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A Puzzling Facial Rash on a 17-Year-Old Boy

http://cme.medscape.com/viewarticle/575109_2

Background

A 17-year-old male high school student presents to the pediatric infectious disease clinic complaining of a 10-day history of a facial rash that "won't get better." The patient had previously visited his primary care provider (PCP), who started the patient on amoxicillin-clavulanic acid 8 days ago. The rash did not improve on the antibiotic, and as a result, it was discontinued and the patient switched to trimethoprim-sulfamethoxazole. No improvement was noted with the second round of antibiotic therapy; the rash continued to spread, and the lesions increased in number. The patient was subsequently advised to follow up with the infectious disease clinic.

At the infectious disease clinic, the patient states that the rash started with several pimples over the forehead and cheek and then continued to spread and involve most of the right side of his face. The lesions are not itchy, but they are painful. The patient has no known drug allergies. His immunizations are up to date. He is very active on the wrestling team and was happily preparing for an upcoming competition. The patient denies having any weight loss, headaches, dizziness, photophobia, fever, or chills. The family history is non-contributory.

On physical examination, the patient is alert and orientated. His oral temperature is 97.0°F (36.1°C). The patient has normal heart sounds, his pulse has a regular rhythm of 97 bpm, and his blood pressure is 125/75 mm Hg. His lungs are clear, and his respiratory rate is 12 breaths/min. The examination of the head, eyes, ears, and nose is remarkable for multiple vesicular lesions measuring about 0.5 cm in diameter (see Figures 1 and 2). There is bilateral submandibular lymph gland enlargement measuring 1.5 cm by 1 cm. The neck is supple. His abdomen is soft and nontender to deep palpation in the epigastric region, and no organomegaly is noted. A complete blood count (CBC) taken at the PCP's office showed a white blood cell (WBC) count of 7.4 × 103/µL (7.4 × 109/L), with a normal differential; a hemoglobin of 13.6 g/dl (136 g/L); a hematocrit of 38.3% (0.3830); and a platelet count of 298 × 103/µL (298 × 109/L).


Hint: The patient was disqualified from wrestling because of his lesions.
 Tinea faciale
 Impetigo
 Bacterial cellulitis
 Herpes gladiatorum


Discussion:

Herpes gladiatorum (HG) is an infection caused by the herpes simplex virus (HSV) type 1. HG most commonly occurs among wrestlers and other athletes who participate in close skin contact sports such as wrestling (herpes gladiatorum) and rugby (herpes rugbiaforum). HG is also known as "mat herpes" among wrestlers. HG is spread by direct skin-to-skin contact. The lesions appear within 7 to 14 days after exposure; however, in some cases the lesions take longer to appear. Our patient presented with a primary herpes gladiatorum (PHG) infection, which is usually more severe than the recurrent infections. His lesions presented with disseminated vesicles, punched-out erosions, and central crusting on the forehead and right cheek. The patient was at an increased risk of contracting PHG because of his participation in wrestling. Herpes simplex virus DNA was detected with a polymerase chain reaction (PCR) examination.[3,6]

Outbreaks of HG have occurred countless times during the last decade; several outbreaks of HG have occurred among wrestlers across the United States. It is critical that health care providers, athletic trainers, coaches, and athletes recognize the threat of HG skin infection to minimize the risk of outbreaks. Vigilant surveillance and appropriate antiviral treatment will curtail the transmission of HG among wrestlers.[7] Lack of proper understanding of PHG disease could lead to misdiagnosis and frequent outbreaks.[4]

HSV is a double-stranded DNA virus. About 80% of adults have antibodies to HSV-1, and about 20% of the population has antibodies to HSV-2. HSV-1 is commonly known to cause herpes labialis and keratitis. Most childhood HSV infections are caused by HSV-1. HSV-2 is commonly known to cause genital herpes infections, which is one of the most common sexually transmitted diseases in the United States. HSV-2 is transmitted primarily by direct contact with lesions, and it is most often transmitted venereally. Generalized or localized cutaneous and mucosal lesions characterize initial infection by HSV. Recurrent infections are milder because fewer viruses are shed and a stronger immune response is elicited. HSV remains dormant in the nerve ganglia; febrile illness, stress, immunosuppressive drugs, and ultraviolet light can precipitate recurrent eruptions. In rare cases, the initial replication of HSV can lead to meningitis or encephalitis. HSV persists for life in a latent form. The virus is sometimes confused with herpes zoster because the site of latency for HSV is the trigeminal ganglion. HSV may also manifest as a severe and/or life-threatening infection in immunocompromised individuals and in newborn babies. Specifically, disseminated infections can result in esophagitis, pneumonitis, encephalitis, hepatitis, and adrenal necrosis.[1,3]

Currently, no epidemiologic studies accurately identify the true incidence of HG; however, the National Collegiate Athletic Association (NCAA) estimated an incidence of HG as high as 40% among wrestlers.[2] The most common locations of HG, in descending order, are the head, face, neck, chest, and shoulders. Typically, lesions will be observed on the head, face, neck, cheeks, forehead, shoulders, and arms. According to most studies, about two thirds of wrestlers will have the herpetic lesions on the right side of the body. Hence, HG is transmitted during close skin-to-skin physical contact, known in wrestlers' terminology as the "lock-up position."[1,6]

PHG generally presents with an erythematous rash, sore throat, fever, cervical lymphadenopathy, and vesicles. Occasionally, the HG lesion will lack the grouped vesicles on an erythematous base, and it is sometimes mistaken for impetigo, acne, tinea corporis, atopic dermatitis, varicella, or scabies. A significant complication of PHG in wrestlers is dendritic keratitis with subsequent corneal scarring. Other ocular complications of PHG include conjunctivitis, scleritis, and uveitis. Fluid from the base of unroofed vesicles can be sent for testing by PCR, the test of choice for diagnosing PHG. A Tzanck smear of scrapings from the base of vesicles will demonstrate multinucleated giant cells, a finding that is highly indicative for HSV infection.

