needed to test the hypothesis that the relation between BMI and ovarian cancer varies according to menopausal hormone therapy," write the authors, led by Michael F. Leitzmann, MD, PhD, from the Institute of Epidemiology and Preventive Medicine at the University of Regensburg, in Germany. Dr. Leitzmann was formerly at the National Cancer Institute in the United States, where the study was undertaken.

In discussing the background of the study, Dr. Leitzmann and colleagues note that "convincing epidemiologic evidence links excess body mass to increased risks of endometrial and postmenopausal breast cancers, but the relation between . . . BMI and ovarian cancer risk remains inconclusive."

The new study adds to the literature on ovarian cancer, BMI, and HRT, which is "sparse," say the authors. They also suspect that any ovarian cancer risk that is associated with obesity is likely related to a "hormonal mechanism."

NIH–AARP Diet and Health Study Used

Using a database from the National Institutes of Health (NIH)–American Association of Retired Persons (AARP) Diet and Health Study (1995–1996), the researchers followed up on an initial mailed health questionnaire from that study with a second questionnaire that inquired about HRT use and family history of cancer. In the end, their analysis included 94,525 women, of whom more than 90% were postmenopausal. State cancer registries were used to identify 303 ovarian cancer cases during follow-up, which lasted until the end of 2003.

At baseline, approximately one third (32.4%) of participants were overweight (BMI, 25–29.9 kg/m²) and nearly one quarter (22.0%) were obese (BMI ≥ 30 kg/m²).

Results

In a multivariate analysis adjusted for factors like age, family history of ovarian cancer, oral contraceptive use, and physical activity, the relative risk (RR) of ovarian cancer for obese women in the cohort was 1.26 (95% confidence interval [CI], 0.94 - 1.68), compared with normal-weight women (BMI, 18.5–24.9 kg/m²).

However, among women who never used HRT, the RR for obese vs normal-weight women was 1.83 (95% CI, 1.18 - 2.84). This association was termed "positive" by the investigators, who also noted that the test for interaction between BMI and menopausal hormone therapy was statistically significant (P = .02).

In contrast, no relation between BMI and ovarian cancer was apparent among women who had used HRT when the obese women were compared with the normal-weight women (RR 0.96; 95% CI, 0.65 -1.43).

Exploratory analyses also suggested a "positive association" between BMI and ovarian cancer among women without a family history of ovarian cancer (multivariate RR for obese vs normal-weight women, 1.36; 95% CI, 1.00 - 1.86), but there was no association between BMI and ovarian cancer among women with a positive family history of ovarian cancer (multivariate RR, 0.74; 95% CI, 0.34 - 1.62).

"Ovarian carcinogenesis has a strong hereditary component, a circumstance that may obscure any true association between BMI and ovarian cancer," write the authors about this latter finding.

Sparse, Conflicting Literature

The new study adds to the sparse but conflicting literature on ovarian cancer risk, BMI, and HRT use, say the authors.

One study had similar results to the current study, finding a positive association between BMI and ovarian cancer mortality among women who never used HRT but not among women who had used HRT (Cancer Epidemiol Biomarkers Prev. 2002;11:822-828). This study differed from the current study in a number of ways, including that the fact that it focused on ovarian cancer mortality and not on ovarian cancer incidence.

Another study — a pooled analysis of 12 cohort studies — found no effect modification of the BMI and ovarian cancer relation by HRT use (Cancer Epidemiol Biomarkers Prev. 2008;17:902-912).

Estrogen Effects at Work?

The authors note that a recent meta-analysis showed a 16% increased risk for ovarian cancer in overweight adults and a 30% increased risk in obese adults, compared with normal-weight adults. (The study did not evaluate HRT use.)

With this and other studies like it in hand, researchers have hypothesized that, in postmenopausal women, excess weight and related adiposity increases ovarian cancer risk through the cellular effects of excess estrogens synthesized in adipose tissue by means of aromatization of androgens.

In keeping with this thinking, the relation between adiposity and ovarian cancer should be weaker among HRT users than among nonusers, because users "already exhibit high circulating estrogen levels by means of an exogenous source," say the authors. This type of interaction between adiposity and HRT has been shown previously for various female cancers, including endometrial and breast cancer.

Additional mechanisms might also be in effect, write the authors. Other possible influences include hyperinsulinemia-related insulin-like growth factor (IGF)-1 and androgens. Both IGF-1 and androgens stimulate cell proliferation in ovarian cancer, they note.

FIRST MAXIMIZE STATIN DOSE

Debate About Ezetimibe Not Over Yet: Experts Again Weigh in on Cancer Risk

January 8, 2009 (Boston, Massachusetts) — In its January 1, 2009 issue, the New England Journal of Medicine rings in the New Year with a few high-profile cardiologists once again debating the safety of ezetimibe (Zetia, Merck/Schering-Plough), the controversial cholesterol-lowering medication featured so prominently in the news last year [1,2].

At the heart of an exchange of letters between Dr Steven Nissen (Cleveland Clinic, OH) and Dr Rory Collins and Sir Richard Peto (Clinical Trials Service Unit, Oxford Unit) is whether or not a conclusion can be made that there is "no credible evidence" regarding a cancer risk associated with ezetimibe.

"Provided an appropriate distinction is made between hypothesis-generating and hypothesis-testing findings (as in our article), the trial results provide no credible evidence of an adverse effect of ezetimibe," state Collins and Peto.

Nissen, on the other hand, is not convinced, pointing to an analysis of cancer mortality data that only rules out a risk of death from cancer of 84% or more. "The conclusion that there is no 'credible evidence' for a cancer risk associated with ezetimibe is simply not supported by the data," argues Nissen.

