IMATINIB FOR POLYCYTHEMIA RUBRA VERA?

Int J Hematol. 2008 Nov 15. [Epub ahead of print]

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Phase II open label trial of imatinib in polycythemia rubra vera.

Jones CM, Dickinson TM, Salvado A.

The Jones Clinic, 7710 Wolf River Circle, Germantown, TN, 38138, USA, jonesmd@bellsouth.net.

Polycythemia rubra vera is a chronic myeloproliferative disorder characterized by panmyelosis with the resultant potential for thrombosis, myelofibrosis, and acute leukemia. Treatment has rested on phlebotomy and hydroxyurea. In 2002, we reported two patients who were unable to tolerate hydroxyurea but responded to imatinib mesylate (Gleevec). These patients have remained in complete hematologic remission on imatinib since 1999. As a result we began a phase II, open label trial of imatinib in patients with polycythemia vera. Patients meeting the Polycythemia Vera Study group criteria for the diagnosis of polycythemia vera, either naïve or intolerant to prior treatment were allowed to enroll. Initial therapy was begun with imatinib mesylate at 400 mg a day and two dose escalations, one to 600 and second to 800 mg a day, were allowed for patients not achieving a target hematocrit of 44 or less; or a platelet count of less than 600,000/mm(3). Twenty patients were enrolled, 15 achieved complete hematologic remission within 12 weeks and ten remain on study. Six patients remain in remission on 400 mg a day and four on 500 mg a day. Gastrointestinal or cutaneous toxicities were primarily grade I or II. All patients were negative for bcr/abl. Imatinib mesylate is capable of producing hematologic remission in the majority of patients with polycythemia vera and provides another option for patient management, particularly in those intolerant to hydroxyurea.

NO ROLE FOR DOCETAXEL CONSOLIDATION

J Clin Oncol. 2008 Nov 10. [Epub ahead of print]

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Phase III Study of Cisplatin, Etoposide, and Concurrent Chest Radiation With or Without Consolidation Docetaxel in Patients With Inoperable Stage III Non-Small-Cell Lung Cancer: The Hoosier Oncology Group and U.S. Oncology.

Hanna N, Neubauer M, Yiannoutsos C, McGarry R, Arseneau J, Ansari R, Reynolds C, Govindan R, Melnyk A, Fisher W, Richards D, Bruetman D, Anderson T, Chowhan N, Nattam S, Mantravadi P, Johnson C, Breen T, White A, Einhorn L.

Indiana University Melvin and Bren Simon Cancer Center; Hoosier Oncology Group, Indianapolis; Michiana Hematology Oncology, South Bend; Ball Memorial Hospital Cancer Center, Muncie; Center for Cancer Care at Goshen Health System, Goshen; Cancer Care Center, Inc, New Albany; Ft Wayne Medical Oncology and Hematology; Radiation Oncology Associates PC, Ft Wayne, IN; Kansas City Cancer Centers, Overland Park, KS; U.S. Oncology, Houston; Texas Cancer Center, Abilene; Tyler Cancer Center, Tyler; Mid Cities Oncology, Bedford, TX; Chandler Medical Center, Lexington, KY; New York Oncology Hematology PC, Albany, NY; Ocala Oncology Center, Ocala, FL; and Washington University Siteman Cancer Center, St Louis, MO.

PURPOSE: Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non-small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. PATIENTS AND METHODS: Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second >/= 1 L, and less than 5% weight loss. Patients received P 50 mg/m(2) intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m(2) IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m(2) IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis). RESULTS: On the basis of evidence of futility, a data and safety monitoring board recommended early termination after an analysis of the initial 203 patients. Patient characteristics (n = 203) were as follows: 34% female; median age, 63 years; 39.4% stage IIIA; and 60.6% stage IIIB. One hundred forty-seven (72.4%) of 203 patients were randomly assigned to docetaxel (n = 73) or observation (n = 74). Grade 3 to 5 toxicities during docetaxel included febrile neutropenia (10.9%) and pneumonitis (9.6%); 28.8% of patients were hospitalized during docetaxel (v 8.1% in observation arm), and 5.5% died as a result of docetaxel. The MST for all patients (n = 203) was 21.7 months; MST was 21.2 months for docetaxel arm compared with 23.2 months for observation arm (P = .883). CONCLUSION: Consolidation docetaxel after PE/XRT results in increased toxicities but does not further improve survival compared with PE/XRT alone in patients with stage III inoperable NSCLC.

AFTER KRAS IT IS TIME FOR BRAF

J Clin Oncol. 2008 Nov 10. [Epub ahead of print]

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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer.

Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A.

Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo; The Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda; Italian Foundation for Cancer Research-Institute of Molecular Oncology, Milan, Italy; Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno; and Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland.

PURPOSE: Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS: We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. RESULTS: KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION: BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

SMOKING RATE IS DECLINING IN DEVELOPED COUNTRIES

Smoking Rate Is Declining in US

November 17, 2008 — The percentage of Americans who smoke cigarettes has fallen below 20% for the first time since at least the mid-1960s, according to a new report.

The CDC says in its Morbidity and Mortality Weekly Report that the prevalence of smoking fell in 2007 to 19.8%, nearly a full percentage point from 20.8% in 2006.

"This is good news," Matthew McKenna, MD, MPH, director of the CDC's Office on Smoking and Health, tells WebMD. "But deaths related to cigarette smoking are still increasing. Almost one in five adult Americans smoke, and many former smokers are succumbing to their habit again."

Tom Glynn, PhD, director of International Cancer Control of the American Cancer Society, says the CDC report shows that major progress is being made in the government's war on smoking, but hard battles still loom.

"This is the lowest level since the late 1920s, at least," Glynn tells WebMD. "We've gotten back to where we were more than 80 years ago."

The CDC says cigarette smoking prevalence has been dropping steadily among Americans 18 and older since it began keeping records in 1965, when 42.4% smoked. The proportion dropped below 30% for the first time in 1987, when 28.8% of Americans smoked.

"We think the proportion is dropping because of excise taxes that make cigarettes more expensive, smoke-free laws [that apply to most workplaces], and the availability of counseling and medications," McKenna says.

In 2007, the CDC says 22.3% of adult males and 17.4% of adult women smoked. It says 19.8% of African-Americans smoked in 2007, and 21.4% of whites.

The CDC says 443,000 deaths annually are attributed to tobacco use.

Lung cancer, the leading cause of cancer death among men and women, kills about 157,000 Americans a year. A greater number of people die of lung cancer than of colon, breast, and prostate cancers combined.

Trying to Quit Smoking

"The most important thing people can do if they are smoking is to quit," McKenna says. "These studies show 30% to 40% of smokers try to quit, but chances of being successful without help are only 4% to 5%."

Progress would be better if more people were aware that their doctors could help and if they knew about a toll-free counseling "quit line" offering advice at 800-QUIT-NOW (800-784-8669), McKenna tells WebMD.

