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Targeting Oncogenic ALK: A Promising Strategy for Cancer Treatment.

Recently, the anaplastic lymphoma kinase (ALK) has been found to be altered in several solid and hematologic tumors. Novel drugs targeting this tyrosine kinase receptor are under development, and early clinical trials are showing promising activity in non-small cell lung cancer patients with ALK+ tumors.

Here, we review the structure and function of the ALK receptor, the mechanisms associated with its deregulation in cancer, methods for ALK detection in tumor samples, its potential as a new marker for candidate patient selection for tailored therapy, and novel drugs under development that target ALK. Mol Cancer Ther; 10(4); 569-79. ©2011 AACR.

New Targets in Advanced NSCLC: EML4-ALK.

Targeted therapies aimed at inhibiting oncogenic tyrosine kinases are becoming commonplace in the treatment of cancer. The EML4-ALK fusion gene was first identified as a potentially targetable oncogenic driver in non-small cell lung cancer in 2007. A small molecule ALK inhibitor, crizotinib, may now be on the verge of approval by the US Food and Drug Administration for the treatment of ALK-rearranged lung cancer.

Here we review the discovery of EML4-ALK, the development of clinical diagnostics for ALK rearrangements, the clinical epidemiology of lung cancers driven by EML4-ALK, and ongoing ALK inhibitor-based clinical trials.

Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: A Canadian Thoracic Society clinical practice guideline.

Dyspnea is a cardinal symptom of chronic obstructive pulmonary disease (COPD), and its severity and magnitude increases as the disease progresses, leading to significant disability and a negative effect on quality of life. Refractory dyspnea is a common and difficult symptom to treat in patients with advanced COPD. There are many questions concerning optimal management and, specifically, whether various therapies are effective in this setting.

The present document was compiled to address these important clinical issues using an evidence-based systematic review process led by a representative interprofessional panel of experts. The evidence supports the benefits of oral opioids, neuromuscular electrical stimulation, chest wall vibration, walking aids and pursed-lip breathing in the management of dyspnea in the individual patient with advanced COPD. Oxygen is recommended for COPD patients with resting hypoxemia, but its use for the targeted management of dyspnea in this setting should be reserved for patients who receive symptomatic benefit. There is insufficient evidence to support the routine use of anxiolytic medications, nebulized opioids, acupuncture, acupressure, distractive auditory stimuli (music), relaxation, handheld fans, counselling programs or psychotherapy. There is also no evidence to support the use of supplemental oxygen to reduce dyspnea in nonhypoxemic patients with advanced COPD.

Recognizing the current unfamiliarity with prescribing and dosing of opioid therapy in this setting, a potential approach for their use is illustrated. The role of opioid and other effective therapies in the comprehensive management of refractory dyspnea in patients with advanced COPD is discussed.

Inappropriate Overuse of Inhaled Corticosteroids for COPD Patients: Impact on Health Costs and Health Status.

The aim of this study was to evaluate the relationship between inappropriate overuse of inhaled corticosteroids and self-reported health status and the annual cost of patients with stable chronic obstructive pulmonary disease (COPD) recruited in the primary-care setting.

An observational, crossover, descriptive study was conducted. Patients with stable COPD and aged ≥40 years, evaluated in primary care, were included. Data collected were demographic variables, clinical characteristics, self-reported health status (SF-12), the severity of the illness, treatment, and health-care resource utilization in the past year. The patients were recruited during a period of 3 months (from January 1 to March 31, 2003). Use was considered inappropriate when corticosteroids were prescribed by physicians for patients not meeting criteria for its use as recommended in guidelines.

A total of 10,711 patients [75.6% males; mean age = 67.1 (SD = 9.66) years] were evaluated. Disease severity was mild in 35.5% of the cases, moderate in 53.4%, and severe in 11.2%. Among them, 3,697 (34.5%) subjects were prescribed inhaled corticosteroids or drug combinations containing such therapies, with a rate of inappropriate use of 18.2%. Physical health status was significantly lower among patients showing inappropriate corticosteroids use: 37.35 (SD = 9.53) vs. 40.7 (SD = 9.80) (p < 0.05). The annual cost per patient of COPD management was significantly higher in the group with inappropriate inhaled corticosteroids use: <euro>1,590 (SD = 1,834) vs. <euro>1,157 (SD = 1,536) (p < 0.05). Factors statistically associated with inappropriate use of corticosteroids were educational attainment [OR: 2.77 (95% CI: 1.36-5.63) for nonuniversity training], a history of heart disease [OR: 1.42 (95% CI: 1.02-1.97)], depression [OR: 1.47 (95% CI: 1.05-2.05)], any allergy [OR 1.69 (95% CI: 1.13-2.54)], and physical health status [OR 0.97 (95% CI: 0.96-0.98)].

Lack of adherence to the recommended criteria for using inhaled corticosteroids therapy in the management of COPD patients was associated with lower self-reported health status and higher costs. Factors statistically associated with inappropriate use of corticosteroids were educational attainment, a history of heart disease, depression, any allergy, and physical health status.

The advent of recombinant allergens and allergen cloning

When the allergen nomenclature system was adopted in 1986, allergens were identified by their behavior on electrophoresis and chromatography and by reactivity to shared antisera. Not only was this unsatisfactory for standardization, but the processes of allergic sensitization and immunotherapy could not be studied in the framework of antigen processing and B- and T-cell epitopes. Recombinant technologies developed in the 1980s for cloning cDNA from low-abundance mRNA permitted the cloning of allergens, beginning with the major house dust mite allergen Der p 1 and hornet allergen Dol m 5. After this, a wave of cloning with IgE immunoscreening resulted in the cloning of Der p 2, Der p 5, Bet v 1, Bet v 2, and Dac g 2 along with Fel d 1 cloned after amino acid sequencing. Recombinant allergens have now been used to define the important allergens for a wide range of allergies and to develop new types of immunotherapy, some of which have shown efficacy in human trials. The clonally pure allergens have been used to solve the tertiary structures of allergens and from this how allergens might activate innate immunity. Proprietary recombinant allergens are now being used in improved diagnostic tests.

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