The NCAA has developed recommendations on "time until return to competition" for primary herpes gladiatorum and for recurrent infection. For a primary outbreak of herpes, the wrestler must be examined by a clinician or an experienced certified athletic trainer; the following recommendations must be met before a wrestler returns to competition[7]:
The athlete must have no signs of systemic symptoms of viral infection.

The athlete must be free of any new lesions for 3 days or more prior to start of competition.

The skin lesions must be dried and surmounted by a firm adherent crust.

The athlete must have been on appropriate antiviral therapy for at least 120 hours before the beginning of a competition.

For recurrent HG, the NCAA has also established several recommendations. First, vesicles must be completely dry and crusted. Second, the wrestler must have been on the appropriate dosage of antiviral therapy for 120 hours or more at the time of tournament. For questionable cases, a Tzanck preparation should be performed, and the wrestler's status should be deferred until Tzanck prep or HSV assay results are available.[7]

Antiviral drugs with activity against viral DNA synthesis have been effective against PHG infections. Acyclovir, famciclovir, and valacyclovir inhibit virus replication and suppress clinical manifestations, but they are not a cure for PHG, since HSV remains latent in sensory ganglia. Oral acyclovir has been shown to be effective in suppressing PHG in wrestlers; it is the drug of choice for treating PHG. Acyclovir reduces the duration of symptomatic lesions and is indicated for patients presenting within 2-3 days of the appearance of a herpetic rash. Most patients on acyclovir will experience less pain and quicker resolution of their vesicular lesions. Several effective treatments for adult patients include oral acyclovir 200 mg 5 times daily or 400 mg 3 times daily for 7-10 days or until clinical resolution occurs. The recommended dose of acyclovir for PHG in the pediatric age group is 20-30 mg/kg/d, in 5 divided doses, for 7-10 days. As with all infections, prevention is better than treatment.[2]

In addition to the above treatment, wrestlers must practice effective hygiene immediately after wrestling. It is critical to frequently clean competition gear and change towels. Regular hand-washing and thorough cleaning of the mats are critical. Wrestling mats should be cleaned between matches with household bleach (one-quarter cup of bleach in 1 gallon of water). Early identification and treatment can allow the wrestler to return to participation earlier and prevent teammates from contracting the disease. Despite these precautions, PHG will spread during wrestling and other close-contact sports resulting from contact with asymptomatic infected athletes.[1,6]

The patient in this case was started on acyclovir 400 mg 3 times a day for 1 week at the first visit to the pediatric infectious disease clinic. It was strongly suspected that his lesions were caused by PHG, since there had been no improvement with the 2 courses of antibiotic treatment that had been initially tried by his primary care provider. After 1 week of acyclovir, most of his facial lesions were dry and had an adherent crust; however, there were still 2 moist lesions on his right shoulder, which resolved completely by the second week of treatment. The patient and his parents were advised repeatedly to call and report any eye symptoms, seizure, alteration of mental status, personality changes, photophobia, or headaches. It was noted on subsequent follow-up that the patient's 13-year-old brother had developed similar lesions; it was later learned that he had borrowed his older brother's headgear, which was the most likely the cause of his lesions. The rash on the brother also resolved after starting acyclovir.

Tanks pose possible dengue threat

Simon Grose 
Abstract

As Australian homeowners act on incentives to install rainwater tanks in response to global warming, they are creating new breeding opportunities for the Aedes aegypti mosquito, which carries dengue fever and prefers to lay its eggs in stagnant water. According to a new study, proliferation of domestic water storage systems is likely to provide a greater stimulus to the southward expansion of dengue than a warming climate 

ΕΝΗΜΕΡΩΣΗ ΣΥΓΓΕΝΩΝ

 
Should Physicians Inform Relatives of Genetic Risks, Without the Consent of the Patient?

Roxanne Nelson 

Medscape Medical News 2009. © 2009 Medscape 

March 5, 2009 — Do physicians have an obligation to disclose genetic-risk information to relatives, even without the consent of the patient?

This is the question posed — using BRCA1/2 mutation in breast cancer as an example — in a report published in the March issue of the Lancet Oncology, and explored here in a couple of in-depth interviews with Medscape Oncology .

Protecting patient confidentiality and protecting family members from potential harm presents a dilemma for healthcare professionals. The results of genetic testing reveal information not only about the patient, but about their relatives as well, and the information could be of great value to them.

For instance, if a women with breast cancer has the BRCA1/2 mutation, her siblings might also carry it. Although the patient can certainly inform her siblings that she is carrying the BRCA1/2 mutation, current laws in the United Kingdom prevent her physician from doing so without the consent of the patient. The report questions whether breaking confidentiality outweighs the good that could be done by a doctor informing a patient's relatives, and whether the time has come to change patient confidentiality laws.

"There are, at times, ethical hierarchies based on critical values," said Ross McKinney, Jr, MD, professor of pediatrics, molecular genetics, and microbiology, and director of the Trent Center for Bioethics, Humanities and History of Medicine at Duke University School of Medicine, in Durham, North Carolina. "In this case, the 2 values in question are autonomy — the right to personally control your own destiny, which in this case includes privacy — and the right to optimal health and safety."

The problems develop when the decisions affected by those values overlap and the results of the decisions do not align.

"The problems develop when the decisions affected by those values overlap and the results of the decisions do not align," he told Medscape Oncology.

In the case of the BRCA mutation, what happens when a patient's right to privacy (not wanting people to know about an increased risk for breast cancer) imposes itself on her sister's right to optimize her healthcare (breast cancer can be treated more effectively if caught early, or even prophylactically by mastectomies) and know her risk? "As a society, we are in the uncomfortable position of ordering these values hierarchically, which is a problem when we don't have a consensus," said Dr. McKinney.

"In truth, I think most people in the United States would place a higher value on the person's right to critical information that can keep them healthier," he added. "However, we're unsure enough that we'd like to find a win–win solution, like 'let someone else — a third party — notify my sister so that I don't have to reveal my own risk.' But sooner or later, that discussion between sisters will probably happen, no matter who hears it first."