The report also says that:

• 43.4 million Americans are smokers.
• Smoking has declined over at least the past 40 years among all socio-demographic groups.
• Smoking prevalence varies according to education levels. Smokers who had a general education development diploma had the highest prevalence rate at 44%. People with nine to 11 years of education had a prevalence rate of 33.3%, compared with 11.4% of those with college degrees and 6.2% with graduate degrees.
• Mortality rates for people with chronic obstructive pulmonary disease (COPD) increased 8% from 2000 to 2005.
• COPD deaths among women rose to 60,229 annually between 2000 and 2004, up from 56,363 between 1997 and 2001. Among men, annual deaths remained about the same in both periods at 58,000. COPD, which is treatable, is caused mainly by cigarette smoking, but also occupational hazards, air pollution, and secondhand smoke.
• Exposure to tobacco smoke resulted in 5.1 million years of potential life lost during 2000-2004 and $96.8 billion in annual productivity losses ($64.2 billion for males, $32.6 billion for females.)

Smoking and Disease

McKenna tells WebMD that the three leading causes of smoking-related death are lung cancer, heart disease, and COPD. He says between 30% and 40% of smokers try to quit annually, but the success rate is only one in five.

It's unlikely, he adds, that the U.S. will reach its goal of reducing smoking prevalence to 12% in the next two years. But he says media campaigns, excise taxes, and rules implementing smoke-free environments are playing roles in reducing smoking.

Also, he says, "there are now more former smokers than active smokers."

Benefits for those who quit are significant, he says, because stopping smoking drastically reduces risks of cardiovascular disease and COPD.

Glynn says the American Cancer Society fears many people who've quit may start again because "they are thinking they are self-medicating for anxiety and economic difficulties."

He says studies "have shown that smoking in the movies" induces youths to smoke. Glynn also says nonsmoking women are getting lung cancer at higher rates than nonsmoking men, but the reasons aren't clear.

The CDC studies, Glynn says, reinforce that "if we raise taxes [on cigarettes] and continue to widen access to cessation treatment," prevalence will go down more.

STENT NOT FOR EVERY ARTERY

ASN 2008: Stents Provide No Benefit in Renal Artery Revascularization

November 14, 2008 (Philadelphia, Pennsylvania) — New data reveal that using stents to open up kidney arteries, a procedure commonly used to treat patients with atherosclerotic renovascular disease, provides no benefit. This is the conclusion of the Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial, which was presented here at Renal Week 2008, the American Society of Nephrology Annual Meeting, by Keith Wheatley, professor of medical statistics and codirector, University of Birmingham (UK) Clinical Trials Unit.

From 2000 to 2007, Dr. Wheatley and his colleagues, including lead nephrologist Phil Kalra, MD, and lead interventional radiologist Professor Jon Moss, studied 806 patients with atherosclerotic disease. Patients were randomized to revascularization with medical therapy or medical therapy alone. Study end points were renal function (serum creatine level), blood pressure, major renal and vascular events, and mortality.

Outcomes were measured at 5 years using repeated measures analysis for continuous data, and survival analysis for time-to-event data with hazard ratios (HR) and 95% confidence intervals (CI) reported. Baseline values (means) were age, 71 years; serum creatine, 179 µmol/L; glomerular fraction rate, 40 mL/minute; blood pressure, 150/76 mm Hg; percent receiving stenosis, 76%; and men, 63%.

Study data revealed no difference between the revascularization and medical-treatment only groups for renal events (46 vs 47; HR, 0.98; 95% CI, 0.66 - 1.48; P = .90); cardiovascular events (95 vs 107; HR, .90; 95% CI, 0.66 - 1.15, P = .30); or mortality (79 vs 81; HR, .92; 95% CI, 0.68 - 1.26; P = .60). The overall mortality rate during the study was 43%.

"In the group of patients with incidental renal artery stenosis, our findings are that there is no benefit whatsoever of renal revascularization over purely medical treatment. These are the groups of patients for whom one discovers incidental renal disease," Dr. Kalra told Medscape Nephrology.

"Also, in patients with advanced CKD [chronic kidney disease] with renal artery stenosis, or with severe hypertension, there is no benefit found either in renal or blood pressure levels as a result of revascularization, so there is no point in subjecting patients to a procedure that has definite dangers," continued Dr. Kalra, who is affiliated with the department of renal medicine, Salford Royal Hospital, Manchester, United Kingdom.

"Our study showed no apparent benefit for revascularization to any subgroups," Professor Wheatley told Medscape Nephrology. "Such 'negative' trials are, nevertheless, very useful and enable treatments that do not work, and which may have risks associated with them, to be eliminated from practice."

"We haven't answered the whole question here," Dr. Kalra continued. "There might be subgroups that might benefit from revascularization ... We anticipate further subgroup evaluation, several post hoc analyses to look at other issues, such as severity of disease and mortality within subgroups."

"This is a disease that is important, and is increasing in frequency as best as we can tell, and we don't have a lot of data about whether the use of stents for renal artery stenosis is better or doesn't do anything for these patients," Stuart Linas, MD, told Medscape Nephrology. "As such, this is really the first big study published in this area, and is very important in that regard.

"After saying that, I have a couple of concerns that we can't quite make the kinds of generalized conclusions that the authors make, that maybe we shouldn't be performing these stenting procedures. ... I don't agree that the ASTRAL study is really going to answer that question," said Dr. Linas, who is a professor of medicine, University of Colorado Health Sciences Center, Denver Health Medical Center.

"The study authors are very proud of the fact that the study entry criteria were pretty broad-based," Dr. Linas continued. "I'm not sure yet, from what I've seen, that these populations are well-matched with regard to underlying cardiovascular disease, underlying chronic kidney disease, and things like that."

"The second thing that concerns me is that I don't know what the extent of renal artery stenosis is in all these patients. The authors don't define it as well as I would like them to, with regard to whether they know if these are clinically significant renal artery lesions. By that I mean, is it something that is really a tight stenosis, that might lead to one outcome; or is it not such a tight stenosis. I wish they had better defined that issue before doing the study, because it is possible [that] they were stenting people that didn't need to be stented in the first place."

"The last comment that I would make, which I think is important, is that they standardized as 'stent' or 'no stent,' and stated that everybody got 'treated medically.' I don't know what that means — were the patients in those groups treated to the same level of blood-pressure control, because we know that that will affect both the CV [cardiovascular] outcomes and the kidney outcomes; were they all on ACEs [angiotensin-converting enzymes] or ARBs [angiotensin receptor blockers], or was there a difference between the groups; was their statin and other cholesterol management the same; were they all on angiotensin receptor blockers, or were some on and some not?"

"The bottom line is that this is an important topic, and the researchers deserve a lot of credit," Dr. Linas continued. "But there are a lot of things about this study that make me worry that it is not as generalizable as they would have you believe."

