Reviews on Recent Clinical Trials - Volume 7, Issue 1, 2012

The article in this issue concerning Bowen's disease brings to mind the overall increasing incidence of nonmelanoma skin cancer. Rogers et al. [1] performed an analysis to estimate the incidence of nonmelanoma skin cancer (NMSC) in the US population in 2006, and to evaluate trends in numbers of procedures for skin cancer treatment. They performed a descriptive analysis of population-based claims and US Census Bureau data combined with a populationbased cross-sectional survey using multiple US government data sets, including the Centers for Medicare and Medicaid Services Fee-for-Service Physicians Claims databases, to calculate totals of skin cancer procedures performed for Medicare beneficiaries in 1992 and from 1996 to 2006 and related parameters. The National Ambulatory Medical Care Service database was utilized to estimate NMSC-related office visits. They combined these to estimate totals of new skin cancer diagnoses and affected individuals in the overall US population [1]. They found that the total number of procedures for skin cancer in the Medicare fee-for-service population increased by 76.9% from 1,158,298 in 1992 to 2,048,517 in 2006. From 2002 to 2006 (the years for which the databases allow procedure linkage to patient demographics and diagnoses), the number of procedures for NMSC in the Medicare population increased by 16.0%. In this period, the number of procedures per affected patient increased by 1.5%, and the number of persons with at least 1 procedure increased by 14.3%. They concluded that the number of skin cancers in Medicare beneficiaries increased dramatically over the years 1992 to 2006, due mainly to an increase in the number of affected individuals [1]. The increasing trends in the incidence of these malignancies should encourage physicians to carefully examine patients' skin, as well as educate individuals to practice proper skin protection. This issue also covers other important issues, including the use of antibiotics in bronchiectasis and vascular effects of estrogenic menopausal hormone therapy. Oncologic reviews include Esophagitis, Treatment-Related Toxicity in Non-Small Cell Lung Cancer, Positron Emission Tomography for Neck Evaluation Following Definitive, Treatment with Chemoradiotherapy for Locoregionally Advanced Head and Neck Squamous Cell Carcinoma, and Therapeutic Intervention in Cancer and Chronic Viral Infections: Antibody Mediated Manipulation of PD-1/PD-L1 Interaction. The final article examines the prevention and treatment of diabetic retinopathy with fenofibrate. It is my hope that you will find this issue educational and enjoyable.

Paliperidone Palmitate is a long-acting intramuscular atypical antipsychotic drug indicated for the acute maintenance treatment of schizophrenia in adults. Its mechanism of action, like all other atypical agents, is attributed to the antagonism of brain dopamine D2 and serotonin 5-HT2A receptors. The pharmacodynamics, pharmacokinetics, and metabolism of paliperidone palmitate are reviewed. Current studies for clinical efficacy of paliperidone palmitate for both acute and maintenance treatment and adherence in adults with schizophrenia are discussed. Studies for safety and tolerability are also reviewed.

Programmed Death-1(PD-1) is a negative regulator of T cell activation and proliferation that mediates suppressive action by binding to its ligands PD-L1 and PD-L2. The well-established immunosuppressive properties of PD-1/PDL1 interaction resulting in the re-establishment of peripheral tolerance makes PD-1 an interesting target for therapeutic intervention in cancer patients. In addition to its relevance in tumor-specific immunity, recent studies demonstrate that PD-1 expression on T cells correlates with viral load in HIV and HCV infected patients and further identified PD-1 expression as a marker for exhausted virus-specific CD8+ T cells. In particular, PD-1+CD8+ T cells show impaired effector functions and PD-1 associated T cell exhaustion could be restored by blocking the PD-1/PD-L1 interaction. This results in recovery of virus-specific CD8+ T cell mediated immunity, suggesting that interrupting PD-1 signaling using an antagonistic antibody restores T-cell effector functions. Thus, immunotherapy based on the blockade of PD-1/PD-L1 interaction does not only result in breakdown of effector T-cell tolerance to tumor antigens, but in addition also represents a promising therapeutic strategy for reactivation of virus-specific effector T cells to exert pathogen eradication in chronic viral infections. In this review, we give a comprehensive overview about the immunological functions of PD-1 mediated signaling in T cells with special emphasis on its immune regulatory functions in the context of cancer and chronic viral infections. Moreover, we will summarize recent data obtained in animal models, in-vitro preclinical approaches in patients and their implementation in clinical trials for treating patients with cancer and chronic viral infections.

Bronchiectasis is defined by the presence of abnormal bronchial widening and occurs as a consequence of chronic airway infection. It is an important and common cause of respiratory disease. Antibiotics are the main therapy used for the treatment of this condition. The article will review the use of antibiotics for the treatment of bronchiectasis. Antibiotics can be given as short-term therapy for exacerbations or as long-term/maintenance therapy. Antibiotics given by the inhalational route and macrolides are two relatively new classes of medication that may be useful for long-term therapy. There are significant concerns about the overuse resulting in antibiotic resistance. It should be emphasized that nearly all of the trials in the literature have only had small numbers of subjects. The data that is available describing the use of antibiotics in bronchiectasis can generally be regarded as preliminary.

