Day: 03/22/2011

Role of 18F-Fluorodeoxyglucose Positron Emission Tomography in Predicting Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer

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To compare 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) imaging characteristics in non-small cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutations.

Methods. We retrospectively identified NSCLC patients who underwent EGFR mutation testing and pretreatment FDG-PET and CT scans. The maximum standard uptake value (SUVmax) of the primary tumor and any metastases was measured and normalized to the SUV of blood in the pulmonary artery. We compared normalized SUVmax values between EGFR-mutant and wild-type patients and modeled radiographic and clinical predictors of EGFR mutation status. Receiver operator characteristic (ROC) curves were used to identify potential SUV cutoffs predictive of genotype.

Results. We included 100 patients (24 EGFR-mutant and 76 wild-type). There was a trend for higher normalized SUVmax in the primary tumors among patients with EGFR-wild-type versus mutant (median, 3.4; range, 0.6–12.8; versus median, 2.9; range, 0.4–5.0; p = .09). Normalized SUVmax of nodal and distant metastases, and CT characteristics were not associated with genotype. On multivariate analysis, low normalized SUVmax of the primary tumor was predictive for EGFR mutation (odds ratio, 0.72; 95% confidence interval, 0.53–0.98; p = .034). ROC curve analyses yielded an area under the curve of 0.62, and identified a potential cutoff of ≥5.0 to distinguish wild-type from mutant tumors.

Conclusions. In this retrospective study, high FDG avidity (normalized SUVmax ≥5) correlated with EGFR-wild-type genotype. Although genotyping remains the gold standard, further work to validate FDG-PET as a surrogate for tumor genotype may provide useful information in patients without available tumor tissue.

source: the oncologist

Circadian Rhythms in Blood Pressure Regulation and Optimization of Hypertension Treatment With ACE Inhibitor and ARB Medications

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Specific features of the 24 h-blood pressure (BP) pattern are linked to the progressive injury of target tissues and risk of cardiac and cerebrovascular events. Studies have consistently shown an association between blunted asleep BP decline and increased incidence of fatal and nonfatal cardiovascular events. Thus, there is growing interest in how to achieve better BP control during nighttime sleep in addition to during daytime activity, according to the particular requirements of each hypertension patient. One approach takes into consideration the endogenous circadian rhythm-determinants of the 24-h BP pattern, especially, the prominent day–night variation of the renin–angiotensin–aldosterone system, which activates during nighttime sleep. A series of clinical studies have demonstrated a different effect of the angiotensin-converting enzyme (ACE) inhibitors benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, and trandolapril when routinely ingested in the morning vs. the evening. In most cases, the evening schedule exerts a more marked effect on the asleep than awake BP means. Similarly, a once-daily evening, in comparison to morning, ingestion schedule of the angiotensin receptor blockers (ARBs) irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with normalization of the circadian BP profile toward a more dipping pattern, independent of drug terminal half-life. Chronotherapy, the timing of treatment to body rhythms, is a cost-effective means of both individualizing and optimizing the treatment of hypertension through normalization of the 24-h BP level and profile, and it may constitute an effective option to reduce cardiovascular risk.

source:American Journal of Hypertension

Clinical Experience to Date With Nilotinib in Gastrointestinal Stromal Tumors

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Nilotinib, a novel tyrosine kinase inhibitor (TKI) that inhibits BCR-ABL, the stem cell factor receptor (KIT), and platelet-derived growth factor receptor-alpha (PDGFRα), is approved for the treatment of patients with newly diagnosed Philadelphia chromosome–positive chronic myelogenous leukemia (CML) and those with CML that is imatinib-resistant or -intolerant. Due to its potent inhibition of KIT and PDGFRα—the two tyrosine kinases that are the central oncogenic mechanisms of gastrointestinal stromal tumors (GIST)—nilotinib also has been investigated for potential efficacy and safety in patients with GIST who have progressed on other approved treatments. Initial results have been encouraging, as nilotinib has demonstrated clinical efficacy and safety in a phase I trial as either a single agent or in combination with imatinib, as well as in heavily pretreated patients with GIST in a compassionate use program. In addition, the phase III trial of nilotinib versus best supportive care (with or without a TKI at the investigator’s discretion) indicated that nilotinib may have efficacy in some third-line patients. Furthermore, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST g1 trial), a phase III randomized, open-label study comparing the safety and efficacy of imatinib versus nilotinib in the first-line treatment of patients with GIST, is currently under way. Other studies with nilotinib either have been initiated or are in development. Based on published and accruing clinical data, nilotinib shows potential as a new drug in the clinician’s armamentarium for the management of GIST.

