Virtual reality as a non-medical tool in the treatment of anxiety, pain, and perception of time in children in the maintenance phase of acute lymphoblastic leukemia treatment.

Introduction: Management of pediatric cancer patients involves invasive procedures such as punctures, injections, catheter placements, and chemotherapy which can generate fatigue, nausea, vomiting, anxiety, and pain. Virtual Reality (VR) is a nonpharmacological intervention classified as a cognitive-behavioral method to relieve symptoms. Methods: We designed a crossover protocol and included 20 patients between 9 and 12 years old; ten were male. All patients had acute lymphoblastic leukemia diagnosis and were treatedwith St. Jude's XV protocol in the maintenance phase. Pain and anxiety were measured with validated scales in the pediatric population. Results: Although we used a small group of patients, we found statistical difference in the reduction of anxiety and perception of time. Discussion: These results open a window to non-pharmacological treatments and show a strategy to improve quality of life in children inside the hospital.

[Tratamiento nutricional hiperproteico precirugía bariátrica en obesidad mórbida]. / High-protein diet in morbidity obesity patient before bariatric surgery.

OBJETIVO: Comparar la efectividad de un plan de alimentación hipocalórico hiperproteico con otro normoproteico sobre la composición corporal, los parámetros bioquímicos y las citocinas inflamatorias en pacientes obesos precirugía bariátrica sometidos a un tratamiento integral. MÉTODO: Se estudiaron 76 pacientes con un índice de masa corporal (IMC) ≥ 40 kg/m² previamente a la cirugía bariátrica. Un grupo fue tratado con una dieta hipocalórica hiperproteica y se comparó con una dieta hipocalórica normoproteica. Se evaluaron parámetros bioquímicos, parámetros antropométricos, composición corporal y valores de citocinas inflamatorias en suero al inicio y después de 4 meses de tratamiento. RESULTADOS: En ambos grupos se observó una disminución de peso, de IMC y de masa grasa, así como un incremento de la masa muscular respecto al momento basal (p < 0.05), sin diferencias entre los grupos estudiados. No se encontraron cambios en los parámetros bioquímicos ni en las concentraciones séricas de factor de necrosis tumoral (TNF) e interleucina (IL)-6 antes y después de 4 meses de tratamiento, ni entre los grupos evaluados (p > 0.05). Las concentraciones séricas de IL-1ß disminuyeron únicamente con la dieta hipocalórica normoproteica (p = 0.02). CONCLUSIONES: La dieta hipocalórica hiperproteica no muestra ventajas en la reducción de peso y grasa corporal, ni en la ganancia de masa muscular, en comparación con la dieta hipocalórica normoproteica en pacientes con obesidad mórbida precirugia bariátrica sometidos a un tratamiento integral. OBJECTIVE: Compare the effectiveness of a hyperproteic hypocaloric feeding plan with a normoproteic on body composition, biochemical parameters and inflammatory cytokines in obese pre-bariatric surgery patients in the integral treatment. METHOD: Seventy-six pre-bariatric surgery patients with body mass index (BMI) ≥ 40 kg/m² were studied. One group was treated with a hyperproteic hypocaloric diet and compared with a normoproteic hypocaloric diet. Biochemical parameters, anthropometric parameters, body composition and levels of tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1ß in serum were evaluated at the initiation of treatment and after 4 months. RESULTS: In both groups studied, a decrease in weight, BMI and fat mass was observed, as well as an increase in muscle mass compared to baseline (p < 0.05), no differences showed between the groups studied. No change was found in the biochemical parameters and serum levels of TNF and IL-6 before and after 4 months of treatment, nor among the groups evaluated (p > 0.05). Serum IL-1ß levels decreased after treatment with only a normoprotein hypocaloric diet (p = 0.02). ­. CONCLUSIONS: Hyperproteic hypocaloric diet does not show advantages in weight reduction and body fat or in muscle mass gain compared to the normoproteic hypocaloric diet in patients with morbid obesity bariatric pre-surgery in the integral treatment.

[Conceptualizations on care for persons with dementia in nursing homes]. / Conceptualizaciones sobre la atención a personas con demencia en residencias de mayores.

