Photosensitivity Reactions to Vandetanib: Redevelopment after Sequential Treatment with Docetaxel

Vandetanib (ZD6474, Zactima™) is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis, including vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and rearranged during transfection tyrosine kinase activity. The most frequently reported adverse events attributed to vandetanib include diarrhea, elevated aminotransferase, asymptomatic corrected QC interval prolongation, and hypertension. In a few randomized, double-blinded studies, cutaneous adverse events including these general symptoms have been reported, but there are only a few reports on the photosensitivity reaction to vandetanib domestically as conducted by dermatologists. In this report, we describe two cases of photosensitivity reactions induced by vandetanib. After improvement with steroid and antihistamine, the photosensitivity reaction was redeveloped by sequential treatment with docetaxel

Bevacizumab for the Treatment of Recurrent Glioblastoma

Despite advances in upfront therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is poor as almost all recur and result in disease-related death. Glioblastoma are highly vascularized cancers with elevated expression levels of vascular endothelial growth factor (VEGF), the dominant mediator of angiogenesis. A compelling biologic rationale, a need for improved therapy, and positive results from studies of bevacizumab in other cancers led to the evaluation of bevacizumab in the treatment of recurrent GBM. Bevacizumab, a humanized monoclonal antibody that targets VEGF, has been shown to improve patient outcomes in combination with chemotherapy (most commonly irinotecan) in recurrent GBM, and on the basis of positive results in two prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration (FDA) as a single agent in recurrent GBM. Bevacizumab therapy is associated with manageable, class-specific toxicity as severe treatment-related adverse events are observed in only a minority of patients. With the goal of addressing questions and controversies regarding the optimal use of bevacizumab, the objective of this review is to provide a summary of the clinical efficacy and safety data of bevacizumab in patients with recurrent GBM, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in managing GBM

Clinical improvements in temporospatial gait variables after a spinal tap test in individuals with idiopathic normal pressure hydrocephalus

Background: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological condition that often presents gait disturbance in the early stages of the disease and affects other motor activities. This study investigated changes in temporospatial gait variables after cerebrospinal fluid (CSF) removal using a tap test in individuals with idiopathic normal pressure hydrocephalus (iNPH), and explored if the tap test responders and non-responders could be clinically identified from temporospatial gait variables. Methods: Sixty-two individuals with iNPH were recruited from an outpatient clinic, eleven were excluded, leaving a total of 51 who were included in the analysis. Temporospatial gait variables at self-selected speed were recorded at pre- and 24-hour post-tap tests which were compared using Paired t-tests, Cohen’s d effect size, and percentage change. A previously defined minimal clinical important change (MCIC) for gait speed was used to determine the changes and to classify tap test responders and non-responders. A mixed model ANOVA was used to determine the within-group, between-group, and interaction effects. Results: Comparisons of the data between pre- and post-tap tests showed significant improvements with small to medium effect sizes for left step length, right step time, stride length and time, cadence, and gait speed. Gait speed showed the largest percentage change among temporospatial gait variables. Within-group and interaction effects were found in some variables but no between-group effect was found. Tap test responders showed significant improvements in right step length and time, stride length and time, cadence, and gait speed while non-responders did not. Conclusions: Some individuals with iNPH showed clinically important improvements in temporospatial gait variables after the tap test, particularly in step/stride length and time, cadence, who could be classified by gait speed. However, gait-related balance variables did not change. Therefore, additional treatments should focus on improving such variables

Specific Inhibition of SRC Kinase Impairs Malignant Glioma Growth In Vitro and In Vivo

Malignant glioma is a severe cancer with a poor prognosis. Local occurrence and rare metastases of malignant glioma make it a suitable target for gene therapy. Several studies have demonstrated the importance of Src kinase in different cancers. However, these studies have focused mainly on Src-deficient mice or pharmacological inhibitors of Src. In this study we have used Src small hairpin RNAs (shRNAs) in a lentiviral backbone to mimic a long-term stable treatment and determined the role of Src in tumor tissues. Efficacy of Src shRNAs was confirmed in vitro demonstrating up to 90% target gene inhibition. In a mouse malignant glioma model, Src shRNA tumors were almost 50-fold smaller in comparison to control tumors and had significantly reduced vascularity. In a syngenic rat intracranial glioma model, Src shRNA-transduced tumors were smaller and these rats had a survival benefit over the control rats. In vivo treatment was enhanced by chemotherapy and histone deacetylase inhibition. Our results emphasise the importance of Src in tumorigenesis and demonstrate that it can be efficiently inhibited in vitro and in vivo in two independent malignant glioma models. In conclusion, Src is a potential target for RNA interference-mediated treatment of malignant glioma