source: science direct

Premastication of Food by Caregivers of HIV-Exposed Children

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Premastication (i.e., chewing foods or medicines before feeding to a child) was reported recently as a route of human immunodeficiency (HIV) transmission through blood in saliva (1) and has been associated with transmission of other pathogens (2–7). Approximately 14% of caregivers in the United States report premastication (8); however, the frequency of this behavior among HIV-infected caregivers is unknown. To assess the prevalence of premastication among caregivers of children being treated in pediatric HIV clinics, which include perinatally HIV-exposed children (i.e., HIV-uninfected and HIV-infected children born to an HIV-infected mother), CDC conducted a cross-sectional survey at nine such clinics in the United States during December 2009–February 2010. This report describes the results of that survey, which indicated that among primary caregivers of children aged ≥6 months, 48 (31%) of 154 reported the children received premasticated food from themselves or someone else. Approximately 37% of black caregivers reported premastication, compared with 20% of non-black caregivers (prevalence ratio [PR] = 1.8). Premastication decreased with caregiver age and was used to feed children aged 1–36 months. Public health officials and health-care providers should educate the public about the risk for disease transmission via premastication and advise HIV-infected caregivers against the practice.

Pediatric HIV clinics with which the CDC had collaborated previously in premastication-related or longitudinal, HIV-related epidemiologic studies participated in this investigation. These clinics were located in Atlanta, Georgia; Dallas, Texas; Houston, Texas; Memphis, Tennessee; Miami, Florida; New Orleans, Louisiana; Newark, New Jersey; San Juan, Puerto Rico; and the District of Columbia. A 10-minute, self-administered paper questionnaire was distributed to primary caregivers during their child’s clinic visit. A primary caregiver was defined as the person responsible for feeding, clothing, and housing the child. One survey per child with an appointment was allowed; therefore, multiple interviews were possible if a caregiver had multiple children with appointments. After completion of the survey, caregivers were provided written information and counseled about the risk for disease transmission through premastication. Of 203 primary caregivers approached, 192 (95%) were surveyed (11 declined participation).

Of the 192 primary caregivers surveyed, the majority were biologic mothers of the children (81%) and U.S.-born (86%). Approximately 66% of caregivers were non-Hispanic black, 24% were Hispanic, and 7% were non-Hispanic white. The median age was 31 years for primary caregivers (range: 15–77 years) and 2 years for children (range: <1–18 years). Approximately 30% of caregivers had less than a high school education, and 49% had an annual household income of less than $12,000.

Given the decreased likelihood that children are fed solid foods during the first months of life, CDC limited its analysis to caregivers of children who were aged ≥6 months at the time of investigation (155 [81%] of 192). Among primary caregivers of these children, 44 (29%) of 153 reported ever premasticating food for the child. Fourteen (10%) of 140 primary caregivers reported that someone else had given premasticated food to the child. Overall, 48 (31%) of 154 primary caregivers stated that they or someone else had premasticated food for the child, with biologic mothers representing 79% of premasticators. Black caregivers more frequently reported ever premasticating food, compared with non-blacks (37% versus 20%, respectively; PR = 1.8) (Table 1). Premastication decreased with increasing caregiver age at interview. Caregivers aged ≤19 years were significantly more likely to premasticate than those aged ≥40 years (44% versus 13%, respectively; PR = 3.5), as were those aged 20–29 years (38% versus 13%, respectively; PR = 2.9) and those aged 30–39 years (36% versus 13%, respectively; PR = 2.8). Similar prevalences of premastication were found regardless of the sex of the child and the primary caregiver’s country of origin, education level, and income (Table 1).

Primary caregivers started premastication of food for children as young as age 1 month (median age: 7 months) and stopped premastication as late as age 36 months (median age: 13 months). Among 38 premasticating primary caregivers who described frequency of the behavior, 15 (39%) reported premasticating 1–3 days in a typical week, 14 (36%) reported 4 or more days, and nine (24%) reported less than once a week. The most commonly reported reasons for premastication, reported from a predetermined list, were “child wanting some of the caregiver’s food” (64%), “caregiver not wanting the child to choke” (62%), and “prechewing is done in my family” (31%) (Table 2). Meat and fish (80%) and fruit (39%) were the most commonly reported food types premasticated by caregivers.