Breaching the Law

Although current laws in the United Kingdom are designed to protect patient confidentiality, there are well-recognized justifications for breaching it. According to Richard Ashcroft, PhD, professor of biomedical ethics at Queen Mary, University of London, in the United Kingdom, the 3 main reasons for breaching confidentiality are the consent of the patient, the necessity of preventing a significant risk for serious harm to a third party, and promotion of a significant public interest.

In the case of HIV infection, the situation is more clear cut, because notification of sexual partners is necessary to prevent a significant risk for serious harm and further spread of the virus. The situation of genetic mutations, such as BRCA1/2, is far more ambiguous. In the Lancet Oncology report, Dr. Ashcroft points out that although the risk posed by an adverse BRCA1/2 mutation is serious, it is not usually imminent, so there is time to discuss disclosure with the patient. There is also the complex issue of the right not to know one's genetic risk.

HIV infection is an example of a "safe-harbor entity," explained Dr. McKinney. "If I have a newly identified HIV-infected patient, I am required to notify the state, who then tracks their sexual contacts."

With HIV cases, it has been determined that the health of others and their right to treatment circumvents the right of the patient to privacy concerning his or her HIV diagnosis. "However, our attempt at a win–win [situation] means that the doctor doesn't do the notification of partners, thus protecting the physician–patient relationship," said Dr. McKinney. "In reality, we've codified a system that values the at-risk person's right to receive treatment over the privacy of the infected person."

In the United States, patient confidentiality is already riddled with exceptions, explained Hank Greely, JD, professor of law at Stanford University, in Palo Alto, California, and an expert on the legal, ethical, and social issues surrounding health law and the biosciences. American doctors "are obligated to report a number of otherwise confidential facts about patients to the state, from the existence of some infectious diseases, to evidence of child or elder abuse, to pesticide poisoning, to the presence of gunshot or knife wounds," he told Medscape Oncology. "They have also been obligated to report to third parties facts learned from a patient that a reasonable doctor would realize would put a third party at grave risk. These cases are mainly about family members and contagious diseases."

Court Cases Leave Issue Open

A number of cases involving confidentiality issues have been heard in courts around the United States that illustrate some of the complexities involved, Mr. Greely said in an interview. In 1 court case in Tennessee, a man died from Rocky Mountain spotted fever, which is tick borne and not spread by human-to-human contact. His wife also contracted it and died, and his son sued the doctor for not warning his mother. "He won the case. The Court held that the doctor should have warned the wife that, as the husband had suffered a bite from an infectious tick, she might have been bitten, too, and should watch out for symptoms," said Mr. Greely.

Court cases specifically involving genetic disclosure are uncommon, Mr. Greely said, and 2 cases related to cancer reached somewhat different conclusions. The first case, heard by the Florida Supreme Court, involved a woman diagnosed with medullary thyroid carcinoma whose mother had been diagnosed with the same disease 3 years earlier. The patient claimed the doctor should have known it was highly genetic and warned her. She then might have discovered the cancer earlier when it was more treatable.

"The lower court threw out her claim on the ground that the doctor owed her no duty," said Mr. Greely. "The Florida Supreme Court reversed it, saying he could owe her a duty, but that whether he did or not was determined by the relevant standard of care."

But the Florida case, without expressly addressing confidentiality, put in a strong limitation on the claim, stating that "thus, we emphasize that in any circumstances in which the physician has a duty to warn of a genetically transferable disease, that duty will be satisfied by warning the patient."

The second case, explained Mr. Greely, was heard by the New Jersey Appellate Division and involved a woman with colon cancer who learned that she had familial adenamotous polyposis. Her father had been treated many years earlier for colon cancer and she sued the estate of the physician (now deceased), claiming that he should have informed the family of the genetic risk.

The court rejected the limitation set previously by the Florida case, which said that "in all circumstances, the duty to warn will be satisfied by informing the patient. It may be necessary, at some stage, to resolve a conflict between the physician's broader duty to warn and his fidelity to an expressed preference of the patient that nothing be said to family members about the details of the disease."

However, the Court went on to note that if evidence was produced to show that the physician had received instructions from his patient not to disclose details of the illness or of genetic risk, "the Court will be required to determine whether, as a matter of law, there are or ought to be any limits on physician–patient confidentiality, especially after the patient's death, where a risk of harm survives the patient, as in the case of genetic consequences."

Whether it is just the patient or whether the duty goes further remains to be determined.

Although it might be surprising to many physicians in the United States, patient confidentiality laws probably do not bar them from disclosing genetic risks to family members, explained Mr. Greely. "Whether it is just the patient or whether the duty goes further remains to be determined."

Dr. McKinney agrees. "There are no 'right' answers," he said, and this is the reason that these issues are controversial. "But I tend to prefer something like the HIV notification model. It's clumsy, but orders the values in the same way I would."

The Exception Rather Than the Rule

The American Society of Human Genetics has issued a policy statement on this topic, which Wylie Burke, MD, PhD, professor and chair of the Department of Bioethics and Humanities, University of Washington, in Seattle, feels provides a very balanced review.

"This statement emphasizes that every effort should be made first to encourage the patient to disclose risk to relatives," she said. "Only if that effort has failed and the benefits of disclosure outweigh the harms should the doctor inform relatives directly. This judgment has to be made on a case-by-case basis."

My impression from my own practice and from talking to colleagues is that family members rarely refuse to disclose information about shared risk to their relatives.

But instances where patients are unwilling to share information with relatives seem to be the exception rather than rule. "My impression from my own practice and from talking to colleagues is that family members rarely refuse to disclose information about shared risk to their relatives," said Dr. Burke. "Certainly, they may wish sometimes to keep their own results private, but as a general rule, family members are willing and often eager to let relatives know about a genetic risk running in the family or an opportunity to have genetic testing."

Genetic information should be disclosed if a clear health benefit can be achieved, but physicians need to be rigorous in justifying their action, explained Dr. Burke. "The patient should be told that the disclosure will occur, and why — and should be offered as much support and sympathy as possible."