Despite the importance of family perceptions when analyzing care for the elderly in nursing homes, little is said about this aspect. This study aims to identify preferences and areas for improvement in care for persons with dementia, as perceived by families. A qualitative study was performed, based on Grounded Theory, combining two data collection techniques (participant observation and in-depth interviews) in a theoretical sample of institutionalized persons with dementia. The ideal model of care for persons with dementia, as perceived by participants, was based on specialized and individualized care and family participation in the care provided. Areas for improvement included aspects pertaining to specialized training in geriatrics, human relations, and the culture of institutional work. Faced with the current trend towards technification of care, families are now demanding personalized, small-scale care in which they form an active part of the team.

Conceptualizaciones sobre la atención a personas con demencia en residencias de mayores / Conceptualizations on care for persons with dementia in nursing homes / Conceitualizações sobre cuidados para as pessoas com demência em instituições de longa permanência para idosos

A pesar de la importancia de las percepciones familiares en el análisis de la atención en residencias de mayores, apenas se han indagado estos ascpetcos. El objetivo de este estudio es conocer las preferencias y las áreas de mejora percibidas por los familiares sobre los cuidados a personas con demencia. Se realizó un estudio cualitativo, a partir de la Teoría Fundamentada, combinando dos técnicas de recogida de datos (observación participante y entrevistas en profundidad) en una muestra teórica de familiares de personas con demencia institucionalizadas. El modelo de atención óptima a personas con demencia, percibido por los participantes, se basó en una atención especializada e individualizada y en la participación de la familia en el cuidado. Entre las áreas de mejora se incluyeron aspectos relacionados con una mayor formación específica en Geriatría, relaciones humanas y con la cultura del trabajo institucional. Frente a la vigente tendencia de tecnificación del cuidado, las familias exigen una atención personalizada y en pequeña escala, donde ellas mismas sean parte activa del proceso de atención.

Despite the importance of family perceptions when analyzing care for the elderly in nursing homes, little is said about this aspect. This study aims to identify preferences and areas for improvement in care for persons with dementia, as perceived by families. A qualitative study was performed, based on Grounded Theory, combining two data collection techniques (participant observation and in-depth interviews) in a theoretical sample of institutionalized persons with dementia. The ideal model of care for persons with dementia, as perceived by participants, was based on specialized and individualized care and family participation in the care provided. Areas for improvement included aspects pertaining to specialized training in geriatrics, human relations, and the culture of institutional work. Faced with the current trend towards technification of care, families are now demanding personalized, small-scale care in which they form an active part of the team.

Apesar da importância da percepção da família na análise do atendimento em lares de idosos, praticamente não se fala neste aspecto. O objetivo deste estudo é identificar as preferências e as áreas de melhoria percebidas pelos familiares sobre os cuidados a pessoas com demência. Realizou-se um estudo qualitativo com base na Teoria Fundamentada, combinando-se duas técnicas de coleta de dados (observação participativa e entrevistas em profundidade) em uma amostra teórica de familiares de pessoas internadas com demência. O modelo ideal de atendimento a pessoas com demência percebido pelos participantes baseou-se em um atendimento especializado e individualizado, e na participação da família nos cuidados prestados. Entre as áreas de melhoria foram incluídos aspectos relacionados à formação especializada em Geriatria, às relações humanas e à cultura do trabalho institucional. Confrontadas com a atual tendência de tecnificação do cuidado, as famílias exigem um atendimento personalizado e em pequena escala, em que elas sejam parte ativa da equipe.

Cetuximab concomitant with gemcitabine and radiotherapy in advanced squamous cell carcinomas of upper aerodigestive tract: a pilot study.