Reported by

N Rakhmanina, MD, Children’s National Medical Center; S Hader, MD, A Denson, Dept of Health, Washington, DC. A Gaur, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee. C Mitchell, MD, Miller School of Medicine, Univ of Miami. S Henderson, MD, Emory Univ, Atlanta, Georgia. M Paul, MD, Baylor College of Medicine, Texas Children’s Hospital, Houston; T Barton, MD, Southwestern Medical Center, Dallas, Texas. M Herbert-Grant, MD, University Hospital, New Jersey Medical School. E Perez, Univ of Puerto Rico. J Malachowski, Tulane Univ School of Public Health, New Orleans, Louisiana. K Dominguez, MD, S Danner, S Nesheim, MD, Div of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; W Ivy, PhD, D Iuliano, PhD, EIS officers, CDC.

Editorial Note

In 2007, an estimated 13% of 159 diagnoses of HIV and acquired immunodeficiency syndrome (AIDS) among children aged <13 years were attributed to modes other than perinatal transmission, including hemophilia, blood transfusion, and risk factors not reported or identified.* In 2008, a case series of three pediatric HIV cases concluded that premastication was the likely mode of transmission for these children, a route not reported previously (1). Bleeding gums at the time of premastication were reported in caregivers of two of the three children in the case series. The third caregiver could not recall her dental condition at the time of premastication. One of these transmissions was to a child whose mother was not HIV-infected. HIV transmission via premastication is presumed to require blood in the mouth of the caregiver. No evidence suggests that saliva alone can transmit HIV.

In addition to HIV, transmission of hepatitis B virus (3) and group A streptococcus (6) by premastication has been documented. Furthermore, premastication has been found to be associated with increased risk for infection with Helicobacter pylori (7), Streptococcus mutans (2), human herpesvirus 8 (4), and Epstein Barr virus (5). Only one study has indicated that premastication can be associated with decreased risk for infection; that study involved respiratory syncytial virus in Alaska Native infants aged <6 months (9).

The prevalence of premastication observed in this investigation is particularly important because most of the caregivers and premasticators were biologic mothers; thus, most caregivers were HIV-infected, posing a potential risk for HIV transmission to children in their care who are uninfected. Furthermore, the higher prevalence of premastication among black and younger caregivers suggests the need for targeted prevention messages for these populations.

The reasons given by caregivers for premastication might suggest that the practice is mostly situational or in response to immediate circumstances, as opposed to reasons that reflect an inability to provide baby food or formula. Therefore, prevention messages might be effective among this population, particularly those with situational reasons for premastication. Qualitative research on premastication might be helpful to explore the reasons for premastication and to determine helpful, realistic alternatives for HIV-infected caregivers.

The findings in this report are subject to at least three limitations. First, gathering HIV status information on caregivers was not possible because surveys were completed in a setting where caregivers were accompanied by their children and other family members, some of whom might have been unaware of their caregiver’s HIV status. However, given that all caregivers were surveyed in pediatric HIV clinics and 81% of primary caregivers were biologic mothers, the majority of the caregivers surveyed likely were HIV-infected. Second, the surveyed caregivers were asked to recall behaviors that might have taken place several years before survey administration; therefore, these data might be affected by recall bias. Finally, this cross-sectional investigation included a convenience sample of caregivers of children seen in HIV clinics and is not generalizable to all HIV-infected caregivers.

Although research on the risk for HIV transmission via premastication is limited, CDC recommends that HIV-infected caregivers not premasticate food for HIV-uninfected children because of the possibility of transmitting HIV to the child. Public health officials and health-care providers should continue to educate the public about the risk for disease transmission, including HIV, via premastication.

source: CDC

The European Commission has granted Novartis approval for Gilenya® (fingolimod) 0.5 mg daily as a disease modifying therapy in patients with highly active relapsing-remitting multiple sclerosis (RRMS)

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The European Commission has granted Novartis approval for Gilenya® (fingolimod) 0.5 mg daily as a  disease modifying therapy in patients with highly active relapsing-remitting multiple sclerosis (RRMS) despite treatment with beta interferon, or in patients with rapidly evolving severe RRMS.