"There is a study under way called the CORAL study (Cardiovascular Outcomes in Renal Artery Lesions), funded by the NIH [National Institutes of Health]," he continued. "This study perhaps better defines population groups and degree of stenosis, and addresses the concerns I have. That's the one I think will be more helpful to answer some of these questions."

The ASTRAL study received no commercial funding. Dr. Wheatley, Dr. Kalra, and Dr. Linas reported no relevant financial relationships.

RARE TESTICULAR TUMOR

Summary

Background: A 65-year-old man presented to an oncology clinic with bilateral testicular masses, lower extremity edema, and cushingoid appearance.
Investigations: Measurements of serum cortisol and adrenocorticotropic hormone levels, testicular ultrasound and abdominal CT scans, and review of histopathology to identify the cellular origin of the ectopic cortisol production.
Diagnosis: Cushing syndrome was diagnosed on the basis of a markedly elevated 24-hour urine free cortisol level and classic cushingoid features. The etiology of Cushing syndrome was determined to be an adrenocortical carcinoma arising from testicular adrenal rest cells. Nevertheless, the possibility of a malignant Leydig cell tumor with ectopic cortisol production could not be excluded.
Management: Mitotane and metyrapone were used to decrease cortisol production. Excess mineralocorticoid activity was blocked with spironolactone; sodium retention was also managed with sodium restriction and diuretics. Despite initial success with this regimen, the patient died as a result of tumor progression and complications of poorly controlled hypercortisolism.

BE CAREFUL WITH TANNING DRUGS

Health Regulators Warn About Tanning Drug

LONDON (Reuters) Nov 17 - Health regulators warned people on Monday not to use an injectable tanning drug because its potential side-effects are unknown.

Melanotan, which is available over the Internet and at some salons and gyms, produces a tan in users by boosting the amount of melanin, the body's natural protection from the sun.

However the treatment is unlicensed and tests have not been carried out to see what possible side-effects there are or how serious they could be, the Medicines and Healthcare Products Regulatory Agency (MHRA) said.

"We are warning people not to use this product. Don't be fooled into thinking that Melanotan offers a shortcut to a safer and more even tan," said David Carter, Head of the Medicines Borderline Section at the MHRA.

"The safety of these products is unknown and they are unlicensed in the UK. The side-effects could be extremely serious."

One user of Melanotan said it required about 10 injections to produce a "nice tan" and a further weekly injection to maintain it.

"Now I've started using it and seen the difference it makes, I'll carry on using it until I hear something different," Stacey Boardman told the BBC.

Illicit sales of medicines via the Web are a growing problem since many of the products are counterfeits of dubious quality and potentially dangerous.

Last week authorities in nine countries including Britain raided businesses suspected of supplying medicines illegally over the Internet.

BREAST CANCER AND USE OF NSAIDs

Breast Cancer and Use of Nonsteroidal Anti-inflammatory Drugs: A Meta-analysis

Abstract

Background: Breast cancer is one of the leading causes of mortality among women. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reduced risk for breast cancer, but results from these studies of the association have been inconsistent.
Methods: Studies that examined the association between risk of breast cancer and use of NSAIDs, including aspirin and ibuprofen, that were published between January 1, 1966, and July 1, 2008, were identified using Medline, EMBASE, and other databases. We performed meta-analysis by pooling studies according to the inverse of their variances and performed separate analyses of studies pooled according to aspirin use and ibuprofen use. We evaluated publication bias and study quality.
Results: A total of 38 studies (16 case–control studies, 18 cohort studies, 3 case–control studies nested in well-defined cohorts, and 1 clinical trial) that included 2 788 715 subjects were identified. The results of these studies suggest that overall, NSAID use was associated with reduced risk for breast cancer (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.84 to 0.93). Specific analyses for aspirin (RR = 0.87, 95% CI = 0.82 to 0.92) and ibuprofen (RR = 0.79, 95% CI = 0.64 to 0.97) yielded similar results.
Conclusions: This meta-analysis provides evidence that NSAID use is associated with reduced risk for breast cancer. Future research should include careful evaluation of the biologic mechanisms involved in the relationship between NSAIDs and breast cancer

BEVAZICUMAB INCREASES VENOUS THROMBOEMBOLISM

Bevacizumab Significantly Increases Venous Thromboembolism Risk

November 18, 2008 — The angiogenesis inhibitor bevacizumab (Avastin, Genentech/Roche) significantly increases the risk for venous thromboembolism (VTE), a new meta-analysis concludes. Because the drug is being increasingly used in the routine treatment of cancer patients, the authors suggest that this new finding might merit a black-box warning.

Currently, the product information includes only arterial thromboembolic events in its warnings section. That finding comes from a meta-analysis of 5 clinical trials involving 1745 patients, which did not find an increase in the risk of VTE (J Natl Cancer Inst. 2007;99:1232-1239).

However, many more trials have been conducted since then, and this new, much larger, meta-analysis found a significant increase in the risk for VTE. The finding is reported in the November 19 issue of the Journal of the American Medical Association.

The new meta-analysis examined 15 randomized controlled clinical trials involving 7956 patients with various advanced cancers, and found that the risk of developing VTE for patients taking bevacizumab was 33% greater than for controls (relative risk, 1.33; 95% confidence interval, 1.13 - 1.56; P < .001).

"It is imperative for physicians and patients to recognize this risk," write the authors, headed by Shobha Rani Nalluri, MD, from Stony Brook University, in New York. "In the event of venous thromboembolism, anticoagulation is indicated and bevacizumab may be continued if the benefits of the drugs outweigh the risk," they add.

Not Surprising, But of Concern Clinically

The finding is of concern because of the risk for morbidity and mortality related to VTE, senior author Shenhong Wu, MD, PhD, assistant professor of medical oncology at Stony Brook, commented to Medscape Oncology. Patients with cancer undergoing treatment are already at an increased risk of developing VTE, he explained — the incidence of all-grade VTE among such patients is about 9.9%. This new result suggests that bevacizumab raises this risk by 29%, he added.

The finding is not particularly surprising, commented George Sledge, MD, from Indiana University Cancer Center, in Indianapolis. Dr. Sledge was not involved in the study, and serves as an expert site advisor to Medscape Oncology. He pointed out that arterial thromboembolic events are already a known complication, so "it is not particularly surprising that the incidence of VTE events is modestly increased; these are, after all, drugs that affect blood vessels."

Bevacizumab is a monoclonal antibody that neutralizes vascular endothelial growth factor (VEGF), which results in the inhibition of angiogenesis.

VTE is an "emerging complication" of many angiogenesis inhibitors, Dr. Wu and colleagues write. Thalidomide and its derivative lenalidomide, which both act on VEGF and other factors, have also been associated with this complication — VTE has been reported at an incidence of 12% with thalidomide and 8% with lenalidomide, which compares with the 11.9% incidence now reported with bevacizumab, the authors note.

