Clinical genetic counseling and translation considerations for polygenic scores in personalized risk assessments: A Practice Resource from the National Society of Genetic Counselors.

Polygenic scores (PGS) are primed for use in personalized risk assessments for common, complex conditions and population health screening. Although there is growing evidence supporting the clinical validity of these scores in certain diseases, presently, there is no consensus on best practices for constructing PGS or demonstrated clinical utility in practice. Despite these evidence gaps, individuals can access their PGS information through commercial entities, research programs, and clinical programs. This prompts the immediate need for educational resources for clinicians encountering PGS information in clinical practice. This practice resource is intended to increase genetic counselors' and other healthcare providers' understanding and comfort with PGS used in personalized risk assessments. Drawing on best practices in clinical genomics, we discuss the unique considerations for polygenic-based (1) testing, (2) clinical genetic counseling, and (3) translation to population health services. This practice resource outlines the emerging uses of PGS, as well as the critical limitations of this technology that need to be addressed before wide-scale implementation.

Delay in the administration of all-trans retinoic acid and its effects on early mortality in acute promyelocytic leukemia: final results of a multicentric study in the United States.

Early death (ED) occurs in 10-30% of patients with acute promyelocytic leukemia (APL). Is all-trans retinoic acid (ATRA) promptly given and does it decrease overall early mortality? ATRA was administered within 24h of morphological suspicion in only 44% of the 120 consecutive patients treated in the four collaborating centers. Absence of disseminated intravascular coagulation (p=0.012) and admission to a non-university-affiliated hospital (p=0.032) were independent predictors of ATRA delay. ED occurred in 17% of patients, and was independently correlated only with ICU admission (p=0.002). Our results do not demonstrate that prompt (versus delayed) ATRA administration decreases overall early death.

Reversal of cardiomyopathy with tocilizumab in a case of HIV-negative Castleman's disease.

The association between Castleman's disease (CD) and cardiomyopathy has been rarely reported and the optimal therapeutic approach remains unknown. We report a previously healthy 20-year-old African American female who presented with fever, dyspnea, anasarca, and generalized lymphadenopathy. Diagnostic workup, including an axillary lymph node biopsy, revealed that she had human immunodeficiency virus-negative and human herpes virus-8-negative multicentric CD. She had a non-anaphylactoid infusion reaction during her fourth rituximab infusion. A few weeks later, she developed new-onset severe cardiomyopathy requiring inotropic therapy, warranting consideration for left ventricular assist device. Several clinical clues indicated her new-onset heart failure was a manifestation of her CD. Interestingly, a trial of tocilizumab (an anti-interleukin-6 receptor monoclonal antibody) resulted in complete resolution of her cardiomyopathy and other manifestations of CD. Tocilizumab received orphan drug approval for the treatment of CD in Japan, but is not yet approved for this indication in the United States. Clinicians should be aware of its potential clinical utility in CD.

Thymidylate Synthase as a Predictive Biomarker for Pemetrexed Response in NSCLC.

In recent years, major strides in cancer research have made it possible to select personalized chemotherapy recommendations based on an individual patient's tumor biology. The prognostic and/or predictive ability of biomarkers seeks to tailor the use of targeted chemotherapy and can result in improved clinical outcomes with reduced toxicity. A proliferation of new technology and pharmacotherapeutics in the setting of current FDA Clinical Laboratory Improvement Amendment (CLIA) standards has resulted in a recent surge in direct-to-physician biomarker tests. However, in the absence of clinical validation, there is the concern that the biomarkers may be utilized prematurely, resulting in improper chemotherapy selection and patient harm. Thymidylate synthase (TS) has been marketed as a predictive biomarker for the use of pemetrexed in NSCLC. We will examine the evidence behind the use of TS as a predictive biomarker to predict response to pemetrexed in NSCLC. At this time, the evidence does not currently support using TS assays to guide chemotherapy selection outside of a clinical research protocol.

Hypoxia, angiogenesis, and lung cancer.

Lung cancer is responsible for more deaths than any other cancer in America. As a result, novel ways to treat it are needed to improve patient outcomes. A tumor must form new blood vessels to grow and metastasize to distant sites; this angiogenesis is mediated by factors such as vascular endothelial growth factor (VEGF). Because it increases VEGF levels, hypoxia has been thought to be a primary trigger of angiogenesis. Tumor hypoxia and higher levels of serum markers of angiogenesis have been associated with poor prognosis in non-small cell lung cancer (NSCLC). In recent years, antiangiogenic compounds have been developed and tested in various solid malignancies, including NSCLC, for which bevacizumab, a monoclonal antibody against VEGF, was recently approved. Combinations of antiangiogenic drugs and conventional cytotoxic chemotherapy are currently under development.