Lancet Oncol. 2009;10:210-211.

ZAVOS IS SPEAKING: HP EVERYWHERE

J Neurol. 2009 Feb 25. [Epub ahead of print]

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Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer's disease.

Kountouras J, Boziki M, Gavalas E, Zavos C, Grigoriadis N, Deretzi G, Tzilves D, Katsinelos P, Tsolaki M, Chatzopoulos D, Venizelos I.

Department of Gastroenterology, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, jannis@med.auth.gr.

Infectious agents have been proposed as potential causes of Alzheimer's disease (AD). Recently, we documented a high prevalence of Helicobacter pylori (Hp) infection in patients with AD. We aim to access the effect of Hp eradication on the AD cognitive (MMSE: Mini Mental State Examination and CAMCOG: Cambridge Cognitive Examination for the Elderly) and functional (FRSSD: Functional Rating Scale for Symptoms of Dementia) status parameters. In the first part of the study, a total of 50 consecutive patients with AD and 30 age-matched anaemic controls underwent an upper gastrointestinal endoscopy, and gastric mucosal biopsies were obtained to detect the presence of Hp infection by histologic analysis and rapid urease test. Serum anti-Hp-specific IgG level was analysed by enzyme-linked immunosorbent assay. In the second part, Hp-positive AD patients received a triple eradication regimen (omeprazole, clarithromycin and amoxicillin), and all patients were followed up for 2 years, while under the same treatment with cholinesterase inhibitors. Hp was detected in 88% of AD patients and in 46.7% of controls (P < p =" 0.049">

RISK FACTORS FOR CONTRALATERAL MASTECTOMY

Risk Factors Warranting Contralateral Prophylactic Mastectomy for Breast Cancer Identified

January 29, 2009 — Risk factors that may warrant contralateral prophylactic mastectomy (CPM) for breast cancer have been identified, according to the results of a study reported in the January 26 Online First issue of Cancer.

"Although...CPM reduced the risk of contralateral breast cancer in unilateral breast cancer patients, it was difficult to predict which patients were most likely to benefit from the procedure," write Min Yi, MD, from The University of Texas M. D. Anderson Cancer Center in Houston, and colleagues. "The objective of this study was to identify the clinicopathologic factors that predict contralateral breast cancer and thereby inform decisions regarding performing CPM in unilateral breast cancer patients."

The study sample consisted of 542 patients with unilateral breast cancer who underwent CPM at The University of Texas M. D. Anderson Cancer Center from January 2000 to April 2007. Clinicopathologic factors predicting contralateral breast cancer were determined from logistic regression analysis.

Occult malignant tumor was present in the contralateral breast in 25 (5%) of patients. At final pathologic evaluation of the contralateral breast, 82 patients (15%) had moderate-risk to high-risk histologic findings.

Three independent factors predicting malignant tumor in the contralateral breast, based on multivariate analysis, were ipsilateral invasive lobular histologic findings, ipsilateral multicentric tumor, and 5-year Gail risk of 1.67% or greater. Independent predictors of moderate-risk to high-risk histologic findings in the contralateral breast were age 50 years or older at the time of the initial cancer diagnosis and an additional ipsilateral moderate-risk to high-risk pathologic finding.

Limitations of this study include single-institutional, retrospective design and relatively short follow-up time.

"CPM may be a rational choice for breast cancer patients who have a 5-year Gail risk ≥1.67%, an additional ipsilateral moderate-risk to high-risk pathology, an ipsilateral multicentric tumor, or an ipsilateral tumor of invasive lobular histology," the study authors write. "Evaluating 5-year Gail risk and histologic findings in the ipsilateral breast in unilateral breast cancer patients may help predict the likelihood of contralateral breast cancer and assist in stratifying risk and counseling patients."

HER2 ECD ASSESSMENT

J Clin Oncol. 2009 Mar 2. [Epub ahead of print]

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Utility of Serum HER2 Extracellular Domain Assessment in Clinical Decision Making: Pooled Analysis of Four Trials of Trastuzumab in Metastatic Breast Cancer.

Lennon S, Barton C, Banken L, Gianni L, Marty M, Baselga J, Leyland-Jones B.

Roche Products Ltd, Welwyn Garden City, United Kingdom; F Hoffmann-La Roche Ltd, Basel, Switzerland; Istituto Tumori, Milan, Italy; Hôpital Universitaire Saint Louis, Paris, France; Vall d'Hebron University Hospital, Barcelona, Spain; and the Emory University, Winship Cancer Institute, Atlanta, GA.

PURPOSE: Trastuzumab is a humanized monoclonal antibody directed against human epidermal growth factor receptor 2 (HER2). Trastuzumab alone or in combination with chemotherapy has been shown to be effective in patients with HER2-positive early and metastatic breast cancer. The extracellular domain (ECD) of the HER2 protein may be shed into the serum and is detectable using an enzyme-linked immunosorbent assay. Correlations have been reported between raised baseline ECD levels and response to trastuzumab, suggesting that serum ECD levels may be useful in making treatment decisions in patients with HER2-positive breast cancer. We investigated this relationship, and also the effect of trastuzumab and chemotherapy on ECD levels, in patients with advanced breast cancer. METHODS: This study analyzed sequential ECD determinations on 322 patients treated with six different treatment regimens in four clinical trials. RESULTS: Baseline values were available in 296 patients, and of these, 205 (69%) had raised levels (> 15 ng/mL). No clear relationship was found between baseline ECD levels and tumor response. After initiating combination therapy, ECD levels declined irrespective of treatment received and tumor response. For trastuzumab monotherapy, some trend between changes in ECD levels in early cycles and best response was discernable, but the overlap was too broad to be clinically useful. Disease progression was not reliably predicted by rising ECD levels in the majority of patients. CONCLUSION: Based on our data, we cannot recommend using serum HER2 ECD levels to make trastuzumab or other treatment decisions for individual patients with advanced/metastatic breast cancer.