PURPOSE: To explore the response and toxicity of advanced non-metastatic squamous cell carcinomas of upper aerodigestive tract (SCC-UADT) to a combination of cetuximab concomitant with gemcitabine and radiotherapy. METHODS: We managed patients with concomitant treatment of cetuximab (400 mg/m(2) as uploading dose, then 250 mg/m(2), IV) concomitant with gemcitabine (50 mg/m(2)) weekly for seven courses, and radiotherapy in classical fractionation until completion of 70 Gy. Primary endpoints were complete response (CR) to treatment and toxicity. We evaluated patients for toxicity on a weekly basis; evaluation of response included physical examination, endoscopy, computed tomography (CT) scan and biopsy when indicated, and was performed 6 weeks after completion of radiotherapy. Additional evaluations were done every 3 months to document disease status. Between November 2004 and November 2005, 20 patients were included. RESULTS: CR was 82.4%, overall response was 100%. Neck disease reached CR in 61.5% and partial in 38.5% of patients. The main toxicities were nausea, lymphopenia, neutropenia and mucositis. Grade 3 and 4 side effects were presented in 70.6% of patients, but mucositis, and lymphopenia without clinical repercussions, occurred in 88.2% of patients. Gastrostomy was required in 11.8% of patients to maintain nutrition. Radioepithelitis developed in 76.5%, but only three of these (23.1%) were grade III. Median overall survival was 53 months (range 6-55 months) and median progression-free survival has not yet been reached at the time of evaluation. CONCLUSIONS: Although toxicity is important, this approach has interesting activity and deserves further investigation.

HDAC inhibitor valproic acid upregulates CAR in vitro and in vivo.

BACKGROUND: The presence of CAR in diverse tumor types is heterogeneous with implications in tumor transduction efficiency in the context of adenoviral mediated cancer gene therapy. Preliminary studies suggest that CAR transcriptional regulation is modulated through histone acetylation and not through promoter methylation. Furthermore, it has been documented that the pharmacological induction of CAR using histone deacetylase inhibitor (iHDAC) compounds is a viable strategy to enhance adenoviral mediated gene delivery to cancer cells in vitro. The incorporation of HDAC drugs into the overall scheme in adenoviral based cancer gene therapy clinical trials seems rational. However, reports using compounds with iHDAC properties utilized routinely in the clinic are pending. Valproic acid, a short chained fatty acid extensively used in the clinic for the treatment of epilepsy and bipolar disorder has been recently described as an effective HDAC inhibitor at therapeutic concentrations. METHODS: We studied the effect of valproic acid on histone H3 and H4 acetylation, CAR mRNA upregulation was studied using semiquantitative PCR and adenoviral transduction on HeLa cervical cancer cells, on MCF-7 breast cancer cells, on T24 transitional cell carcinoma of the bladder cells. CAR mRNA was studied using semiquantitative PCR on tumor tissue extracted from patients diagnosed with cervical cancer treated with valproic acid. RESULTS: CAR upregulation through HDAC inhibition was observed in the three cancer cell lines with enhancement of adenoviral transduction. CAR upregulation was also observed in tumor samples obtained from patients with cervical cancer treated with therapeutic doses of valproic acid. These results support the addition of the HDAC inhibitor valproic acid to adenoviral mediated cancer gene therapy clinical trials to enhance adenoviral mediated gene delivery to the tumor cells.

Global DNA hypermethylation-associated cancer chemotherapy resistance and its reversion with the demethylating agent hydralazine.

BACKGROUND: The development of resistance to cytotoxic chemotherapy continues to be a major obstacle for successful anticancer therapy. It has been shown that cells exposed to toxic concentrations of commonly used cancer chemotherapy agents develop DNA hypermethylation. Hence, demethylating agents could play a role in overcoming drug resistance. METHODS: MCF-7 cells were rendered adriamycin-resistant by weekly treatment with adriamycin. Wild-type and the resulting MCF-7/Adr cells were analyzed for global DNA methylation. DNA methyltransferase activity and DNA methyltransferase (dnmt) gene expression were also determined. MCF-7/Adr cells were then subjected to antisense targeting of dnmt1, -3a, and -b genes and to treatment with the DNA methylation inhibitor hydralazine to investigate whether DNA demethylation restores sensitivity to adriamycin. RESULTS: MCF-7/Adr cells exhibited the multi-drug resistant phenotype as demonstrated by adriamycin resistance, mdr1 gene over-expression, decreased intracellular accumulation of adriamycin, and cross-resistance to paclitaxel. The mdr phenotype was accompanied by global DNA hypermethylation, over-expression of dnmt genes, and increased DNA methyltransferase activity as compared with wild-type MCF-7 cells. DNA demethylation through antisense targeting of dnmts or hydralazine restored adriamycin sensitivity of MCF-7/Adr cells to a greater extent than verapamil, a known inhibitor of mdr protein, suggesting that DNA demethylation interferes with the epigenetic reprogramming that participates in the drug-resistant phenotype. CONCLUSION: We provide evidence that DNA hypermethylation is at least partly responsible for development of the multidrug-resistant phenotype in the MCF-7/Adr model and that hydralazine, a known DNA demethylating agent, can revert the resistant phenotype.