Nevertheless, this finding is important and "certainly of concern clinically, particularly in patients who are already at an increased risk for thromboembolic events," Dr. Sledge commented to Medscape Oncology. "It should represent part of the informed consent for clinical trials," he added, although the question of whether it warrants a black-box warning on the product label, as the authors suggest, is "within the [US Food and Drug Administration's] purview."

"At this point, clinicians should be aware of the potential risk for VTE, although the presence and exact size of any risk (if there is one) is still unclear and may be considered controversial," commented Herbert Hurwitz, MD, from Duke University Medical Center, in Durham, North Carolina. Dr. Hurwitz was the senior author of the previous smaller meta-analysis that found no increase in the risk for VTE. he most important issue for clinicians remains prompt and careful management of VTE if and when it occurs," Dr. Hurwitz told Medscape Oncology. "Fortunately, very few of these events were fatal," he pointed out (in the current meta-analysis, only 3 VTE-related deaths occurred, 2 in the bevacizumab group and 1 in the control group).

"To date, use of full-dose anticoagulation with bevacizumab has been shown to be safe in patients who have a clear indication for anticoagulation (i.e., the presence of a VTE), provided that the patient does not have other underlying risks," Dr. Hurwitz commented. "Nevertheless, anticoagulants have intrinsic risks, particularly if used broadly." Therefore, he said, "until this issue is further clarified, routine use of anticoagulants in bevacizumab-treated patients probably cannot be recommended at this time."

The other issue for clinicians and researchers is whether the background rate of VTE (independent of any increase related to bevacizumab) justifies the prophylactic use of anticoagulants more broadly, Dr. Hurwitz said. This is an issue that merits further study, he added. It is also a rather controversial subject, and is hotly debated by oncologists, most recently at the 33rd European Society of Medical Oncology Congress in Stockholm, Sweden, as reported at the time by Medscape Oncology.

According to Genentech/Roche, the manufacturer of bevacizumab, the incidence of VTEs reported in this meta-analysis is consistent with the drug's safety profile as documented in the product label and in previously presented data. "VTEs are typically managed with anticoagulant medication and can occur in people with cancer, regardless of the treatment they are receiving for their cancer," the company said.

Risk Varied Across Different Tumor Types

The meta-analysis found that bevacizumab increased the risk not only for all-grade VTE, but also for clinically significant high-grade VTE, the authors point out. The incidence was 11.9% for all-grade VTE and 6.3% for high-grade VTE. In addition, the risk was significantly and similarly increased by both the low dose (2.5 mg/kg per week) and the high dose (5 mg/kg per week).

However, there was difference in the risk seen among patients with different types of tumors. The highest incidence of all-grade VTE was observed among patients with colorectal cancer (19.1%), whereas the lowest risk was seen in patients with renal cancer (3%). In between were patients with non-small-cell lung cancer (14.9%) and patients with breast cancer (7.3%). A similar pattern across these tumor types was seen with the incidence of high-grade VTE.

This difference in VTE by cancer may be related to biology (for example, higher incidence in aerodigestive malignancies), but may also reflect other factors, such as previous treatment and performance status, say the authors.

Dr. Wu suggested that the high risk found in patients with colorectal cancer and lung cancer may warrant the use of prophylaxis in these patients, for example with enoxaparin (Lovenox), warfarin (Coumadin) or acetylsalicylic acid (ASA). However, further studies on such prophylaxis need to be performed, he added.

The authors point out several limitations to their meta-analysis, including potential overlap between the various grades of VTE, and the fact that the incidence of VTE varied greatly across the individual clinical trials (ranging from 3% to 19%). What this analysis lacks is an exploration of predisposing factors for VTE events," commented Dr. Sledge. One such factor clearly appears to be tumor type, but other factors important for clots include history of clotting episodes, age, obesity, family history, and smoking history. "If these were examined, my suspicion is that we would be able to separate out low and high groups," he told Medscape Oncology.

Dr. Wu reported acting as a speaker for Pfizer, receiving honoraria from Onyx Pharmaceuticals, and being partially supported by the Research Foundation of the State University of New York.

JAMA. 2008;300:277-2285.

GENETIC MARKERS FOR PROSTATE CANCER

AACR FCPR 2008: Genetic Markers May Identify Prostate Cancer Risk

November 19, 2008 — Black men and those with a family history are at a 2- to 7-fold increased risk for prostate cancer. Although assessing risk has been difficult in these populations, researchers now report that 5 genetic single-nucleotide polymorphisms (SNPs) might be useful in determining prostate cancer risk in men who are already at higher risk for the disease.

Compared with white men, black men tend to carry more of the genetic risk markers, according to the data that were presented at the Seventh Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research, held in Washington, DC. There was also a trend toward earlier development of prostate cancer in black men who carry more of these risk markers.

"Assessing the risk for prostate cancer through genetic testing is not available, as it is for breast cancer, and efforts toward preventing deaths from prostate cancer in these men have been focused on early detection," said lead author Veda N. Giri, MD, director of the Prostate Cancer Risk Assessment Program at Fox Chase Cancer Center, in Philadelphia, Pennsylvania.

However, this process often results in men who are deemed to be at higher risk, undergoing unnecessary biopsies, Dr. Giri pointed out during a press briefing. "The question is, how can we accurately predict the risk of prostate cancer in high-risk men in order to make personalized recommendations for screening and diagnoses?"

The More Markers, the Higher the Risk

In recent years, several genetic markers have been reported to be associated with prostate cancer. Five SNPs located at chromosomal loci 8q and 17q (rs1859962, rs6983267, rs4430796, rs1447295, and rs16901979) were found to have a cumulative increased association with prostate cancer in multiple studies. The more of these markers that men carry, the higher the risk for prostate cancer, explained Dr. Giri.

"The goal now is to determine the clinical use of these genetic markers in prospective populations, especially among men at high risk," she said.

The Prostate Cancer Risk Assessment Program is a prospective screening program for high-risk men that includes more than 700 participants, 60% of whom are black. The objective of the current study was to characterize the distribution of these 8q/17q risk markers, and to assess the time to prostate cancer based on the markers.

Men between the ages of 35 and 69 years were considered high risk if they had 1 first-degree relative with prostate cancer or 2 second-degree relatives with prostate cancer on the same side of the family. In addition, any black male, regardless of family history, and men with BRCA1/2 mutations were considered high risk.

Criteria for undergoing a biopsy included levels of prostate-specific antigen (PSA) higher than 2.0 ng/mL, PSA levels from 1.5 to 2.0 ng/mL with free PSA less than 25%, any abnormality observed on digital rectal examination, or PSA velocity of 0.75 ng/mL per year.

Genotyping was performed and standard statistical methods were used to determine allele and genotype distributions by race. Cox models used the number of high-risk SNPs to determine time to prostate cancer diagnosis.

Genotypes were determined for all 5 SNPs in 633 of the participants, and average follow-up time was 3 to 4 years. The researchers observed a statistically significant difference in the baseline distribution of risk alleles and risk genotypes of these 5 SNPs within the racial groups. Among white participants, the age-adjusted baseline PSA levels differed significantly among high-risk men. Participants carrying the risk genotype at rs4430796 had higher baseline PSA levels than those without the risk genotype at this SNP.

