Efficacy and tolerability of quetiapine in the treatment of behavioral and psychological symptoms of dementia

Behavioral symptoms start to appear in mild and moderate dementia and become increasingly severe with the progression of the disease. Agitation, aggressiveness, and psychosis can be seen in Alzheimer's disease, and in particular are common manifestations in Lewy body dementia. It is the behavioral disturbances rather than the cognitive disorders that are more often the cause of the institutionalization of these patients because of the heavy assistance and emotional burden they represent for caregivers. Traditionally, these kinds of symptoms were controlled by classical antipsychotic agents, which after long-term use cause severe extrapyramidal effects, late dyskinesia, sedation, orthostatic hypotension, and cognitive function impairment. More recently, atypical antipsychotic agents have shown a better tolerability profile, with a reduced incidence of extrapyramidal effects, orthostatic hypotension, sedation, and a reduced impact on cognitive function. The aim of this study is to evaluate the efficacy and tolerability of quetiapine in a group of patients with a diagnosis of dementia and concomitant psychotic disorders. The response to treatment was evaluated by the Neuropsychiatric Inventory (NPI) and the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD). The NPI and BEHAVE-AD were administered at baseline and after 4 weeks and 12 weeks of therapy. Tolerability was assessed by the incidence of clinically evident side effects. The results show that quetiapine is effective in reducing behavioral symptoms, deliria and hallucinations, aggressiveness, and sleep disturbances. Quetiapine tolerability proved to be satisfactory. The only side effect of clinical significance was orthostatic hypotension, which was, however, partially preventable by a slower drug titration.     

Comparative Planning Study for Proton Radiotherapy of Benign Brain Tumors

PURPOSE: A comparative study of different systems for proton-based radiotherapy was conducted. MATERIAL AND METHODS: The Paul Scherrer Institute method for spot scanning was compared with the systems for passive scattering from the Helax-TMS and the Varian Eclipse. Twelve cases of "benign" brain tumors were considered (meningiomas, neurinomas, and hypophyseal adenomas). Organs at risk included chiasm, brainstem, eyes and optic nerves as well as the not otherwise specified healthy brain tissue in view of long-term toxicity. RESULTS: The results showed that high target coverage was achievable (V(90) > 98% for all systems). Plans designed with the spot-scanning technique presented the minimum involvement of healthy tissue (e. g., the lowest maximum significant dose to healthy brain [25.6 Gy] or the lowest conformity index [CI(95) = 1.3], between 38% and 46% lower than for the other techniques). CONCLUSION: In this study, no definitive indication of superiority of any technique can be drawn but spot scanning can better conform dose distributions and minimize the irradiation of healthy volumes at medium to low dose levels, a factor of interest when long life expectancy is considered.     

Pharmacogenetics of ABCG2 and adverse reactions to gefitinib

Gefitinib is an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase with activity in non-small-cell lung cancer. Diarrhea and skin toxicity are prominent gefitinib-related adverse events that potentially limit its use. Gefitinib is a substrate for ABCG2 (ABCP, BCRP, MXR), a polymorphic efflux transporter protein that is highly expressed in the intestines and liver. Here we investigated associations between allelic variants of EGFR, ABCG2, and the transporter protein ABCB1 with diarrhea and skin toxicity in gefitinib-treated patients. One variant, a common functional single-nucleotide polymorphism (SNP) in the ABCG2 gene, was associated with diarrhea in 124 patients treated with oral gefitinib 250 mg once daily; seven (44%) of 16 patients heterozygous for ABCG2 421C>A (Q141K) developed diarrhea, versus only 13 (12%) of 108 patients homozygous for the wild-type sequence (P = .0046). However, this SNP was not associated with skin toxicity (P = .99). The finding suggests that patients with reduced ABCG2 activity due to a common genetic variant are at increased risk for substrate drug-induced diarrhea, with implications for optimizing treatment with such agents.     

Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential

The failure to eradicate most cancers and in particular melanoma may be as fundamental as a misidentification of the target. The identification of cancer stem/initiating cells within the tumour population with a crucial role for tumour formation may open new pharmacological perspectives. Our data show three main novelties for human melanoma: firstly, melanoma biopsy contains a subset of cells expressing CD133 (CD133+) and the latter is able to develop a Mart-1 positive tumour in NOD-SCID mice. Secondly, the WM115, a human melanoma cell line, has been found to express both CD133 and ABCG2 markers. This cell line grows as floating spheroids, expresses typical progenitors and mature neuronal/oligodendrocyte markers and is able to transdifferentiate into astrocytes or mesenchymal lineages under specific growth conditions. As in xenografts generated with CD133+ biopsy melanoma cells, those produced by the cell line displayed lower levels of CD133 and ABCG2. Thirdly, the WM115 cells express the most important angiogenic and lymphoangiogenic factors such as notch 4, prox1 and podoplanin which can cooperate in the development of the tumourigenic capability of melanoma in vivo. Therefore, in this study, we demonstrate the presence of stem/initiating subsets in melanoma both in biopsy and in an established melanoma cell line grown in vitro and in xenografts. Interestingly, considering that melanoma gives metastasis primarily through lymphatic vessels, herein, we demonstrated that a melanoma cell line expresses typical lymphoangiogenic factors.     

Curative and organ-preserving treatment with intra-arterial carboplatin induction followed by surgery and/or radiotherapy for advanced head and neck cancer: single-center five-year results

Background  

This study evaluated the feasibility, toxicity, response rate and survival of neoadjuvant superselective intra-arterial infusion of high dose carboplatin in advanced head and neck cancer.