Review of pemetrexed in combination with cisplatin for the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a resistant form of lung cancer, and its incidence continues to rise in Europe and Australia. Until recently, chemotherapy had not been shown to be effective in the treatment of this slowly progressive disease. In 2004, the combination of pemetrexed and cisplatin was shown to induce high response rates in MPM. This article reviews the published literature describing the development and testing of this therapeutic combination in mesothelioma, and examines in detail the key phase III clinical trial that led to the approval of pemetrexed by the US FDA. Ongoing research will further define the role of pemetrexed plus cisplatin in the treatment of MPM.

Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition).

BACKGROUND: The solitary pulmonary nodule (SPN) is a frequent incidental finding that may represent primary lung cancer or other malignant or benign lesions. The optimal management of the SPN remains unclear. METHODS: We conducted a systematic literature review to address the following questions: (1) the prevalence of SPN; (2) the prevalence of malignancy in nodules with varying characteristics (size, morphology, and type of opacity); (3) the relationships between growth rates, histology, and other nodule characteristics; and (4) the performance characteristics and complication rates of tests for SPN diagnosis. We searched MEDLINE and other databases and used previous systematic reviews and recent primary studies. RESULTS: Eight large trials of lung cancer screening showed that both the prevalence of at least one nodule (8 to 51%) and the prevalence of malignancy in patients with nodules (1.1 to 12%) varied considerably across studies. The prevalence of malignancy varied by size (0 to 1% for nodules < 5 mm, 6 to 28% for nodules 5 to 10 mm, and 64 to 82% for nodules > 20 mm). Data from six studies of patients with incidental or screening-detected nodules showed that the risk for malignancy was approximately 20 to 30% in nodules with smooth edges; in nodules with irregular, lobulated, or spiculated borders, the rate of malignancy was higher but varied across studies from 33 to 100%. Nodules that were pure ground-glass opacities were more likely to be malignant (59 to 73%) than solid nodules (7 to 9%). The sensitivity of positron emission tomography imaging for identifying a malignant SPN was consistently high (80 to 100%), whereas specificity was lower and more variable across studies (40 to 100%). Dynamic CT with nodule enhancement yielded the most promising sensitivity (sensitivity, 98 to 100%; specificity, 54 to 93%) among imaging tests. In studies of CT-guided needle biopsy, nondiagnostic results were seen approximately 20% of the time, but sensitivity and specificity were excellent when biopsy yielded a specific benign or malignant result. CONCLUSIONS: The prevalence of an SPN and the prevalence of malignancy in patients with an SPN vary widely across studies. The interpretation of these variable prevalence rates should take into consideration not only the nodule characteristics but also the population at risk. Modern imaging tests and CT-guided needle biopsy are highly sensitive for identifying a malignant SPN, but the specificity of imaging tests is variable and often poor.

Management options for malignant pleural mesothelioma: clinical and cost considerations.

Malignant pleural mesothelioma (MPM) is a resistant form of lung cancer that is often related to prior asbestos exposure. While surgical resection and radiotherapy techniques have been refined in recent years, neither has been proven to significantly extend patient survival compared with untreated controls. Until the release of pemetrexed in 2004, even combination chemotherapy regimens often resulted in a response rate of <20%. A recent phase III trial documented a 41.3% response rate for cisplatin plus pemetrexed. In the future, new multimodality regimens featuring novel targeted therapies directed against molecular targets, such as the vascular endothelial growth factor, hold the greatest promise for improved outcomes in MPM. The standard radiographic assessment of response to MPM therapy remains a poor surrogate for clinically relevant endpoints such as median survival. Furthermore, it is not currently known whether aggressive multimodality treatment for MPM will improve survival or quality of life above and beyond symptomatic care. Ongoing clinical trials are comparing chemotherapy and surgery with supportive care in an effort to define the role of different therapies in MPM. MPM treatment is a costly public health issue; after efficacy is proven, additional studies are needed to measure the cost effectiveness of MPM treatment regimens.

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.