Hydralazine target: from blood vessels to the epigenome.

Hydralazine was one of the first orally active antihypertensive drugs developed. Currently, it is used principally to treat pregnancy-associated hypertension. Hydralazine causes two types of side effects. The first type is an extension of the pharmacologic effect of the drug and includes headache, nausea, flushing, hypotension, palpitation, tachycardia, dizziness, and salt retention. The second type of side effects is caused by immunologic reactions, of which the drug-induced lupus-like syndrome is the most common, and provides clues to underscoring hydralazine's DNA demethylating property in connection with studies demonstrating the participation of DNA methylation disorders in immune diseases. Abnormalities in DNA methylation have long been associated with cancer. Despite the fact that malignant tumors show global DNA hypomethylation, regional hypermethylation as a means to silence tumor suppressor gene expression has attracted the greatest attention. Reversibility of methylation-induced gene silencing by pharmacologic means, which in turns leads to antitumor effects in experimental and clinical scenarios, has directed efforts toward developing clinically useful demethylating agents. Among these, the most widely used comprise the nucleosides 5-azacytidine and 2'deoxy-5-azacytidine; however, these agents, like current cytotoxic chemotherapy, causes myelosuppression among other side effects that could limit exploitation of their demethylating properties. Among non-nucleoside DNA demethylating drugs currently under development, the oral drug hydralazine possess the ability to reactivate tumor suppressor gene expression, which is silenced by promoter hypermethylation in vitro and in vivo. Decades of extensive hydralazine use for hypertensive disorders that demonstrated hydralazine's clinical safety and tolerability supported its testing in a phase I trial in patients with cancer, confirming its DNA demethylating activity. Hydralazine is currently being evaluated, along with histone deacetylase inhibitors either alone or as adjuncts to chemotherapy and radiation, for hematologic and solid tumors in phase II studies.

Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines.

BACKGROUND: Among the epigenetic alterations occurring in cancer, DNA hypermethylation and histone hypoacetylation are the focus of intense research because their pharmacological inhibition has shown to produce antineoplastic activity in a variety of experimental models. The objective of this study was to evaluate the combined antineoplastic effect of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in a panel of cancer cell lines. RESULTS: Hydralazine showed no growth inhibitory effect on cervical, colon, breast, sarcoma, glioma, and head & neck cancer cell lines when used alone. On the contrary, valproic acid showed a strong growth inhibitory effect that is potentiated by hydralazine in some cell lines. Individually, hydralazine and valproic acid displayed distinctive effects upon global gene over-expression but the number of genes over-expressed increased when cells were treated with the combination. Treatment of HeLa cells with hydralazine and valproic acid lead to an increase in the cytotoxicity of gemcitabine, cisplatin and adriamycin. A higher antitumor effect of adriamycin was observed in mice xenografted with human fibrosarcoma cells when the animals were co-treated with hydralazine and valproic acid. CONCLUSION: Hydralazine and valproic acid, two widely used drugs for cardiovascular and neurological conditions respectively have promising antineoplastic effects when used concurrently and may increase the antitumor efficacy of current cytotoxic agents.

Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study.