STATIN USE AND PROSTATE CANCER

Statin Use and Risk of Prostate Cancer: Results from a Population-based Epidemiologic Study

Ilir Agalliu; Claudia A. Salinas; Philip D. Hansten; Elaine A. Ostrander; Janet L. StanfordAm J Epidemiol. 2008;168(3):250-260. ©2008 Oxford University Press

Posted 09/10/2008

Abstract and Introduction

Abstract

Epidemiologic studies of statin use in relation to prostate cancer risk have been inconclusive. Recent evidence, however, suggests that longer-term use may reduce risk of more advanced disease. The authors conducted a population-based study of 1,001 incident prostate cancer cases diagnosed in 2002-2005 and 942 age-matched controls from King County, Washington, to evaluate risk associated with statin use. Logistic regression was used to generate odds ratios for ever use, current use, and duration of use. No overall association was found between statin use and prostate cancer risk (odds ratio (OR) = 1.0, 95% confidence interval (CI): 0.8, 1.2 for current use; OR = 1.1, 95% CI: 0.7, 1.8 for >10 years' use), even for cases with more advanced disease. Risk related to statin use, however, was modified by body mass index (interaction p = 0.04). Obese men (BMI ≥ 30 kg/m²) who used statins had an increased risk (OR = 1.5, 95% CI: 1.0, 2.2) relative to obese nonusers, with a stronger association for longer-term use (OR = 1.8, 95% CI: 1.1, 3.0 for ≥ 5 years' use). Although statin use was not associated with overall prostate cancer risk, the finding of an increased risk associated with statin use among obese men, particularly use for extended durations, warrants further investigation.

ABIRATERONE AGAIN

GUCS 2009: Abiraterone Show Promise in Metastatic Prostate Cancer Patients

March 5, 2009 — More details about the experimental compound abiraterone (Cougar Biotechnology) in the treatment of advanced prostate cancer have been released from small phase 2 trials, confirming that it shows promise in this disease.

In 1 of the latest reports, abiraterone reduced prostate-specific antigen (PSA) levels by 50% or more in 71% of men with advanced prostate cancer after 12 weeks of treatment. The men were chemotherapy-naïve and had failed previous therapy with luteinizing-hormone-releasing hormone (LHRH) analogues and other hormonal agents.

These phase 2 results, from an interim analysis of a small study, were presented at 2009 Genitourinary Cancers Symposium in Orlando, Florida. The symposium is cosponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

To date, 21 patients have evaluable PSA responses and 81% (17 of 21 men) showed some response, reported the study authors, led by Charles J. Ryan, MD, from the University of California, San Francisco Comprehensive Cancer Center.

At week 12, declines of 50% or greater were observed in 71% (15 of 21) of patients. Two patients had achieved undetectable PSA levels at that time.

A majority of adverse events reported were grade 1 or 2. One patient experienced grade 3 treatment-related hypertension, according to Dr. Ryan and colleagues.

The median age in the study was 71.5 years and the median PSA at baseline was 24.7 ng/dL. The median number of previous hormonal therapies was 2 — all patients received an LHRH agonist, and 54.5% had received an anti-androgen.

The trial was conducted by the Prostate Cancer Clinical Trials Consortium and was sponsored by the US Department of Defense.

In Search of a Biomarker Predictive of Efficacy

Like other targeted therapies in oncology, abiraterone would benefit from a biomarker that could help predict which men will likely respond to treatment and which men won't. Investigators from the University of Texas MD Anderson Cancer Center, in Houston, presented data at the symposium on just such a potential biomarker: baseline bone-marrow testosterone levels.

In a study of 41 patients, they noted a correlation between depleted baseline bone-marrow testosterone levels and early progression.

In the study, serum and bone-marrow testosterone levels were measured before and after abiraterone treatment. A decline in both serum and bone-marrow testosterone levels to below detectable levels (less than 10 ng/mL) was seen in all 41 patients. Patients with depleted baseline bone-marrow testosterone levels (less than 10 ng/mL) appeared to progress earlier when treated with abiraterone (P = .05) than patients with measurable baseline bone-marrow testosterone levels.

Further examination of the bone-marrow biopsies of patients treated with abiraterone in this study revealed overexpression of both androgen receptor and CYP17, the enzyme abiraterone inhibits.

A phase 3 trial in chemotherapy-naïve men with metastatic disease is now planned. Abiraterone is also being studied in men with metastatic disease who have failed chemotherapy. A phase 3 trial in that population is underway.

"We are just waiting for the results of the [currently underway] phase 3 trial to see if the earlier results from smaller phase 2 trials hold up," said Mark N. Stein, MD, from the Cancer Institute of New Jersey and UMDNJ-Robert Wood Johnson Medical School, in New Brunswick, who is not involved in abiraterone research.

Not all men with metastatic disease — chemotherapy-naïve or failures — will benefit from abiraterone, suggested Daniel C. Danila, MD, from Memorial Sloan-Kettering Cancer Center, in New York City, and colleagues, who also presented data on the drug at the symposium. "A proportion of castration-resistant prostate cancers express androgen-synthetic enzymes and are dependent on androgens for growth," they note in a poster.

A Large Unmet Need

Abiraterone inhibits androgen synthesis and thus denies prostate cancer cells of the hormones that could stimulate their growth.

Abiraterone is 1 of a number of new targeted therapies for advanced prostate cancer that have shown potential in phase 2 trials. Another is MDV3100 (Medivation, Inc), an androgen-receptor antagonist that inhibits androgen-receptor function, as previously reported by Medscape Oncology.

Any new treatment for metastatic prostate cancer will be a welcome addition, suggested Dr. Stein.

"Docetaxel is the only treatment for [castration-resistant] metastatic disease. So, there is a large unmet need because everyone progresses on docetaxel," he said in an interview with Medscape Oncology, noting that 6 to 7 months is the median time on the drug.

Abiraterone is the new therapy that is most far along, said Dr. Stein, who hopes the drug will be available in the next 1 to 2 years.