An integrative paradigm to impart quality to correlative science

Correlative studies are a primary mechanism through which insights can be obtained about the bioactivity and potential efficacy of candidate therapeutics evaluated in early-stage clinical trials. Accordingly, well designed and performed early-stage correlative studies have the potential to strongly influence further clinical development of candidate therapeutic agents, and correlative data obtained from early stage trials has the potential to provide important guidance on the design and ultimate successful evaluation of products in later stage trials, particularly in the context of emerging clinical trial paradigms such as adaptive trial design

Flavonoids from the Brazilian plant Croton betulaster inhibit the growth of human glioblastoma cells and induce apoptosis

This study investigated the effects of the flavonoids 5-hydroxy-7,4′-dimethoxyflavone, casticin, and penduletin, isolated from Croton betulaster Müll Arg., Euphorbiaceae, a plant utilized in popular medicine in Brazil, on the growth and viability of the human glioblastoma cell line GL-15. We observed that 5-hydroxy-7,4′-dimethoxyflavone and casticin were not toxic to GL-15 cells after 24 h of exposure. However, casticin and penduletin inhibited the metabolic activity of glioblastoma cells significantly at a concentration of 10 μM (p ≤ 0.05). Flavonoids casticin and penduletin also induced a significant and dose-dependent growth inhibition beginning at 24 h of exposure, and the most potent flavonoid was penduletin. It was also observed that penduletin and casticin induced an enlargement of the cell body and a reduction of cellular processes, accompanied by changes in the pattern of expression of the cytoskeletal protein vimentin. Signs of apoptosis, such as the externalization of membrane phosphatidyl serine residues, nuclear condensation, and fragmentation, were also detected in cells treated with 50–100 μM flavonoids. Our results indicate that flavonoids extracted from C. betulaster present antitumoral activity to glioblastoma cells, with penduletin proving to be the most potent of the tested flavonoids. Our results also suggest that these molecules may be promising supplementary drugs for glioblastoma treatment

Prediction of Glioblastoma Multiform Response to Bevacizumab Treatment Using Multi-Parametric MRI

Glioblastoma multiform (GBM) is a highly malignant brain tumor. Bevacizumab is a recent therapy for stopping tumor growth and even shrinking tumor through inhibition of vascular development (angiogenesis). This paper presents a non-invasive approach based on image analysis of multi-parametric magnetic resonance images (MRI) to predict response of GBM to this treatment. The resulting prediction system has potential to be used by physicians to optimize treatment plans of the GBM patients. The proposed method applies signal decomposition and histogram analysis methods to extract statistical features from Gd-enhanced regions of tumor that quantify its microstructural characteristics. MRI studies of 12 patients at multiple time points before and up to four months after treatment are used in this work. Changes in the Gd-enhancement as well as necrosis and edema after treatment are used to evaluate the response. Leave-one-out cross validation method is applied to evaluate prediction quality of the models. Predictive models developed in this work have large regression coefficients (maximum R2 = 0.95) indicating their capability to predict response to therapy

Carbonic anhydrase 9 is a predictive marker of survival benefit from lower dose of bevacizumab in patients with previously treated metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Carbonic anhydrase 9 (CA9) is a marker for hypoxia and acidosis, which is linked to a poor prognosis in human tumors. The purpose of this comparative analysis was to evaluate whether CA9 and VEGF expression are associated with survival outcomes in patients with metastatic colorectal cancer (mCRC) after treatment with bevacizumab as second or later line treatment.</p> <p>Methods</p> <p>Thirty-one mCRC patients who were treated with bevacizumab-containing chemotherapy as second or later line treatment and who had analyzable tumor paraffin blocks were selected for this study. The planned dose of bevacizumab was 5 mg/kg/2-week. Immunohistochemical (IHC) staining of CA9 and VEGF was performed and their expression was scored by the intensity multiplied by percentage of stained area.</p> <p>Results</p> <p>The overall response rate was 19.4% and the disease control rate (DCR) was 61.3% with 6 partial responses and 13 cases of stable disease. The DCR was significantly higher in patients with a lower CA9 expression score compared to those with a higher score (80.0% vs. 27.3%, respectively, P = 0.004). The patients with a low CA9 expression score also showed better outcomes with regard to the median progression-free survival (P = 0.028) and overall survival (P = 0.026). However, VEGF expression was not associated with the DCR and survival.</p> <p>Conclusion</p> <p>Lower degree of CA9 expression was associated with better clinical outcomes in patients with mCRC treated with lower dose bevacizumab-based chemotherapy. Prospective studies are now needed to determine the correlation between CA9 expression and clinical outcomes after bevacizumab treatment, at different doses and in varied settings.</p