From SEAS To IMPROVE-IT and SHARP

The cancer signal first arose in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a trial presented at the European Society of Cardiology (ESC) in Munich, Germany last year and reported by heartwire at that time. Among those treated with the ezetimibe/simvastatin (Vytorin, Merck/Schering-Plough Pharmaceuticals) combination, there were significantly more cases of fatal or nonfatal cancer compared with those treated with placebo.

When the cancer findings became known, it led to an independent analysis of two ongoing ezetimibe studies, the IMPROVE-IT and SHARP trials, by the Oxford investigators, to determine whether the cancer risk was real or chance.

In IMPROVE-IT and SHARP, which provided more cancer data than the SEAS trial alone, including more data in patients with at least three years of follow-up, there was no increased risk of incident cancer or cancer mortality. When all three trials were combined, there remained an increased risk of death from cancer in the active-treatment arm.

As he also pointed out in his letter to the editor, Nissen, in speaking with heartwire, said the decision to analyze data from IMPROVE-IT and SHARP before those studies were completed sets a dangerous precedent, raises scientific and ethical issues, and is not reliable for the evaluation of drug safety.

"A decision to unblind a clinical trial is something that should be done under only the most extreme circumstances," said Nissen. "Once you unblind a trial, you forever alter the conduct of that study. Most individuals who think very hard about clinical trials will tell you that you better have an extremely good reason for unblinding an ongoing clinical trial, and I don't think there was a good reason here."

Moreover, Nissen said these two incomplete trials represent an incomplete experiment and notes that the mean exposure time to the drug in some patients is insufficient, and this dilutes the signal of risk.

Collins, on the other hand, told heartwire, that unblinding the ongoing studies was appropriate because it is not in the interest of public health to label ezetimibe unsafe without credible evidence that it causes cancer, something that might have occurred if only data from the SEAS trial were available. He said it would have been more shocking not to present the analysis from IMPROVE-IT and SHARP than to present it.

"A dangerous precedent is having this drug being withdrawn from the market, and already we're seeing substantial reductions in its use, when it has been shown to be effective at reducing LDL-cholesterol levels," Collins told heartwire. "Unblinding the study helped us rule out the risk of cancer, and we will continue to study its safety and efficacy in these patients."

In their response to Nissen's letter, Peto and Collins point out that the ongoing studies involve more than four times as many cancers as SEAS but do not suggest an increase in cancer incidence, either in the overall patient population or among those receiving the drug for at least three years. Death from cancer was nonsignificant, although numerically higher and given to rise to the confidence interval highlighted in Nissen's letter.

Cancer Deaths and Incident Cancer

Commenting on the issue for heartwire, Dr Richard Karas (Tufts University School of Medicine, Boston, MA), who has studied cholesterol levels, cholesterol drugs, and cancer risks, pointed out that the cancer risk observed in SEAS occurred primarily in the first year of exposure to the medication. Assessing the hypothesis-testing cancer findings from the IMPROVE-IT and SHARP studies, even though they were incomplete, is justified given that the cancer signal in SEAS occurred so early.

Regarding the unblinding issue, Karas said he is not particularly troubled by the analysis performed by the Oxford investigators. While reporting adverse events before the study is complete is unusual, these studies are not about cancer.

"They didn't spoil anything about the studies," said Karas. "I agree with the Oxford group in that it is unfair to wrongly suggest that a drug is unsafe if it is safe. It is equally important to figure out if those accusations are correct or incorrect in both directions."

Speaking with heartwire, Nissen said he disagreed with the approach and that the medical community would have to live with uncertainty regarding ezetimibe based on the SEAS trial. In the face of such uncertainty, rather than unblind two ongoing studies, "the right approach is to go back to what we know works and go back to what we know is safe, and that is statin therapy, until those trials are done," said Nissen.

Sales of the ezetimibe/simvastatin combination and ezetimibe alone have been on the decline since January 2008, when the results of the ENHANCE carotid intima-media thickness study were made known. In March, at the American College of Cardiology Scientific Sessions in Chicago, IL, where the full results were presented, a panel of experts, including Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), called for a "return to first principles, optimizing the doses of statin medications," rather than adding ezetimibe to a low-dose statin.

According to a recent report in the Associated Press, the total number of US prescriptions for the two drugs was 3.23 million in January 2008, but was down 39% to around two million at the end of November 2008 [3].

1. Nissen SE. Analyses of cancer data from three ezetimibe trials: to the editor. N Engl J Med 2009; 360:86-87. Abstract
2. Collins R, Peto R. Analyses of cancer data from three ezetimibe trials: the authors reply. N Engl J Med 2009; 360:86-87.
3. Johnson L. Schering says cholesterol drug sales falling again. Associated Press, December 18, 2008. Available at www.ap.org

FIRST MAXIMIZE STATIN DOSE

Debate About Ezetimibe Not Over Yet: Experts Again Weigh in on Cancer Risk

January 8, 2009 (Boston, Massachusetts) — In its January 1, 2009 issue, the New England Journal of Medicine rings in the New Year with a few high-profile cardiologists once again debating the safety of ezetimibe (Zetia, Merck/Schering-Plough), the controversial cholesterol-lowering medication featured so prominently in the news last year [1,2].

At the heart of an exchange of letters between Dr Steven Nissen (Cleveland Clinic, OH) and Dr Rory Collins and Sir Richard Peto (Clinical Trials Service Unit, Oxford Unit) is whether or not a conclusion can be made that there is "no credible evidence" regarding a cancer risk associated with ezetimibe.

"Provided an appropriate distinction is made between hypothesis-generating and hypothesis-testing findings (as in our article), the trial results provide no credible evidence of an adverse effect of ezetimibe," state Collins and Peto.