Phase 2 Results in Castration-Resistant Chemo-Naïve Patients

In the phase 2 clinical trial that was discussed at the symposium, abiraterone, in combination with prednisone, was administered once daily to chemotherapy-naïve, ketoconazole-naïve patients with castration-resistant metastatic prostate cancer.

"Abiraterone is a more potent, more targeted version of ketoconazole," noted Dr. Stein.

SALVAGE TREATMENT IN GERM CELL TUMORS

Urologe A. 2009 Mar 4. [Epub ahead of print]

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[Salvage treatment in germ cell tumors : High-dose chemotherapy and the impact of prognostic factors.]

[Article in German]

Lorch A, Oechsle K, Bokemeyer C, Beyer J.

Klinik für Hämatologie, Onkologie und Immunologie, Klinikum der Philipps-Universität, Marburg, Deutschland.

The majority of patients with germ cell tumors who fail first-line treatment will still be cured. Patients without first-line chemotherapy who fail surveillance, radiotherapy, or surgery will be managed according to the treatment algorithms of their primary metastatic disease. These patients usually receive three to four cycles of cisplatin, etoposide, and bleomycin.Salvage treatment of patients who relapse after first-line chemotherapy is more complex and requires an experienced and highly specialized team. Two distinct treatment strategies can be pursued: four cycles of conventional-dose chemotherapy with cisplatin, ifosfamide, and either etoposide, paclitaxel, or vinblastine; or early intensification of first-salvage treatment using sequential high-dose chemotherapy. Salvage surgery is frequently required after completion of salvage chemotherapy to completely resect all radiologic residual manifestations. Patients with brain metastases should receive upfront whole brain radiation concurrent with salvage chemotherapy. Patients with late relapses more than 2 years after first-line treatment should receive immediate salvage surgery whenever this is technically feasible.

ROTTEN EGGS AND ERECTION

Hydrogen Sulfide: Potential Help for ED

March 3, 2009 -- The stench of rotten eggs seems an unlikely aphrodisiac. But new research suggests that a foul-smelling gas could someday become the target of new drugs for erectile dysfunction.

Hydrogen sulfide is present in raw natural gas and in the odor of rotting eggs. Our bodies also produce tiny quantities of hydrogen sulfide, but the gas was long thought to be only a toxic by-product of metabolism.

Research early this decade revealed that many animals actually use hydrogen sulfide to help expand blood vessels. Chemicals that create these expansions in blood flow are called vasodilators.

In previous experiments in mice and monkeys, injecting hydrogen sulfide opened blood vessels and improved erections. But the same chemical pathways weren't yet proven to function in people.

Hydrogen Sulfide for Erectile Dysfunction

For the new study, researchers at the University of Naples in Italy studied penile tissue samples obtained from humans.

They found the same enzymes that produce hydrogen sulfide in animals were present and functional in human tissue. The chemical reactions that produce hydrogen sulfide were generally the same, too. The scientists concluded that hydrogen sulfide does likely contribute to erections in men, just as in animal studies.

Viagra and other drugs for erectile dysfunction work by boosting the effects of nitric oxide, another vasodilator. Viagra slows down a specific enzyme, prolonging nitric oxide's actions. Blood vessels in the penis expand, and erections result from the increased blood flow.

The researchers say greater understanding of hydrogen sulfide's separate chemical pathway could eventually lead to new treatments for erectile dysfunction. The study appears in the online early edition of the journal Proceedings of the National Academy of Sciences.

INFERTILITY AND TESTICULAR CANCER

Male Factor Infertility Linked to Risk for Testicular Cancer

March 3, 2009 — Men with male factor infertility have an increased risk for the subsequent development of testicular cancer, according to the results of a study reported in the February 23 issue of the Archives of Internal Medicine.

"The risk of testicular cancer is thought to be higher among men seeking infertility treatment compared with the general population," write Thomas J. Walsh, MD, MS, from University of California–San Francisco and colleagues. "Confirmation of this risk in a large US cohort of at-risk patients is lacking. This study explored the association between male infertility and subsequent development of testicular cancer in a US-based cohort."

The study cohort consisted of 51,461 couples evaluated for infertility from 1967 to 1998 at 15 California infertility centers. Data from 22,562 identified male partners were linked to the California Cancer Registry. Using the Surveillance Epidemiology and End Results program, the investigators compared the incidence of testicular cancer in this cohort vs an age-matched, general-population sample. A Cox proportional hazards regression model allowed determination of the risk for testicular cancer in men with and without male factor infertility.

Male factor infertility was determined by the clinical presentation with abnormal semen analysis variables as defined by World Health Organization criteria.

There were 34 cases of histologically confirmed testicular cancer in men who had been previously diagnosed with infertility. The risk for the subsequent development of testicular cancer was increased in men seeking infertility treatment (standardized incidence ratio [SIR], 1.3; 95% confidence interval [CI], 0.9 - 1.9), with more than double the increased risk in men with known male factor infertility (SIR, 2.8; 95% CI, 1.5 - 4.8).

Multivariable analysis showed that men with male factor infertility were nearly 3 times more likely to have testicular cancer vs men without this condition (hazard ratio, 2.8; 95% CI, 1.3 - 6.0).

"Men with male factor infertility have an increased risk of subsequently developing testicular cancer, suggesting the existence of common etiologic factors for infertility and testicular cancer," the study authors write.

Limitations of this study include possible unmeasured confounding and lack of data concerning cryptorchidism, which is another potential cause of infertility and testicular cancer.

"The association between infertility and testicular cancer has been shown to be biologically and clinically feasible," the study authors write. "More importantly, the association between male infertility and testicular germ cell cancer should stimulate further research that focuses on the etiology of poor germ cell health in these populations."

LOW LEVELS HER2 AND PROGNOSIS

Am J Surg Pathol. 2009 Feb 26. [Epub ahead of print]

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Even Low-level HER2 Expression May be Associated With Worse Outcome in Node-positive Breast Cancer.