Markers More Informative in Black Men

Black men were more likely to carry 2 or 3 and 4 or 5 risk-associated SNPs than high-risk white men. Among white high-risk men, Dr. Giri pointed out, they did not observe a trend toward time to diagnosis by increasing numbers of genetic markers. However, it was more informative for black men.

Among the 210 black participants who had at least 1 follow-up visit, there was a trend among those with 4 or 5 risk SNPs for earlier time to prostate cancer diagnosis, compared with men with 0 or 1 risk SNP. They also noted that the hazard ratios for prostate cancer risk increased substantially in black men with 4 or 5 SNPs, compared with those with 2 or 3 SNPs (4.28 vs 1.84), although it did not reach statistical significance.

The specific genetic markers studied here might be more informative in black men for predicting time to diagnosis of prostate cancer, explained Dr. Giri. "There is a need to study genetic markers that are associated with prostate cancer in prospective studies to understand their true value in the clinical setting, especially for high risk men."

"The 5 genetic markers that they identified were significant in the population that they evaluated, and that is an important step in the ultimate goal to genetically stratify men by risk," meeting chair Steven M. Dubinett, MD, told Medscape Oncology. "More work needs to be done to determine how useful these risk markers will be for prostate cancer diagnosis."

American Association for Cancer Research's Seventh Annual International Conference on Frontiers in Cancer Prevention Research: Abstract B54. Presented November 17, 2008.

FIRST TRACHEA TRANSPLANT FROM STEM CELLS

First Trachea Transplant From Stem Cells

November 19, 2008 — Doctors in Europe have performed the first trachea transplant that hinges on the patient's own stem cells.

The operation, done in June at Hospital Clinic in Barcelona, Spain, was successful and is detailed in today's online edition of The Lancet.

The patient was a 30-year-old woman whose left airway collapsed as a result of tuberculosis. She'd already had a stent implanted to reopen that airway, but that didn't work out and the stent had been removed.

Doctors got a trachea from an organ donor and stripped the donated trachea of cells that would have been rejected when transplanted into another person.

The doctors took adult stem cells and some other cells from the healthy right airway of the woman needing the trachea transplant, grafted those cells onto the stripped-down donated trachea, and marinated the trachea in chemicals in a lab to coax the trachea into rebuilding itself.

When the trachea was ready, the doctors implanted it into the patient. The procedure worked, and since the trachea had been prepped by the patient's own stem cells before transplantation, her body accepted it without immune-suppressing drugs.

Four months after the surgery, the woman was still doing well. By then, she could "walk up two flights of stairs, walk 500 meters without stopping, and care for her children," write Paolo Macchiarini, MD, and colleagues.

"We are terribly excited by these results," Macchiarini says in a news release.

The results should be "highly regarded," but longer follow-up is needed, states an editorial published with the trachea transplant report. The editorialists included Toshihiko Sato, MD, of the Institute for Frontier Medical Sciences at Japan's Kyoto University. Macchiarini's team agrees that more than six months of follow-up would be helpful before the procedure is tested in a clinical trial.

DIPYRUDAMOLE AND ASPIRIN COMBO BETTER FOR STROKE PREVENTION

Dipyridamole and Aspirin Combo Reduces Vascular Events

NEW YORK (Reuters Health) Nov 19 - According to pooled data from randomized controlled trials, dipyridamole and aspirin are more effective than aspirin alone in the secondary prevention of transient ischemic attack (TIA) or minor stroke, researchers report in the November issue of the Journal of Neurology, Neurosurgery and Psychiatry.

As investigator Dr. Philip M. W. Bath told Reuters Health, "this study pulls together all the available trial data and tells us that we can do better than aspirin alone in preventing recurrent stroke. Instead, we should be using the combination of aspirin and dipyridamole as our first-line therapy."

Dr. Bath of the University of Nottingham City Hospital, UK, and colleagues came to this conclusion after updating a meta-analysis, ultimately involving five studies and more than 7600 subjects.

Compared to the use of aspirin alone, the adjusted hazard ratio for the composite end-point of vascular death, non-fatal myocardial infarction or non-fatal stroke was 0.82 in the combination group.

This continued to be true in a variety of subgroups, including those based on age, sex, hypertension, diabetes, and previous stroke. The researchers, however, point out that data on risk factors were not available for all five trials, thus reducing the numbers available for analysis.

The combination was also more effective than aspirin alone in preventing recurrent stroke (hazard ratio, 0.78).

The superiority of the agents in concert, the investigators observe, is backed by sound evidence. Combination therapy, they conclude, "should be preferred over aspirin after a TIA or minor stroke of presumed arterial origin, as supported by several national guidelines."

CRYOPRESERVE SEMEN BEFORE ORCHIECTOMY

Arch Ital Urol Androl. 2008 Sep;80(3):99-102.

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Semen quality before and after orchiectomy in men with testicular cancer.

Liguori G, Trombetta C, Bucci S, Benvenuto S, Amodeo A, Ocello G, Belgrano E.

Department of Urology, University of Trieste, Italy. gioliguori@libero.it

OBJECTIVE: We evaluated the impact of removal of the tumour bearing testis on semen quality in men with testicular cancer and the effect of tumour histologic feature on semen quality. MATERIAL AND METHODS: We took into account the semen analysis before and after orchiectomy in 30 patients. RESULTS: The median sperm concentration before and after orchiectomy was respectively of 26.7 x 10(6)/ml (range: 0-120 x 10(6)/ml) and 16.6 x 10(6)/ml (range: 0-75 x 10(6)/ml) (p = 0.001). Median sperm concentration before and after surgery in patients affected by seminomatous cancer were respectively of 35.47 x 10(6)/ml and 23.99 x 10(6)/ml, while cases of non-seminomatous cancer were respectively of 17.9 x 10(6)/ml and 8.16 x 10(6)/ml. CONCLUSIONS: Semen quality at the diagnosis was poorer in patients affected by non-seminomatous testicular cancer. Sperm concentration deteriorated after orchiectomy. Our findings suggest that the most appropriate time for cryopreservation of semen is before orchiectomy.

VEGF HAS COMPLEX FUNCTION

VEGF Not Always a Pro-Cancer Molecule

NEW YORK (Reuters Health) Nov 10 - Vascular endothelial growth factor (VEGF) is usually thought of as a molecule that promotes cancer growth by increasing angiogenesis, but findings from two studies, reported in the November 9th online issue of Nature, suggest that in some circumstance, VEGF may suppress tumor growth.

The revelation that VEGF's actions are more complex than originally thought could have important implications for treatments that target this molecule.

"The take-home message could be that anti-angiogenesis approaches need to be evaluated carefully, and potentially in the context of tumor inflammation. And that tumor vascularization is a more complicated matter than the simple equation of more vessels equals bigger tumor, fewer vessels equals tumor reduction." Dr. Randall Johnson, senior author of one of the studies, told Reuters Health.