“Today marks an important step forward in the way we manage this chronic, debilitating disease in Europe,” said Professor Hans-Peter Hartung, Professor and Chairman, Dept. of Neurology, Heinrich-Heine University, Germany. “Gilenya is the first approved therapy for MS that offers significant efficacy in a capsule, which for many patients will come as a welcome additional option.”

The approval was based on the largest clinical trial program submitted to date for a new MS drug, and included data from clinical studies showing significant efficacy in reducing relapses, the risk of disability progression, and the number of brain lesions detected by magnetic resonance imaging (MRI), a measure of disease activity[1],[2].

“Today’s announcement marks another major regulatory approval and we are pleased that Gilenya will become available to more eligible MS patients,” said David Epstein, Division Head of Novartis Pharmaceuticals. “Novartis is dedicated to bringing innovative new treatments to patients where there is significant unmet need. Gilenya has been in clinical development for MS since 2003 and we are grateful for the commitment of those involved, especially the trial participants, who have contributed significantly to the development of this novel medicine.”

Gilenya, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In MS, the immune system damages the covering that protects nerve fibers in the central nervous system (CNS), which includes the brain and spinal cord. The novel mechanism of Gilenya is thought to work by reducing the immune system’s attack on the CNS by retaining certain white blood cells (lymphocytes) in the lymph nodes. This prevents the white blood cells from reaching the CNS, where they could potentially attack the protective covering around the nerve fibers, resulting in less inflammatory damage to the nerve cells. The white blood cell retention is reversible if Gilenya treatment is stopped.

The EU application included data showing Gilenya 0.5 mg reduced relapses by 52% (P<0.001) at one year compared with interferon beta-1a IM (Avonex®), one of the most commonly prescribed treatments for MS Data from a two-year placebo-controlled study showed a reduction in the risk of disability progression among Gilenya patients (30% reduction confirmed at three-month follow-up visit P=0.02, compared with placebo)[2]. In clinical studies, treatment with Gilenya also resulted in statistically significant reductions in brain lesion activity as measured by MRI.

Gilenya has been studied in more than 4000 MS patients. The most common side effects are headache, liver enzyme elevations, influenza, diarrhea, back pain, and cough. Other Gilenya-related side effects include transient, generally asymptomatic, heart rate reduction and atrioventricular block upon treatment initiation, mild blood pressure increase, macular edema, and mild bronchoconstriction.[1],[2]

The rates of infections overall, including serious infections, were comparable among treatment groups, although a slight increase in lower respiratory tract infections (primarily bronchitis) was seen in patients treated with Gilenya. The number of malignancies reported across the clinical trial program was small, with comparable rates between the Gilenya and control groups.

source: novartis release

Once-Daily Darunavir in Treatment-Experienced Patients: ODIN Results Published

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In HIV-infected patients with no darunavir resistance–associated mutations, once-daily darunavir is as effective as twice-daily darunavir, with fewer adverse events.

Darunavir was initially approved for treatment-experienced patients at a dose of 600 mg, with 100 mg of ritonavir, twice daily. However, data from the POWER 1 and 2 trials suggested that the once-daily dose approved for use in treatment-naive patients — 800 mg, with 100 mg of ritonavir — might also be effective in treatment-experienced patients with no baseline darunavir resistance. The ODIN trial, a phase III, open-label, manufacturer-funded study, was designed to evaluate this possibility.

A total of 590 patients who were on a failing regimen and had no darunavir resistance–associated mutations were randomized to receive ritonavir-boosted darunavir either once daily (800 mg, with 100 mg of ritonavir) or twice daily (600 mg, with 100 mg of ritonavir). Both groups received optimized background regimens consisting of 2 nucleoside reverse transcriptase inhibitors. Forty-six percent of the patients had never received a protease inhibitor (PI) before, and 84% of the patients had no major PI mutations.

At week 48, 72% of the once-daily group and 71% of the twice-daily group achieved viral loads <50 copies/mL, establishing noninferiority of the once-daily dose. Only one patient with virologic failure (in the once-daily group) developed major PI mutations. The once-daily group had fewer triglyceride elevations and lower cholesterol levels (total and LDL) than the twice-daily group.

Comment: Based on the results of this trial, on December 13, 2010, the FDA approved once-daily dosing of ritonavir-boosted darunavir for treatment-experienced patients with no darunavir resistance–associated mutations. As the authors point out, most treatment-experienced patients do not have such mutations. For the subset of patients who do, twice-daily dosing should continue to be used.

Published in Journal Watch HIV/AIDS Clinical Care