Nissen, on the other hand, is not convinced, pointing to an analysis of cancer mortality data that only rules out a risk of death from cancer of 84% or more. "The conclusion that there is no 'credible evidence' for a cancer risk associated with ezetimibe is simply not supported by the data," argues Nissen.

From SEAS To IMPROVE-IT and SHARP

The cancer signal first arose in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, a trial presented at the European Society of Cardiology (ESC) in Munich, Germany last year and reported by heartwire at that time. Among those treated with the ezetimibe/simvastatin (Vytorin, Merck/Schering-Plough Pharmaceuticals) combination, there were significantly more cases of fatal or nonfatal cancer compared with those treated with placebo.

When the cancer findings became known, it led to an independent analysis of two ongoing ezetimibe studies, the IMPROVE-IT and SHARP trials, by the Oxford investigators, to determine whether the cancer risk was real or chance.

In IMPROVE-IT and SHARP, which provided more cancer data than the SEAS trial alone, including more data in patients with at least three years of follow-up, there was no increased risk of incident cancer or cancer mortality. When all three trials were combined, there remained an increased risk of death from cancer in the active-treatment arm.

As he also pointed out in his letter to the editor, Nissen, in speaking with heartwire, said the decision to analyze data from IMPROVE-IT and SHARP before those studies were completed sets a dangerous precedent, raises scientific and ethical issues, and is not reliable for the evaluation of drug safety.

"A decision to unblind a clinical trial is something that should be done under only the most extreme circumstances," said Nissen. "Once you unblind a trial, you forever alter the conduct of that study. Most individuals who think very hard about clinical trials will tell you that you better have an extremely good reason for unblinding an ongoing clinical trial, and I don't think there was a good reason here."

Moreover, Nissen said these two incomplete trials represent an incomplete experiment and notes that the mean exposure time to the drug in some patients is insufficient, and this dilutes the signal of risk.

Collins, on the other hand, told heartwire, that unblinding the ongoing studies was appropriate because it is not in the interest of public health to label ezetimibe unsafe without credible evidence that it causes cancer, something that might have occurred if only data from the SEAS trial were available. He said it would have been more shocking not to present the analysis from IMPROVE-IT and SHARP than to present it.

"A dangerous precedent is having this drug being withdrawn from the market, and already we're seeing substantial reductions in its use, when it has been shown to be effective at reducing LDL-cholesterol levels," Collins told heartwire. "Unblinding the study helped us rule out the risk of cancer, and we will continue to study its safety and efficacy in these patients."

In their response to Nissen's letter, Peto and Collins point out that the ongoing studies involve more than four times as many cancers as SEAS but do not suggest an increase in cancer incidence, either in the overall patient population or among those receiving the drug for at least three years. Death from cancer was nonsignificant, although numerically higher and given to rise to the confidence interval highlighted in Nissen's letter.

Cancer Deaths and Incident Cancer

Commenting on the issue for heartwire, Dr Richard Karas (Tufts University School of Medicine, Boston, MA), who has studied cholesterol levels, cholesterol drugs, and cancer risks, pointed out that the cancer risk observed in SEAS occurred primarily in the first year of exposure to the medication. Assessing the hypothesis-testing cancer findings from the IMPROVE-IT and SHARP studies, even though they were incomplete, is justified given that the cancer signal in SEAS occurred so early.

Regarding the unblinding issue, Karas said he is not particularly troubled by the analysis performed by the Oxford investigators. While reporting adverse events before the study is complete is unusual, these studies are not about cancer.

"They didn't spoil anything about the studies," said Karas. "I agree with the Oxford group in that it is unfair to wrongly suggest that a drug is unsafe if it is safe. It is equally important to figure out if those accusations are correct or incorrect in both directions."

Speaking with heartwire, Nissen said he disagreed with the approach and that the medical community would have to live with uncertainty regarding ezetimibe based on the SEAS trial. In the face of such uncertainty, rather than unblind two ongoing studies, "the right approach is to go back to what we know works and go back to what we know is safe, and that is statin therapy, until those trials are done," said Nissen.

Sales of the ezetimibe/simvastatin combination and ezetimibe alone have been on the decline since January 2008, when the results of the ENHANCE carotid intima-media thickness study were made known. In March, at the American College of Cardiology Scientific Sessions in Chicago, IL, where the full results were presented, a panel of experts, including Dr Harlan Krumholz (Yale University School of Medicine, New Haven, CT), called for a "return to first principles, optimizing the doses of statin medications," rather than adding ezetimibe to a low-dose statin.

According to a recent report in the Associated Press, the total number of US prescriptions for the two drugs was 3.23 million in January 2008, but was down 39% to around two million at the end of November 2008 [3].

1. Nissen SE. Analyses of cancer data from three ezetimibe trials: to the editor. N Engl J Med 2009; 360:86-87. Abstract
2. Collins R, Peto R. Analyses of cancer data from three ezetimibe trials: the authors reply. N Engl J Med 2009; 360:86-87.
3. Johnson L. Schering says cholesterol drug sales falling again. Associated Press, December 18, 2008. Available at www.ap.org

ANOTHER REGIMEN FOR SCLC

Gemcitabine/Carboplatin Has Relatively Good Efficacy and Tolerability in SCLC

NEW YORK (Reuters Health) Jan 02 - A chemotherapy regimen of gemcitabine and carboplatin has equal efficacy to the gold standard of cisplatin plus etoposide for the treatment of patients with small-cell lung cancer (SCLC) and a poor prognosis.

However, while gemcitabine and carboplatin has a higher incidence of myelosuppression, the incidence of nausea and alopecia is much lower than with cisplatin plus etoposide, and patients tend to be able to tolerate more rounds of treatment, British investigators report in the January issue of Thorax.