According to Dr. Johnson, a researcher with the University of California, San Diego, his team's study is not the first to look at the effects of VEGF inhibition. However, in previous studies VEGF action was either inhibited globally or only in malignant cells. "This is the first study to remove VEGF secretion specifically and solely from inflammatory cells."

Using murine models, the investigators found that the chaotic, leaky vessels typically found in solid tumors are the result of inflammatory cell VEGF and not VEGF produced by the malignant cells. When production of inflammatory cell VEGF was blocked, the tumors actually grew and progressed more rapidly.

"This latter finding was really a shock to us, and indicated that VEGF expression and its effects on tumors is much more complex then we realized," Dr. Johnson said.

In the second study, which was conducted by many of the same researchers from the first, VEGF was found to be a negative regulator of vascular smooth muscle cells and vessel maturation.

The results, senior author Dr. David A. Cheresh, from UCSD, notes, confirm that VEGF expression does induce endothelial cell proliferation and migration. However, in the context of platelet-derived growth factor-mediated angiogenesis, VEGF disrupts vascular smooth muscle cell coverage of vascular sprouts, which destabilizes the vessel.

Nature 2008.

LOSS OF RB GENE IN BASAL AND LUMINAL B BREAST CANCER TYPES

The Functional Loss of the Retinoblastoma Tumor Suppressor is a Common Event in Basal-Like and Luminal B Breast Carcinomasact and Introduction

Jason I Herschkowitz; Xiaping He; Cheng Fan; Charles M PerouBreast Cancer Res. 2008;10(5) ©2008 BioMed Central, Ltd.

Posted 11/03/2008

Abstract

Introduction: Breast cancers can be classified using whole genome expression into distinct subtypes that show differences in prognosis. One of these groups, the basal-like subtype, is poorly differentiated, highly metastatic, genomically unstable, and contains specific genetic alterations such as the loss of tumour protein 53 (TP53). The loss of the retinoblastoma tumour suppressor encoded by the RB1 locus is a well-characterised occurrence in many tumour types; however, its role in breast cancer is less clear with many reports demonstrating a loss of heterozygosity that does not correlate with a loss of RB1 protein expression.
Methods: We used gene expression analysis for tumour subtyping and polymorphic markers located at the RB1 locus to assess the frequency of loss of heterozygosity in 88 primary human breast carcinomas and their normal tissue genomic DNA samples.
Results: RB1 loss of heterozygosity was observed at an overall frequency of 39%, with a high frequency in basal-like (72%) and luminal B (62%) tumours. These tumours also concurrently showed low expression of RB1 mRNA. p16^INK4a was highly expressed in basal-like tumours, presumably due to a previously reported feedback loop caused by RB1 loss. An RB1 loss of heterozygosity signature was developed and shown to be highly prognostic, and was potentially a predictive marker of response to neoadjuvant chemotherapy.
Conclusions: These results suggest that the functional loss of RB1 is common in basal-like tumours, which may play a key role in dictating their aggressive biology and unique therapeutic responses.

AROMATASE INHIBITORS IN MEN

Breast J. 2008 Oct 13. [Epub ahead of print]

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Breast Cancer in Men-Should Aromatase Inhibitors Become First-Line Hormonal Treatment?

Nordman IC, Dalley DN.

Department of Medical Oncology, St Vincent's Hospital, Sydney, Australia.

Breast cancer is an uncommon malignancy in men; therefore, the approach to treatment is mostly modeled on that used in females. First-line use of aromatase inhibitors (AIs) is now standard practice in hormone-sensitive metastatic breast cancer in postmenopausal females. However, tamoxifen continues to be regarded as first-line treatment in hormone-sensitive male breast cancer. This article reviews the role of second and third generation AIs as first- or second-line hormonal treatment in male patients with metastatic breast cancer. It also explores the potential use of AIs in combination with gonadotropin-releasing hormone analogs or trastuzumab suggesting that in the future this may prove a useful alternative to tamoxifen.

NEW BIOMARKER FOR RESISTANCE TO TAMOXIFEN

Estrogen-Related Receptor Tied to Tamoxifen Resistance in Lobular Breast Cancer

NEW YORK (Reuters Health) Nov 07 - Using a novel model of invasive lobular breast cancer, US researchers have found that increased expression of estrogen-related receptor (ERR) gamma is associated with resistance to tamoxifen.

"Until now, this receptor has not been viewed to be of much importance in any type of breast cancer," lead author Dr. Rebecca Riggins, from Georgetown University Medical Center in Washington, DC, said in a statement. "All that was known is that there were more of these receptors in breast cancer than in normal breast tissue."

According to the report, which appears in the November 1st issue of Cancer Research, most studies examining endocrine resistance have focused on invasive ductal carcinoma. Although that type of breast cancer is the most common, invasive lobular carcinoma still accounts for up to 15% of new cases. Moreover, while rates of ductal disease have remained fairly stable for the last 20 years, rates of lobular disease continue to climb.

In their paper, the research team describes the creation of the first cell culture model of tamoxifen-resistant, invasive lobular breast carcinoma. The cell line they developed showed decreased expression of estrogen receptor alpha and increased expression of ERR-gamma.

Knocking out the ERR-gamma overexpression rendered the cells sensitive to tamoxifen. Conversely, forcing ERR-gamma overexpression in standard lobular breast cancer cells made them resistant to tamoxifen.

Further analyses showed that ERR-gamma-driven transcription was increased in the tamoxifen-resistant cells, but that inhibition of activator protein 1 (AP1) can enhance or even restore tamoxifen sensitivity.

These results, the authors conclude, "support a role for ERR-gamma/AP1 signaling in the development of tamoxifen resistance, and suggest that expression of ERR-gamma may be a marker of poor tamoxifen response."

Cancer Res 2008.

URINE TEST FOR PROSTATE CANCER

Urine Test May Reduce Unnecessary Repeat Prostate Biopsies

NEW YORK (Reuters Health) Nov 07 - Urine testing for prostate cancer gene 3 (PCA3) mRNA can help identify clinically significant prostate cancer and may help reduce the number of unnecessary repeat biopsies performed, European investigators have found.

They explain in their paper in the October issue of European Urology that PCA3 is overexpressed in 95% of prostate cancers. "The PROGENSA PCA3 assay measures PCA3 and PSA mRNA concentrations in post-DRE (digital rectal exam) urine."

Dr. Alexander Haese from University Clinic Hamburg, Germany, and colleagues studied the clinical utility of the urine assay in 463 men with suspected prostate cancer who had one or two previous negative prostate biopsies and were scheduled for repeat biopsy.

Twenty-eight percent of repeat biopsies were positive and, according to the investigators, the probability of a positive repeat biopsy increased with higher PCA3 scores. Mean PCA3 levels were significantly higher in men who were subsequently diagnosed with prostate cancer than in men who were not.