Gilcrease MZ, Woodward WA, Nicolas MM, Corley LJ, Fuller GN, Esteva FJ, Tucker SL, Buchholz TA.

Departments of *Pathology daggerBreast Radiation Oncology double daggerBreast Medical Oncology section signBioinformatics and Computational Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX.

HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients. Although standardized assays are used to help select patients for anti-HER2 therapy, there are no standardized criteria for assessing HER2 as a prognostic marker. Recent data using quantitative image analysis suggest that both high and low HER2 expression are associated with poor clinical outcome. Using the immunohistochemical scoring criteria currently recommended by the College of American Pathologists and American Society of Clinical Oncology to help select patients for trastuzumab, we evaluated HER2 protein expression in tumor tissue microarrays of 91 node-positive patients with invasive breast carcinoma treated with mastectomy and doxorubicin-based chemotherapy without trastuzumab and without irradiation with a median follow-up of 12.5 years. A wide range of HER2 expression (HER2 >/=1+) in the primary tumor was significantly associated with decreased locoregional recurrence-free survival (P=0.014), decreased disease-specific survival (P=0.001), and decreased overall survival (P=0.001). Even in the subset considered HER2 negative by current College of American Pathologists and American Society of Clinical Oncology guidelines, HER2=1+ was associated with worse outcome than HER2=0 in this patient cohort. The association between HER2 >/=1+ and worse outcome had the greatest statistical significance in the hormone receptor-positive subset of patients. These findings support the hypothesis that low-level HER2 expression may have significant clinical implications. Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy.

IMATINIB AND TB

Eur Respir J. 2009 Mar;33(3):670-2.

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Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.

Daniels JM, Vonk-Noordegraaf A, Janssen JJ, Postmus PE, van Altena R.

Department of Pulmonary Diseases, VU University Medical Centre, Amsterdam, The Netherlands. j.m.a.daniels@mca.nl

Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.

NEOADJUVANT OR ADJUVANT CHEMOTHERAPY AND METASTATECTOMY

World J Surg. 2009 Feb 23. [Epub ahead of print]

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Is There a Survival Benefit to Neoadjuvant Versus Adjuvant Chemotherapy, Combined with Surgery for Resectable Colorectal Liver Metastases?

Lubezky N, Geva R, Shmueli E, Nakache R, Klausner JM, Figer A, Ben-Haim M.

Department of Surgery "B", Tel-Aviv Sourasky Medical Center, 6 Weizmann St., Tel-Aviv, 64239, Israel.

BACKGROUND: The benefits of adding chemotherapy to surgery in patients with hepatic colorectal metastases at moderate and high risk for recurrence and the optimal sequence of administration are undetermined. METHODS: We followed the overall-survival and event-free survival rates after operation in patients with resectable colorectal metastases confined to the liver. The adjuvant patients first underwent surgery and then treatment, whereas the neoadjuvant patients underwent treatment, surgery, and re-treatment. Assignment was by oncologist and patient preferences. Chemotherapy was oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) based. RESULTS: Fifty-six of 105 patients who underwent liver resections for colorectal metastases (2002-2005) are included. The two groups were comparable for demographics, characteristics of disease (including recurrence risk), treatment protocols, and follow-up. The respective 1-, 2-, and 3-year overall survival rates were 91%, 91%, and 84%, and the event-free survival rates were 63%, 49%, and 49% for the 19 adjuvant patients, and 95%, 91%, and 70%, and 94%, 50%, and 50% for the 37 neoadjuvant patients. CONCLUSIONS: The midterm overall survival and disease-free survival rates in this group of patients with resectable colorectal metastases to the liver, who were treated with combination of resection and chemotherapy, were similar, regardless of the sequence of treatment.

GEMCITABINE DOUBLETS IN LUNG CANCER

Cancer. 2009 Feb 20. [Epub ahead of print]

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Gemcitabine-based doublets versus single-agent therapy for elderly patients with advanced nonsmall cell lung cancer: a Literature-based Meta-analysis.

Russo A, Rizzo S, Fulfaro F, Adamo V, Santini D, Vincenzi B, Gebbia N, Carreca I.

Section of Medical Oncology, Department of Surgery and Oncology, University of Palermo, Palermo, Italy.

BACKGROUND:: Although platinum-based combinations are considered the best option of care for patients with advanced nonsmall cell lung cancer (NSCLC), single-agent therapy is the preferred treatment for older patients. Since the late 1990s, various combinations of third-generation agents (gemcitabine [G], vinorelbine, docetaxel, and paclitaxel) have been tested, yielding contradictory results. The authors of this report performed a literature-based meta-analysis to assess the efficacy and tolerability of G-based doublets compared with single-agent chemotherapy for elderly patients with NSCLC. METHODS:: Data from all published, randomized, phase 3 trials that compared a G-based doublet with a third-generation single agent in elderly patients were collected from electronic databases (Medline and the Cochrane Central Register of Controlled Trials), relevant reference lists, and abstract books. Pooled odds ratios (ORs) were calculated for the 1-year survival rate, the overall response rate (ORR), and grade 3 and 4 toxicities. RESULTS:: Four eligible trials (1436 patients) were selected from 442 studies that initially were identified. A significant difference in ORR favoring G-based doublets over single agents was observed (OR, 0.65; 95% confidence interval [95% CI], 0.51-0.82 [P < .001]), whereas the trend toward an improved 1-year survival rate was not significant (OR, 0.78; 95% CI, 0.57-1.06 [P = .169]). Grade 3 and 4 toxicities did not differ significantly except for thrombocytopenia (OR, 1.76; 95% CI, 1.12-2.76 [P = .014]). CONCLUSIONS:: G-based doublets appeared to be effective and feasible compared with single agents in the treatment of elderly patients with advanced NSCLC who were not suitable for full-dose, platinum-based chemotherapy. Further prospective, elderly specific, phase 3 trials will be necessary. Cancer 2009. (c) 2009 American Cancer Society.