Dr. S. M. Lee of University College Hospital in London and colleagues randomized 241 previously untreated patients with SCLC with extensive disease or a poor prognosis to six 3-week cycles of either gemcitabine and carboplatin (GC) or cisplatin plus etoposide (PE).

Ninety percent (216) of the patients died during the study period. There was no difference in overall survival between the two groups. Median survival was 8.0 months with GC and 8.1 months with PE. Median progression-free survival was 5.9 months with GC and 6.3 months with PE.

Grade 3/4 myelosuppression was more common with GC than PE, with anemia occurring in 14% of GC and 2% of PE patients, leucopenia in 32% of GC and 13% of PE patients, and thrombocytopenia developing in 22% of GC and 4% of PE patients. However, hospital admissions, infections and mortality were no higher in the GC group than the PE group.

Grade 2/3 alopecia was much less common with GC, occurring in 17% compared with 68% of PE patients. Nausea occurred in 26% of GC patients and 43% of PE patients.

The six cycles of treatment were completed by 89% of GC patients compared with 66% of PE patients. More patients on PE reported distress over alopecia and impaired cognitive functioning on quality-of-life questionnaires than GC patients.

"GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients," Dr. Lee's team concludes

MAMMOGRAPHIC FINDINGS IN MEN WITH BREAST CANCER

Primary Breast Cancer in Men Has Unique Imaging Features

NEW YORK (Reuters Health) Jan 07 - Men who develop primary breast cancer usually present with an irregular subareolar mass with speculated or indistinct margins on mammography, according to a report in the December issue of the American Journal of Radiology.

"These tumors usually present late with a palpable or clinical finding, such as change in overlying skin or nipple," Dr. Wei-Tse Yang from The University of Texas M. D. Anderson Cancer Center, Houston, told Reuters Health. "Be attentive to any palpable masses in men and obtain imaging evaluation early."

Dr. Yang and colleagues described the mammographic, sonographic, and histopathologic findings of primary breast cancer in 244 men, including the axillary nodal status as determined by sonography.

Only 57 of 244 men with primary breast cancer underwent preoperative mammography or sonography, the authors report, and most of these patients presented with a palpable mass (54 of 57) or nipple inversion (2 of 57) or nipple discharge.

Mammographic findings included a noncalcified mass only (69%), a mass with microcalcifications (29%), or microcalcifications only (2%), the report indicates.

The masses were most frequently irregular (50%) with speculated (33%) or indistinct (32%) margins. Masses were either directly subareolar (58%) or eccentric (42%), and 40% of men also had gynecomastia.

Sonography showed visible masses in 90% of men with cancer, the researchers note, and 30% of men had abnormal axillary nodes by sonography.

Histopathology revealed invasive ductal cancer in most cases (51%), and most tumors were positive for estrogen (93%) or progesterone (79%) receptors.

"The clinical implications of this study are that punctuate calcifications on mammography and circumscribed masses on sonography can be associated with cancer in men," the investigators say. "Radiologists should be aware of these findings to avoid the misdiagnosis of cancer in men as a benign lesion."

"We plan to extend the study to include more patients," Dr. Yang said.

PROTECTIVE EFFECT OF COFFEE

Coffee May Protect Against Oral, Pharyngeal and Esophageal Cancer

NEW YORK (Reuters Health) Jan 06 - In the general population of Japan, coffee consumption is related to a lower risk of cancer of the oral cavity, pharynx and esophagus, new research indicates.

Such an association "has been suggested in case-control studies, but few results from prospective studies are available," Dr. Toru Naganuma of Tohoku University, Sendai, and colleagues note in the December 15 issue of the American Journal of Epidemiology.

To investigate further, they turned to the population-based prospective Miyagi Cohort Study in Japan, a country where consumption of coffee is relatively high, as is the incidence of esophageal cancer in men.

Among 38,679 subjects aged 40 to 64 years with no prior history of cancer, 157 cases of oral, pharyngeal and esophageal cancers were identified during 13.6 years follow up in 135 men and 22 women.

The multivariate-adjusted hazard ratio for these cancers for 1 or more cups of coffee consumed per day compared with no coffee consumption was 0.51, Dr. Naganuma and colleagues report.

This inverse association between coffee consumption and oral, pharyngeal and esophageal cancer was consistent across the strata of sex and cancer site and was also observed in populations at high risk for these cancers, namely, those who were current drinkers and/or smokers at baseline, the investigators note.

"Since we conducted this study on the hypothesis that coffee would have a preventive effect on oral, pharyngeal, and esophageal cancers, the observed associations were approximately consistent with our expectation," Dr. Naganuma noted in comments to Reuters Health.

"However, we had not expected that we could observe such a substantial inverse association with coffee consumption and the risk of these cancers, and the inverse association in high-risk groups for these cancers (drinkers and smokers) as well," the researcher added.

"Although cessation of alcohol consumption and cigarette smoking is currently the best known way to help reduce the risk of developing these cancers, coffee could be a preventive factor in both low-risk and high-risk populations," Dr. Naganuma and colleagues conclude.

A NEW "PROMETASTATIC" GENE DISCOVERED

Scientists Find a Gene That Makes Cancer Spread

CHICAGO (Reuters) Jan 06 - A single gene appears to play a crucial role in deadly breast cancers, increasing the chances the cancer will spread and making it resistant to chemotherapy, U.S. researchers said on Monday.

They found people with aggressive breast cancers have abnormal alterations in a gene called MTDH, and drugs that block the gene could keep local tumors from metastasizing or spreading, increasing a woman's chances for survival.

"Not only has a new metastasis gene been identified, but this also is one of a few such genes for which the exact mode of action has been elucidated," said Dr. Michael Reiss of The Cancer Institute of New Jersey in New Brunswick, whose study appears in the journal Cancer Cell.