A PCA3 score cut-off of 35 "provided the optimal balance between sensitivity and specificity, with a specificity of 72% for prostate cancer detection," Dr. Haese and colleagues report.

At this cut point, the PCA3 score had greater diagnostic accuracy than percent free prostate-specific antigen at a cut-off of 25%. The diagnostic accuracy of the PCA3 score was not affected by age, number of previous negative biopsies, prostate volume, and total prostate-specific antigen (PSA) level.

The PCA3 score may also be indicative of the clinical stage and aggressiveness of prostate cancer, the investigators say, noting that the PCA3 score was significantly higher in men with clinical stage T2, biopsy Gleason score of 7 or higher and "significant" prostate cancer, compared to men with clinical stage T1, biopsy Gleason score less than 7 and "indolent" prostate cancer.

The PCA3 score was also significantly higher in men with than without high-grade prostate intraepithelial neoplasia, suggesting that this biomarker may also help identify men at increased risk of developing prostate cancer, Dr. Haese and colleagues note.

In an editorial, Dr. Stacy Loeb of Johns Hopkins Medical Institutions, Baltimore, says these findings indicate that PCA3 "may be useful not only to identify potential candidates for active surveillance (as suggested by the authors) but also to trigger intervention for those already enrolled in expectant management protocols."

"A remaining challenge," Dr. Loeb writes, "is to find the markers that can help identify potentially life-threatening disease at a curable stage. Most likely, this goal will be accomplished with a panel of biomarkers, possibly including PCA3."

VIETNAM WAR AND CANCER

Agent Orange Exposure Linked to Doubled Risk of Prostate Cancer

NEW YORK (Reuters Health) Nov 10 - A study of Vietnam War era veterans shows that exposure to Agent Orange is associated with a significantly increased risk of prostate cancer, earlier disease onset, and more aggressive features.

"Consideration should be made to classify this group of individuals as 'high risk', just like men of African-American heritage and men with a family history of prostate cancer," Dr. Karim Chamie, from the University of California Davis, Sacramento, and colleagues conclude.

As reported in the November 1st issue of Cancer, prior research has established a link between Agent Orange exposure and the development of various soft tissue malignancies. The apparent association with prostate cancer, however, was relatively weak, but this may have been because the studies were conducted nearly a decade ago at a point when many of the veterans had not reached an age when prostate cancer is common.

The current investigation, by contrast, involved men who were entering their 60s and, therefore, had an inherently higher risk of prostate cancer. The study included 6214 veterans who were exposed to Agent Orange from 1962 to 1971 and 6930 veterans who were not exposed to the defoliant. The subjects were followed from 1998 to 2006.

Among the exposed group, 239 men were identified with prostate cancer, compared with 124 cases among the unexposed men, for an odds ratio of 2.19. On average, prostate cancer developed 407 months after Agent Orange exposure, the report indicates.

Agent Orange exposure was associated with a younger age at prostate cancer diagnosis (59.7 vs. 62.2 years), a higher prevalence of Gleason scores 8 to 10 (21.8% vs. 10.5%), and higher rate of metastatic disease at presentation (13.4% vs. 4%).

On multivariate analysis, Agent Orange exposure was found to be the strongest predictor of both developing prostate cancer and of high-grade and metastatic disease on presentation, the authors note.

"The current findings support aggressively screening these veterans for prostate cancer in the hopes of detecting high-risk cancers before metastases develop," the authors state. "The expansion of benefits and screening programs will place further pressures on the VA healthcare system given the current level of budgetary appropriations."

LOW POTTASIUM HIGH BLOOD PRESSURE

Low Potassium Linked to High Blood Pressure, Especially in Blacks

NEW YORK (Reuters Health) Nov 10 - In a multi-ethnic population-based cohort of 3,303 adults, half of whom were African American, a low urinary potassium level correlated with high blood pressure, independent of sodium intake and cardiovascular risk factors.

This observation "supports the hypothesis that dietary potassium deficiency plays an important role in the development of high blood pressure," Dr. Susan Hedayati, of the University of Texas Southwestern Medical Center in Dallas, told Reuters Health.

"The association was stronger in African Americans than non-African Americans, suggesting that there may be racial differences in the pathogenesis of hypertension as it relates to dietary potassium intake," added Dr. Hedayati, who reported the findings over the weekend at the American Society of Nephrology's annual meeting in Philadelphia.

In the cohort, the prevalence of hypertension was 36%. Hypertensive subjects were older, had a higher body mass index, lower glomerular filtration rate, and lower urine potassium than normotensive subjects, and a greater proportion was African American.

According to Dr. Hedayati, the potassium level in urine samples was strongly related to blood pressure. "The lower the potassium in the urine, hence the lower the potassium in the diet, the higher the blood pressure," she noted in a written statement. "This effect was even stronger than the effect of sodium on blood pressure."

"There has been a lot of publicity about lowering salt or sodium in the diet to lower blood pressure, but not enough on increasing dietary potassium," Dr. Hedayati added.

She also mentioned that Dr. Chou-Long Huang, one of the co-investigators on the study, has shown recently that potassium deficiency increases the expression of a gene called WNK1 in animal models. "We are currently doing studies to see if this gene is responsible for the mechanism of potassium deficiency causing hypertension in humans," Dr. Hedayati said.

IMATINIB IN NEUROFIBROMATOSIS

Imatinib Shows Potential in Neurofibromatosis, Trial Underway

November 13, 2008 — The antileukemia drug imatinib (Gleevec, Novartis) has shown a dramatic response against neurofibromatosis in 1 patient who had a life-threatening plexiform neurofibroma compressing her airway. The drug is now being investigated in a clinical trial for this disorder, for which there are currently no available treatments.

The trial is being conducted at the Indiana University School of Medicine, in Indianapolis, where researchers have been exploring the potential impact of imatinib on neurofibromatosis in a series of laboratory studies. One set of studies is reported in the October 31 issue of Cell. This work showed that genetically altered mice transplanted with bone marrow containing reduced C-Kit signaling did not develop neurofibromas, which informed the identification of the molecular target, lead researcher Wade Clapp, MD, professor of pediatrics, explained to Medscape Oncology.

While the laboratory studies were still ongoing, a critically ill patient was treated with the drug under a compassionate-use protocol. The patient, a 3-year-old girl, had a plexiform neurofibroma that was compressing her airway. After administration of imatinib, the tumor decreased by 80%, Dr. Clapp noted. "The patient was treated for 6 months. She has been off therapy for at least that long now, and there has been very limited regrowth," he said.

A phase 2 clinical trial in patients with plexiform neurofibromas is now underway. Forty patients, from 3-year-old children to adults, are receiving imatinib and will be treated with the drug for 1 year, Dr. Clapp said.

Plexiform neurofibromas develop in about 40% of people with neurofibromatosis, and they can be fatal, he explained. These tumors do not respond to chemotherapy, and can be difficult if not impossible to remove surgically. "These are very slow growing tumors that impair people's everyday lives," Dr. Clapp commented in a statement. "These patients often suffer for years, and sometimes die from these tumors."