Objectives: Radiation esophagitis represents a significant complication experienced by non-small cell cancer (NSCLC) patients receiving thoracic irradiation. The objective of the current review was to assess the clinical and dosimetrical parameters that may predict radiation esophagitis. Methods: Studies were identified by searching PubMed electronic databases. Both prospective and retrospective studies were included. Information regarding clinical and dosimetrical parameters predicting for radiation-induced esophagitis was extracted and analyzed. Results: The esophageal clinical and dosimetric parameters that best predict acute esophagitis remain unclear. In many reports, Vx (the volume of esophagus receiving x Gy) stands out, with values of x ranging from 20-70 Gy. Other studies conclude that the maximal dose received by any point of the esophagus is the best predictor of esophagitis. Another metric implicated with esophageal toxicity in some reports is the proportion of the esophageal circumference or surface area that receives high doses of radiation. Conclusions: Technological advancements in patient immobilization, setup verification, and radiotherapy delivery are increasingly being employed to limit the toxicity of thoracic irradiation. Future efforts are required to determine how these complex techniques should best be implemented to minimize the risks of acute and long-term esophageal injury.

Objectives: The objective of the current review was to assess published data on the role of Positron Emission Tomography (PET) for evaluation of nodal residual disease after definitive chemoradiotherapy for head and neck squamous cell carcinoma (HNSCC). Methods: Studies were identified by searching PubMed electronic databases. Only studies using a post-chemoradiotherapy PET for nodal residual disease evaluation were included in the present review. Both prospective and retrospective studies were included. Information regarding sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET for detecting nodal residual disease after definitive chemoradiotherapy for HNSCC was extracted and analyzed. Results: Twenty published studies were included in the present review. Existing data suggest that a negative postchemoradiotherapy PET scan is associated with a negative predictive value up to 100%. The sensitivity of PET in detecting nodal residual disease is greater for scans performed ≥ 10 weeks after definitive treatment with chemoradiotherapy for HNSCC. Conclusions: Further studies are needed to quantify the reliability of PET in detecting nodal residual disease after chemoradiotherapy for locoregionally advanced HNSCC. The optimal timing of PET imaging after chemoradiotherapy remains to be defined.

Background: Bowen's disease is a form of squamous cell carcinoma in situ that can be transformed into invasive squamous cell carcinoma and should be treated according to its anatomical position. The aim of this article is to offer an overview of treatment options with an emphasis on radiation therapy in the treatment of Bowen's disease. Methods and Materials: We performed overview of the literature based on database searches in PubMed/MEDLINE and we included articles till December 2010. Only papers published in English were included. Results: There was no standard fractionation regimen: some physicians prescribed high doses, such as the ones of invasive skin cancer, whereas others prescribed lower doses because of the noninvasive nature of the disease, the sensitive anatomic location (e.g., extremity) and the large treatment area. Various studies demonstrate high rates of tumor control with minimal morbidity following definitive radiation therapy in the treatment of Bowen's Disease. Through a multidisciplinary assessment, the treatment of Bowen's disease can be individualized to optimize patient care. Conclusions: Radiation therapy is an effective treatment option for Bowen's disease of the skin. Local recurrences seem to be equally low in patients treated with high- and low-dose regimens. Radiotherapy preserves normal tissues ensuring a superior esthetic and functional outcome.

Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/ progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the ‘timing hypothesis’, which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms.

Diabetic retinopathy (DR) remains a leading cause of preventable vision loss, despite advances in diabetes care. The burden of DR is likely to increase as the evolving pandemic of type 2 diabetes progresses. Tight control of blood glucose levels and blood pressure are essential for preventing or arresting the development of diabetic retinopathy, but are often difficult to achieve, and DR thus develops in a high proportion of patients. Current treatments for DR such as laser photocoagulation, intravitreous injections of corticosteroids or anti-vascular endothelial growth factor (VEGF) agents are indicated for advanced DR and have significant adverse effects. Therefore, new pharmacological treatments for the early stages of DR are needed. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial included a lipid management arm, in which patients satisfying additional inclusion criteria for the atherogenic dyslipidemia phenotype were randomly assigned to fenofibrate or placebo, each with a statin. In the ACCORD-EYE substudy, randomization to fenofibrate was associated with a significant reduction in the risk of progression of DR. These data confirm and extend the results of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, in which type 2 diabetes patients randomized to fenofibrate benefitted from a significantly lower incidence of laser treatment for retinopathy, progression of retinopathy or a composite measure of retinopathy outcomes. The results of ACCORD-EYE, together with those of FIELD, identify a place for fenofibrate for the prevention of retinopathy alongside intensive management of traditional risk factors, such as hyperglycemia and high blood pressure.