"That gives us a real shot at developing a drug that will inhibit metastasis," he said in a statement.

Stopping cancer's spread is important -- while more than 98 percent of patients with breast cancer that has not spread live five years or more, only 27 percent of patients whose cancer has spread to other organs survive.

Reiss and Yibin Kang of Princeton University used several different research approaches to find the gene, which helps tumor cells stick to blood vessels in distant organs.

To get them in the right general area, they used big computer databases of breast tumors and found that a small segment of human chromosome 8 was repeated many times in people with aggressive breast tumors.

While most normal DNA sequences contain only two copies of a gene, they found some breast tumors had as many as eight copies of this gene segment.

The team then turned to human breast tumor samples taken from 250 patients to look for these genetic abnormalities and found the gene MTDH was overly active or expressed in aggressive tumors.

EXISTS IN EVERY CELL

"This gene exists in every one of our cells," Kang said in a telephone interview. "Somehow the tumor gains extra copies and overexpresses them."

"We saw 30 to 40 percent of them overexpressed this gene."

The researchers then injected lab mice with tumor cells from patients who had this genetic alteration and found the mice formed tumors that were more likely to spread.

They also were more likely to resist treatment with traditional chemotherapy drugs, such as paclitaxel.

But when the researchers genetically altered these tumors, inhibiting the MTDH gene, the tumor cells were less able to spread and were more vulnerable to chemotherapy.

Kang said he is hopeful the finding will lead to drugs that not only keep breast cancer from spreading, but also make it more responsive to treatment.

"If we have a drug to inhibit this type of gene, one stone hits two birds," Kang said.

He said MTDH may also play a role in other types of cancers, including prostate cancer. "It's likely to be a broad influence gene," he said.

Kang said he thinks it would be possible to develop an antibody to neutralize the activity of the gene.

Already, it has gained the attention of drugmakers. Kang said he plans to meet with Johnson & Johnson next week.

"I'm quite optimistic we will try to develop a drug as quickly as possible," he said.

RADON AND LUNG CANCER

Reducing Indoor Radon's Contribution to Deaths From Lung Cancer

January 7, 2009 — A new analysis of the contribution that indoor radon makes to deaths from lung cancer suggests that universal strategies to reduce radon in the home would be cost-effective and could make a "modest and worthwhile contribution" to reducing deaths from lung cancer, together with existing policies to reduce smoking. The report was published online January 6 in BMJ.

The new analysis, described by an accompanying editorial as the "most extensive and detailed evaluation to date," was carried out in the United Kingdom. However, the conclusions are likely to apply to most developed countries, many of which have higher mean radon concentrations, say the authors, headed by Alistair Gray, PhD, professor of health economics at Oxford University, in the United Kingdom.

Radon is a known lung carcinogen, and many countries already have policies to control radon within homes. Produced by the decay of uranium in the ground, radon seeps upward and enters buildings through cracks or holes in the foundation, the editorialists explain. Preventive measures involve installing a sealed membrane at ground level, under-floor ventilation, and a radon sump pump.

"Of course, smoking is by far the number 1 risk factor for lung cancer, and everything else comes far after it," said Anssi Auvinen, DMedSc, professor of epidemiology at the Tampere School of Public Health, in Finland, who coauthored the editorial. "But among the risk factors that come after smoking, indoor radon is a very close second, along with occupational exposure to asbestos and secondary exposure to smoking."

Indoor radon may account for about 5% of all lung cancer in the United Kingdom, and up to 10% of lung cancer in many other European countries, where radon levels are higher, Dr. Auvinen said in an interview with Medscape Oncology.

Reducing indoor radon levels is an important public-health issue, said Dr. Auvinen. Some authorities, such as radiation-protection agencies, believe that everything possible should be done to reduce radon levels, but there is an alternative view, and some public-health authorities advocate concentrating on tobacco, because most of the radon-induced lung cancers occur in smokers, he said. Radon increases the risk for lung cancer in everybody, but smokers have a much higher absolute risk because smoking substantially increases their baseline risk levels, Dr. Auvinen explained.

His view is that, "providing that we are doing pretty much all we can to combat smoking, we should also fight against indoor radon."

Contribution to Deaths From Lung Cancer

In their paper, Dr. Gray and colleagues used 2006 Cancer Research UK cancer statistics to calculate that radon is responsible for about 3.3% of all deaths from lung cancer, accounting for around 1100 deaths each year. Most of the deaths are caused jointly by radon and active smoking, the researchers comment (about 1 in 7 deaths is caused by radon and not active smoking).

The proportion of lung cancers attributable to radon could be higher in many other European countries, the editorialists comment, because the United Kingdom has relatively low radon concentrations. The mean indoor radon concentration in British homes is 21 becquerels per cubic meter (Bq/m³), the authors note. Dr. Auvinen said that the average indoor radon concentration in Nordic countries is 100 Bq/m³.

Universal Strategy to Reduced Indoor Radon

At present, many countries have policies to control radon only in areas where the concentrations are above a specified value, known as the "action level" or "reference level," Dr. Gray and colleagues comment. In the United Kingdom, this level currently stands at 200 Bq/m³, and current policy is mainly concerned with identifying existing homes with radon measurements above this level and implementing full preventive measures (including under-floor ventilation and a radon sump pump and associated pipework, in addition to the basic preventive measure of a ground-level membrane). There is also a policy of installing basic preventative measures in all new homes in geographic areas that have high radon levels.

In their paper, the authors outline calculations to show that this policy of identifying homes with high radon concentrations and then taking action in them is not cost effective.