"We are very hopeful about the potential of this drug and related therapies," Dr. Clapp commented. "There are no other therapies for these tumors."

LYMPHADENECTOMY FOR ESOPHAGEAL CANCER

Extent of Lymphadenectomy Predicts Survival in Esophageal Cancer

NEW YORK (Reuters Health) Nov 11 - The number of lymph nodes removed during esophagectomy independently predicts survival in patients with esophageal cancer, according to a report in the October issue of the Annals of Surgery.

"The only predictor of survival that can be influenced by the surgeon is the number of lymph nodes removed," Dr. Tom R. DeMeester told Reuters Health. "All other factors, such as tumor depth, number of involved nodes, age, gender, etc., are givens and unchangeable."

Dr. DeMeester, from the Keck School of Medicine at the University of Southern California, Los Angeles, and colleagues studied the relationship between the extent of lymphadenectomy and survival in 2303 patients with esophageal cancer.

The number of involved lymph nodes removed proved to be the strongest predictor of outcome, the authors report, followed by depth of invasion and the total number of involved nodes.

In several models, overall survival and survival by tumor stage were best for patients who had at least 23 lymph nodes removed.

"Twenty-three nodes is the number to be removed to start to see the effect of the principle, but removing more nodes continues to be beneficial up to a point," Dr. DeMeester explained. "We are uncertain where the point is after which the removal of additional nodes are of minimal benefit."

Even when a minimum of 23 lymph nodes was removed, 5-year survival was significantly better after en bloc resection (48%) than after other types of esophageal resections (34%).

"The dominant factor in treatment is an extensive enough surgery to assure the removal of the involved nodes," Dr. DeMeester concluded. "This is best quantitated by the number of nodes removed."

BETTER CARBOPLATIN DOSING FOR OBESE PEOPLE

Cancer Chemother Pharmacol. 2008 Nov 7. [Epub ahead of print]

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Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

Ekhart C, Rodenhuis S, Schellens JH, Beijnen JH, Huitema AD.

Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands, Corine.Ekhart@slz.nl.

PURPOSE: The purpose of this study was to determine the potential utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in underweight, normal weight, overweight and obese patients. METHODS: Clearance values obtained from individual fits using NONMEM were compared to predicted carboplatin clearances calculated using the modified Calvert formula in which creatinine clearance was calculated with the Cockcroft-Gault equation using diverse weight descriptors. RESULTS: This study indicated that lean body mass was the best weight descriptor in underweight and normal weight patients, while adjusted ideal body weight was the best weight descriptor in overweight and obese patients. However, a flat dose based on the population carboplatin clearance performed better in all weight categories than the use of the Cockcroft-Gault equation with diverse weight descriptors. CONCLUSION: These results suggest that in overweight and obese patients, with a normal renal function, a flat carboplatin dose should be administered, based on the population carboplatin clearance (8.38 l/h = 140 mL/min). Thus, in case an AUC of 5 mg min/mL is desired, the appropriate dose for carboplatin would be 5 x 140 = 700 mg.

A RARE LUNG NEOPLASM

Med Oncol. 2008 Nov 7. [Epub ahead of print]

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The role of palliative chemotherapy for advanced pulmonary pleomorphic carcinoma.

Hong JY, Choi MK, Uhm JE, Park MJ, Lee J, Park YH, Ahn JS, Park K, Han JH, Ahn MJ.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, 50 Ilwon-dong Kangnam-gu, 135-710, Seoul, South Korea.

Pulmonary pleomorphic carcinoma is an uncommon malignant tumor of the lung, which has the dual cell components of spindle or giant cells and epithelial cells. The objective of this study was to investigate the clinical course and efficacy of palliative chemotherapy in patients with advanced pulmonary pleomorphic carcinoma. Twelve patients were diagnosed with advanced pulmonary pleomorphic carcinoma and received palliative chemotherapy from February 2000 to December 2007. Among the 12 patients, five patients received gemcitabine/cisplatin, three patients received gemcitabine/carboplatin, two patients received paclitaxel/carboplatin, one patient received paclitaxel/cisplatin, and one patient received docetaxel/cisplatin as first-line chemotherapy. The median patient's age was 62 (range, 32-72 years). Among the 12 patients, nine patients had relapsed disease after curative resection and three patients had metastatic disease at the initial presentation. After treatment with first-line palliative chemotherapy, seven patients (58%) had progressive disease, three patients (25%) had stable disease, and only two patients (17%) had a partial response. The median overall survival from the day of initiation of first-line chemotherapy was only 8 months (95% CI, 6-10) with median follow-up of 26 months. These results showed the dismal prognosis and the poor response to chemotherapy of advanced pulmonary pleomorphic carcinoma. Further studies are needed to investigate whether the current strategy of palliative chemotherapy for the treatment of advanced pulmonary pleomorphic carcinoma can be justified or not. Moreover, additional novel treatment approaches are required.

PEANUT ALLERGY

Early Peanut Consumption May Prevent Peanut Allergy

NEW YORK (Reuters Health) Nov 07 - Contrary to widespread recommendations, early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy, results of a study suggest.

"Our study findings raise the question of whether early introduction rather than avoidance of peanut in infancy is the better strategy for the prevention of peanut allergy," write researchers in the November issue of the Journal of Allergy and Clinical Immunology.

In the UK, Australia and, until recently, the United States, guidelines have recommended avoiding peanuts during pregnancy, breastfeeding and early life, note Dr. George Du Toit of King's College London and colleagues.

They analyzed the prevalence of peanut allergy and dietary histories for 5,171 Jewish children from the UK and 5,615 Jewish children from Israel. They found that children from the UK had a prevalence of peanut allergy that was 10-fold higher than that of children from Israel -- 1.85% versus 0.17% (p <>

"This difference is not accounted for by differences in atopy, social class, genetic background, or peanut allergenicity," the investigators report.

"The most obvious difference in the diet of infants in both populations occurs in the introduction of peanut," they note, with 69% of infants eating peanuts at age 9 months compared with just 10% of those in the UK.

Israeli children aged 8 to 14 months consume a median of 7.1 grams of peanut protein per month, whereas age-matched UK children do not consume any peanut protein, Dr. Du Toit and colleagues point out.

The researchers suggest that recommendations to avoid peanut in early infancy could be behind the increase in peanut allergy in the UK, Australia and the US.

In a written statement, Dr. Jacqueline A. Pongracic, vice chair of the American Academy of Allergy, Asthma & Immunology (AAAAI) Adverse Reactions to Foods Committee cautions that while this study's findings "provide optimism for prevention of peanut allergy in the future, randomized, controlled trials are needed to verify that early introduction of peanut is indeed effective."

The Learning Early about Peanut Allergy (LEAP) study, a large randomized study in the UK, is currently testing the effects of early peanut exposure.