RITUXIMAB MAINTENANCE

Rituximab Should Be Used for Maintenance in Follicular Lymphoma

February 18, 2009 — Rituximab should be used for maintenance therapy in patients with relapsed or refractory follicular lymphoma after successful induction therapy because it significantly improves survival.

This is the conclusion from a new meta-analysis of 5 trials, involving more than 1000 patients, published in the February 18 issue of the Journal of the National Cancer Institute.

"This meta-analysis demonstrates for the first time, to our knowledge, that rituximab maintenance therapy improves overall survival and disease control," say the researchers, headed by Liat Vidal, MD, from the Rabin Medical Center, in Petah-Tikva, Israel.

"Rituximab should be used for patients with relapsed follicular lymphoma after successful induction treatment," Dr. Vidal told Medscape Oncology. Such use is not currently recommended in guidelines, but many physicians are already doing this, she said.

Already Established in First-Line Treatment

Rituximab is already established in the first-line treatment of follicular lymphoma, for which it is often used in combination with chemotherapy. As reported by Medscape Oncology, a recent editorial in the Journal of Clinical Oncology (2008;26:4537-4538) said it was "time to declare a giant leap forward," because patients with follicular lymphoma are now living longer than ever and rituximab has been a major contributor to the progress that has been made in the treatment of this disease.

However, the question of what to do when a patient relapses or becomes refractory has not had a clear answer. Dr. Vidal and colleagues point out that individual trials exploring rituximab use in this situation have shown a prolongation of remission and of the progression-free interval, but have not yielded any clear evidence of an impact on overall survival. As a result, rituximab maintenance for follicular lymphoma is not recommended in treatment guidelines, such as those issued by the National Comprehensive Cancer Network, they point out.

Now, however, Dr. Vidal and colleagues have shown a clear survival advantage from the meta-analysis of 5 trials that they performed. The trials involved 1143 patients, but survival data were available for only 985 patients.

Patients who received rituximab maintenance had significantly better overall survival that those who did not (hazard ratio [HR] for death, 0.60; 95% confidence interval [CI], 0.45–0.79).

However, patients taking rituximab were twice as likely to have an infection-related adverse effect (HR, 1.99; 95% CI, 1.21–3.27), and some of the infections reported in these patients were life-threatening, Dr. Vidal and colleagues report. "The higher rate of infections should be taken into consideration when making treatment decisions," they say.

Survival Advantage Seen With Both Schedules

The 5 trials in the meta-analysis used various drug combinations and administration schedules, but the type of rituximab maintenance schedule had no effect on overall survival, the researchers note.

At the time when the clinical trials were initiated, rituximab was not yet established as a standard in first-line treatment, so some patients received it in their induction regimen and others did not. Some patients were treated with first-line rituximab alone, some with rituximab and chemotherapy, and some with chemotherapy alone.

In addition, the maintenance regimens varied. In 3 trials, rituximab was administered weekly for 4 consecutive weeks (4 doses) every 6 months, whereas in the 2 other trials, a single infusion of rituximab was administered every 2 to 3 months. The duration of treatment varied from 8 to 9 months to 2 years.

"Our results suggest that rituximab maintenance therapy for up to 2 years, either as 4 weekly infusions every 6 months or as a single infusion every 2 to 3 months, should be added to standard therapy of patients with relapsed or refractory follicular lymphoma after successful induction treatment," Dr. Vidal and colleagues conclude

PARASKEYOPOULOS SPEAKING

Br J Cancer. 2009 Feb 17. [Epub ahead of print]

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Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer.

Sharma R, Graham J, Mitchell H, Brooks A, Blagden S, Gabra H.

1Ovarian Cancer Action (HHMT) Research Centre, Imperial College London Hammersmith Campus, Du Cane Road, London W12 ONN, UK.

There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinum-resistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m(-2) on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40-74 years). Median number of prior therapies is three (range 1-8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer.British Journal of Cancer advance online publication, 17 February 2009; doi:10.1038/sj.bjc.6604914 www.bjcancer.com.

ANOTHER MARKER FOR EGFR TARGETED THERAPY RESISTANCE

Cancer Res. 2009 Feb 17. [Epub ahead of print]

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PIK3CA Mutations in Colorectal Cancer Are Associated with Clinical Resistance to EGFR-Targeted Monoclonal Antibodies.

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

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

The monoclonal antibodies (moAb) panitumumab and cetuximab target the epidermal growth factor receptor (EGFR) and have proven valuable for the treatment of metastatic colorectal cancer (mCRC). EGFR-mediated signaling involves two main intracellular cascades: on one side KRAS activates BRAF, which in turn triggers the mitogen-activated protein kinases. On the other, membrane localization of the lipid kinase PIK3CA counteracts PTEN and promotes AKT1 phosphorylation, thereby activating a parallel intracellular axis. Constitutive activation of KRAS bypasses the corresponding signaling cascade and, accordingly, patients with mCRC bearing KRAS mutations are clinically resistant to therapy with panitumumab or cetuximab. We hypothesized that mutations activating PIK3CA could also preclude responsiveness to EGFR-targeted moAbs through a similar mechanism. Here, we present the mutational analysis of PIK3CA and KRAS and evaluation of the PTEN protein status in a cohort of 110 patients with mCRC treated with anti-EGFR moAbs. We observed 15 (13.6%) PIK3CA and 32 (29.0%) KRAS mutations. PIK3CA mutations were significantly associated with clinical resistance to panitumumab or cetuximab; none of the mutated patients achieved objective response (P = 0.038). When only KRAS wild-type tumors were analyzed, the statistical correlation was stronger (P = 0.016). Patients with PIK3CA mutations displayed a worse clinical outcome also in terms of progression-free survival (P = 0.035). Our data indicate that PIK3CA mutations can independently hamper the therapeutic response to panitumumab or cetuximab in mCRC. When the molecular status of the PIK3CA/PTEN and KRAS pathways are concomitantly ascertained, up to 70% of mCRC patients unlikely to respond to EGFR moAbs can be identified. [Cancer Res 2009;69(5):1851-7].