They also question the logic behind the current policy. There is now direct evidence to show that indoor radon causes lung cancer in the general population, not only at high concentrations but also at concentrations below the current action level of 200 Bq/m³, they write. Only 0.4% of all homes in the United Kingdom have radon concentrations of 200 Bq/m³ or higher, and these are designated by the Health Protection Agency as "radon affected." However, they estimate that only 4% of all the radon-related lung cancer deaths would be found in these homes.

"Although people living in such homes have a greater risk than those living in homes with lower measurements, few such people exist," they point out. The great majority of the radon-related lung cancer deaths arise elsewhere, they say, estimating that 70% of these deaths are in homes where the radon concentrations are below 50 Bq/m³.

Dr. Gray and colleagues suggest that the second policy, installing anti-radon measures in all new houses, should be implemented universally, and not just in geographically high-radon areas, because it has more potential to reduce deaths from lung cancer. They outline calculations to show that it would be cost-effective.

During a period of 10 years, the current policy of taking action only in homes with high radon concentrations would avert only 5 deaths per year across the entire British population, whereas the suggested policy of basic measures in all new homes would avert 44 deaths from lung cancer per year, they write.

"We conclude that basic preventive measures against radon in new homes is likely to be a highly cost-effective public-health intervention measure, with the potential to make a modest but worthwhile contribution to reducing the annual number of deaths from lung cancer in the UK, alongside existing policies to reduce smoking," Dr. Gray and colleagues conclude. Because the concentrations of radon in the United Kingdom are lower than in most other countries, "similar policies are likely to be even more cost-effective elsewhere, depending on the extent of smoking-related lung cancer," they add.

Policies Need to Be Tailored Locally and Nationally

The editorialists point out that cost-effectiveness is context specific. "Policies for preventing lung cancer caused by radon should be tailored to the local or national distribution of radon concentrations in dwellings," they advise. For example, it may still be cost-effective to measure levels and take action in areas where there are a large proportion of homes with high indoor radon concentrations.

"The joint effect of radon and smoking is also important," they add. "Because 85% of radon-induced cancers occur in people who smoke, the deleterious effects of indoor radon on health could largely be avoided by eliminating smoking." This is reflected in the finding that reducing indoor concentrations of radon may not be cost-effective for people who have never smoked, the editorialists comment.

HBV REACTIVATION WITH RITUXIMAB

J Clin Oncol. 2008 Dec 15. [Epub ahead of print]

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Hepatitis B Virus Reactivation in Lymphoma Patients With Prior Resolved Hepatitis B Undergoing Anticancer Therapy With or Without Rituximab.

Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, Chan HL, Hui EP, Lei KI, Mok TS, Chan PK.

Departments of Clinical Oncology, Microbiology, and Medicine and Therapeutics, and Stanley Ho Centre for Emerging Infectious Diseases, School of Public Health, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin; and Department of Medicine, Alice Ho Mui Ling Nethersole Hospital, Tai Po, Hong Kong Special Administrative Region, China.

PURPOSE: Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in cancer patients with chronic HBV (hepatitis B surface antigen [HBsAg] positive) undergoing cytotoxic chemotherapy. In patients who have resolved HBV (HBsAg negative and antibody to hepatitis B core antigen [anti-HBc] +/- antibody to hepatitis B surface antigen [anti-HBs] positive), such incidence has been much less common until recent use of rituximab. In this study on HBsAg-negative/anti-HBc-positive lymphoma patients, the objectives were to determine the HBV reactivation rate in patients treated with rituximab-containing chemotherapy and to compare it with the rate in patients treated without rituximab. PATIENTS AND METHODS: Between January 2003 and December 2006, all patients diagnosed with CD20(+) diffuse large B-cell lymphoma (DLBCL) had HBsAg determined before anticancer therapy. They were treated with either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone or rituximab plus CHOP (R-CHOP). HBsAg-negative patients had anti-HBc determined; serum was stored for anti-HBs and HBV DNA. All patients were observed for HBV reactivation, which was defined as detectable HBV DNA with ALT elevation during and for 6 months after anticancer therapy. RESULTS: Among 104 CD20(+) DLBCL patients, 80 were HBsAg negative. Of the latter, 46 patients (44.2%) were HBsAg negative/anti-HBc positive; 25 of these patients were treated with CHOP, and none had HBV reactivation. In contrast, among the 21 patients treated with R-CHOP, five developed HBV reactivation, including one patient who died of hepatic failure (P = .0148). Exploratory analysis identified male sex, absence of anti-HBs, and use of rituximab to be predictive of HBV reactivation. CONCLUSION: Among HBsAg-negative/anti-HBc-positive DLBCL patients treated with R-CHOP, 25% developed HBV reactivation. Close monitoring until at least 6 months after anticancer therapy is required, with an alternative approach of prophylactic antiviral therapy to prevent this potentially fatal condition.

METASTATECTOMY THE BEST CHANCE FOR CURE

Int J Colorectal Dis. 2008 Dec 16. [Epub ahead of print]

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Two-stage hepatectomy (R0) with portal vein ligation-towards curing patients with extended bilobular colorectal liver metastases.

Homayounfar K, Liersch T, Schuetze G, Niessner M, Goralczyk A, Meller J, Langer C, Ghadimi BM, Becker H, Lorf T.

Department of General and Visceral Surgery, University Medical Center Göttingen, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany, khomayounfar@chirurgie-goettingen.de.

BACKGROUND AND AIMS: Patients with bilobular colorectal liver metastases (CRLM) experience poor prognosis, especially when curative resection cannot be achieved. However, resectability in these patients is often limited by low future remnant liver volume (FRLV). The latter can be enhanced by a two-stage liver resection, using portal vein ligation to induce liver hypertrophy. The aim of this prospective pilot study was to evaluate safety, secondary resectability, and time to recurrence of two-stage hepatectomy with portal vein ligation (PVL) and complete surgical clearance of the FRLV in patients with bilobular CRLM. MATERIALS AND METHODS: Out of 24 patients (63 +/- 8.26 years) with extended bilobular CRLM (metachronous n = 10, synchronous n = 14), 18 received preoperative 5-FU-based chemotherapy combined with oxaliplatin or irinotecan. Staging included thoracoabdominal computed tomography and (18)F-fluorodeoxyglucose-positron emission tomography scans. First-stage procedure consisted of PVL, resection of all CRLM in the FRLV, and radiofrequency ablation (RFA) of CRLM situated near the future resection plane. RESULTS: During first-stage procedure, 7x RFA, 4x non-anatomical resections, and 4x bisegmentectomies were performed additionally to PVL. FRLV/body-weight ratio increased from 0.4% to 0.6% within 55 days (median) after PVL. Second-stage hepatectomy was performed in 19 patients without tumor progression. R0 resection was possible in 14 patients. During a median follow-up of 17 months, intrahepatic recurrence occurred in two, and extrahepatic recurrence in nine out of 14 patients. CONCLUSION: Two-stage hepatectomy with PVL and complete surgical clearance of FRLV is safe even after intensified systemic chemotherapy resulting in a curative resection rate of 58.3% (73.7% of re-explored cases).

TIME TO INCLUDE ERCC1 IN CHEMOTHERAPY DECISIONS?

Cancer Chemother Pharmacol. 2009 Jan 3. [Epub ahead of print]

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Expression of ERCC1 and class III beta-tubulin in non-small cell lung cancer patients treated with a combination of cisplatin/docetaxel and concurrent thoracic irradiation.

Azuma K, Sasada T, Kawahara A, Hattori S, Kinoshita T, Takamori S, Ichiki M, Imamura Y, Ikeda J, Kage M, Kuwano M, Aizawa H.

Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan, azuma@med.kurume-u.ac.jp.

INTRODUCTION: The expression of excision repair cross-complementation group 1 (ERCC1) is reported to be correlated with resistance to platinum-based drugs. Class III beta-tubulin is reported to be correlated with resistance to taxanes. METHODS: In the present study, we evaluated whether ERCC1 and class III beta-tubulin expression could be used to predict progression-free and/or overall survival in 34 patients with locally advanced non-small cell lung cancer (NSCLC) receiving concurrent chemoradiation therapy with cisplatin and docetaxel, and immunohistochemistry was used to examine the expression of these two proteins in tumor samples obtained from the patients. RESULTS: Immunostaining for ERCC1 and class III beta-tubulin was positive in 16 and 12 patients, respectively. A significant correlation was observed between ERCC1 expression and response to chemotherapy (P = 0.012), and between class III beta-tubulin expression and histology (P = 0.029). Patients negative for ERCC1 had a significantly longer median progression-free (62.5 vs. 36 weeks, P = 0.009), but not overall (171 vs. 50.5 weeks, P = 0.208), survival than those positive for ERCC1. Expression of class III beta-tubulin was not correlated with progression-free or overall survival (P = 0.563 and P = 0.265, respectively). Multivariate analysis adjusting for possible confounding factors showed that negative ERCC1 expression (hazard ratio = 3.972, P = 0.009) was a significantly favorable factor for progression-free survival. CONCLUSIONS: This retrospective study indicates that immunostaining for ERCC1 may be useful for predicting survival in NSCLC patients receiving concurrent chemoradiotherapy with cisplatin and docetaxel, and can provide information critical for planning personalized chemotherapy.

TRENDS IN MULTIPLE MYELOMA

Eur J Haematol. 2008 Nov 6. [Epub ahead of print]

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Considerations in the treatment of multiple myeloma: A consensus statement from Italian experts.

Patriarca F, Petrucci MT, Bringhen S, Baldini L, Caravita T, Corradini P, Corso A, Di Raimondo F, Falcone A, Ferrara F, Morabito F, Musto P, Offidani M, Petrini M, Rizzi R, Semenzato G, Tosi P, Vacca A, Cavo M, Boccadoro M, Palumbo A.

Division of Hematology and Transplant Unit "Carlo Melzi", Dpt Morphological and Clinical Research, University of Udine.

ABSTRACT Purpose and basic procedure of the study: The availability of new targeted therapies has revolutionised the treatment of multiple myeloma (MM), for both the newly diagnosed and the relapsed and refractory settings. A panel of Italian experts provided guidelines for optimal clinical practice in the treatment of MM. Main findings and conclusions: The panel recommended that treatment should only be initiated in symptomatic patients. Autologous stem cell transplantation (ASCT) with melphalan is the treatment of choice in patients younger than 65 years, and induction therapy including new drugs seems the most suitable preparatory regimen before ASCT. In patients who fail to achieve at least a very good partial response (VGPR) after transplant, a consolidation with a second transplant is of clinical benefit. Also, there is evidence that maintenance with thalidomide after ASCT in young patients failing to reach at least VGPR could prolong survival. In elderly patients, the combination of an alkylating drug with a novel agent should be considered as standard approach. Relapsed MM should be retreated after the reappearance of symptoms and signs of organ and tissue damage. Salvage regimens should include corticosteroids plus bortezomib, thalidomide or lenalidomide.

ORAL BISPHOSPHONATES AND OSTEONECROSIS

J Am Dent Assoc. 2009 Jan;140(1):61-6.

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Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: An institutional inquiry.

Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes S, Lowry B, Shuler CF.

BACKGROUND: Initial reports of osteonecrosis of the jaw (ONJ) secondary to bisphosphonate (BP) therapy indicated that patients receiving BPs orally were at a negligible risk of developing ONJ compared with patients receiving BPs intravenously. The authors conducted a study to address a preliminary finding that ONJ secondary to oral BP therapy with alendronate sodium in a patient population at the University of Southern California was more common than previously suggested. METHODS: The authors queried an electronic medical record system to determine the number of patients with a history of alendronate use and all patients receiving alendronate who also were receiving treatment for ONJ. RESULTS: The authors identified 208 patients with a history of alendronate use. They found that nine had active ONJ and were being treated in the school's clinics. These patients represented one in 23 of the patients receiving alendronate, or approximately 4 percent of the population. CONCLUSIONS: This is the first large institutional study in the United States with respect to the epidemiology of ONJ and oral bisphosphonate use. Further studies along this line will help delineate more clearly the relationship between oral BP use and ONJ. CLINICAL IMPLICATIONS: The findings from this study indicated that even short-term oral use of alendronate led to ONJ in a subset of patients after certain dental procedures were performed. These findings have important therapeutic and preventive implications.

SOLUBLE IL-2 RCEPTORS IN DLBCL

Ann Oncol. 2008 Dec 12. [Epub ahead of print]

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Soluble interleukin-2 receptor retains prognostic value in patients with diffuse large B-cell lymphoma receiving rituximab plus CHOP (RCHOP) therapy.

Ennishi D, Yokoyama M, Terui Y, Asai H, Sakajiri S, Mishima Y, Takahashi S, Komatsu H, Ikeda K, Takeuchi K, Tanimoto M, Hatake K.

Department of Medical Oncology and Hematology, Cancer Institute Hospital, Tokyo.

BACKGROUND: Soluble interleukin-2 receptor (SIL-2R) is known to be a prognostic parameter in patients with diffuse large B-cell lymphoma (DLBCL) receiving cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) therapy. However, its prognostic value has not been well known since the introduction of rituximab. PATIENTS AND METHODS: We retrospectively evaluated the prognostic impact of SIL-2R in 228 DLBCL patients, comparing 141 rituximab-combined CHOP (RCHOP)-treated patients with 87 CHOP-treated patients as a historical control. RESULTS: Patients with high serum SIL-2R showed significantly poorer event-free survival (EFS) and overall survival (OS) than patients with low SIL-2R in both the RCHOP group (2-year EFS, 66% versus 92%, P < p =" 0.005)" style="border-bottom: 1px dashed rgb(0, 102, 204); cursor: pointer;" class="yshortcuts" id="lw_1231353132_16">International Prognostic Index (IPI) and two-categorized IPI revealed that SIL-2R was an independent prognostic factor for EFS and OS in the RCHOP group as well as in the CHOP group. CONCLUSIONS: Our results demonstrate that SIL-2R retains its prognostic value in the rituximab era. The prognostic value of SIL-2R in DLBCL patients receiving rituximab-combined chemotherapy should be reassessed on a larger scale and by long-term follow-up.

GRADE 2 CIN

Nearly Half of Grade 2 Cervical Intraepithelial Neoplasias Will Regress

NEW YORK (Reuters Health) Jan 05 - Approximately 40% of cervical intraepithelial neoplasia grade 2 (CIN2) will regress within 2 years, according to a study published in the January issue of Obstetrics and Gynecology.

However, the same study found that CIN2 caused by human papillomavirus type 16 (HPV-16) is much less likely to regress.

Dr. Philip E. Castle of the National Cancer Institute in Bethesda and colleagues used data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) to compare the cumulative incidences of CIN2, CIN3 or more severe diagnoses in the 2-year study.

ALTS was a multicenter, randomized trial comparing three management strategies for women referred for atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL).

The study population consisted of 3,488 women with ASC-US and 1,572 women with LSIL. There were 397 cases of CIN2 and 542 cases of CIN3 or more severe disease.

The three strategies were immediate colposcopy, HPV triage, or conservative management. In the HPV triage arm, women were referred to immediate colposcopy if they were HPV-positive at enrollment, if there was no information on HPV status at enrollment, or if cytology showed high-grade squamous intraepithelial lesion (HSIL) at enrollment.

Dr. Castle and associates report no significant difference in the cumulative 2-year incidence of CIN3 or more severe disease between the study arms. The rate was 10.9% with conservative management, 10.3% with HPV triage and 10.9% with immediate colposcopy.

In contrast, there was a significant variation in the 2-year incidence of CIN2 between treatment arms. CIN2 incidence was 5.8% for women assigned to conservative management, 7.8% for women assigned to HPV triage, and 9.9% for women assigned to immediate colposcopy.

During the 2-year study period, there was an increasing number of women with CIN2 referred to colposcopy at baseline. The relative differences in incidence of CIN2, by study arm, among women who tested HPV-16 positive at baseline were less pronounced than women who tested positive for other high-risk-HPV genotypes.

"Nearly half of all CIN2, a diagnosis that is considered a precancerous diagnosis and is treated by excisional procedures, will regress without treatment, (although) CIN2 caused by HPV-16 is less likely to regress," Dr. Castle told Reuters Health.

"Thus, many women with CIN2 are being treated for benign lesions that are probably not precancerous. Because treatment has negative reproductive consequences (e.g., preterm delivery), improved management strategies for CIN2 to reduce unnecessary treatment while still identifying and treating women with precancerous lesions are needed."

"HPV-16-positive CIN2 seems less likely to regress, perhaps as the result of its greater tendency to persist and its greater oncogenic potential to progress to precancerous lesions than other HPV genotypes," Dr. Castle and colleagues write.

"When HPV genotyping from validated tests becomes routinely available, detection of HPV-16 may be a useful stratifier of risk for deciding the clinical management of CIN2 diagnoses."

"A clinical trial to determine the best management strategies for CIN2, akin to ALTS for ASC-US and LSIL Pap tests, is needed," they add.