BACKGROUND: The development of cancer has been associated with epigenetic alterations such as aberrant histone deacetylase (HDAC) activity. It was recently reported that valproic acid is an effective inhibitor of histone deacetylases and as such induces tumor cell differentiation, apoptosis, or growth arrest. METHODS: Twelve newly diagnosed patients with cervical cancer were treated with magnesium valproate after a baseline tumor biopsy and blood sampling at the following dose levels (four patients each): 20 mg/kg; 30 mg/kg, or 40 mg/kg for 5 days via oral route. At day 6, tumor and blood sampling were repeated and the study protocol ended. Tumor acetylation of H3 and H4 histones and HDAC activity were evaluated by Western blot and colorimetric HDAC assay respectively. Blood levels of valproic acid were determined at day 6 once the steady-state was reached. Toxicity of treatment was evaluated at the end of study period. RESULTS: All patients completed the study medication. Mean daily dose for all patients was 1,890 mg. Corresponding means for the doses 20-, 30-, and 40-mg/kg were 1245, 2000, and 2425 mg, respectively. Depressed level of consciousness grade 2 was registered in nine patients. Ten patients were evaluated for H3 and H4 acetylation and HDAC activity. After treatment, we observed hyperacetylation of H3 and H4 in the tumors of nine and seven patients, respectively, whereas six patients demonstrated hyperacetylation of both histones. Serum levels of valproic acid ranged from 73.6-170.49 microg/mL. Tumor deacetylase activity decreased in eight patients (80%), whereas two had either no change or a mild increase. There was a statistically significant difference between pre and post-treatment values of HDAC activity (mean, 0.36 vs. 0.21, two-tailed t test p < 0.0264). There was no correlation between H3 and H4 tumor hyperacetylation with serum levels of valproic acid. CONCLUSION: Magnesium valproate at a dose between 20 and 40 mg/kg inhibits deacetylase activity and hyperacetylates histones in tumor tissues.

A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes.

BACKGROUND: The antihypertensive compound hydralazine is a known demethylating agent. This phase I study evaluated the tolerability and its effects upon DNA methylation and gene reactivation in patients with untreated cervical cancer. METHODS: Hydralazine was administered to cohorts of 4 patients at the following dose levels: I) 50 mg/day, II) 75 mg/day, III) 100 mg/day and IV) 150 mg/day. Tumor biopsies and peripheral blood samples were taken the day before and after treatment. The genes APC, MGMT; ER, GSTP1, DAPK, RARbeta, FHIT and p16 were evaluated pre and post-treatment for DNA promoter methylation and gene expression by MSP (Methylation-Specific PCR) and RT-PCR respectively in each of the tumor samples. Methylation of the imprinted H19 gene and the "normally methylated" sequence clone 1.2 was also analyzed. Global DNA methylation was analyzed by capillary electrophoresis and cytosine extension assay. Toxicity was evaluated using the NCI Common Toxicity Criteria. RESULTS: Hydralazine was well tolerated. Toxicities were mild being the most common nausea, dizziness, fatigue, headache and palpitations. Overall, 70% of the pretreatment samples and all the patients had at least one methylated gene. Rates of demethylation at the different dose levels were as follows: 50 mg/day, 40%; 75 mg/day, 52%, 100 mg/day, 43%, and 150 mg/day, 32%. Gene expression analysis showed only 12 informative cases, of these 9 (75%) re-expressed the gene. There was neither change in the methylation status of H19 and clone 1.2 nor changes in global DNA methylation. CONCLUSION: Hydralazine at doses between 50 and 150 mg/day is well tolerated and effective to demethylate and reactivate the expression of tumor suppressor genes without affecting global DNA methylation.

Determination of 5-methyl-cytosine and cytosine in tumor DNA of cancer patients.

The determination of the relative methylation in DNA tumor samples, in order to evaluate the activity of some anti-cancer drugs, has become a very important issue in the clinical field. Capillary electrophoresis (CE) applications in this area have been done previously but no good separation for model samples or tumor samples has been reported. In this work, the CE conditions have been optimized in order to obtain baseline separation and efficient peaks for cytosine and 5-methylcytosine in both, standard mixtures and actual tumor samples; other bases (adenine, uracil, guanine, and thymine) have also been integrated in the optimization studies. More efficient peaks and shorter analysis time compared with the already reported conditions have been obtained employing a fused-silica capillary (75 microm inner diameter) of 44.5 cm effective length, 20 mM carbonate buffer (pH 9.6) plus 80 mM sodium dodecyl sulfate, a separation voltage of 20 kV, and detection at 223 nm.

Circulating nucleosomes and response to chemotherapy: an in vitro, in vivo and clinical study on cervical cancer patients.

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients.

Bioavailability of etoposide after oral administration of the solution marketed for intravenous use: Therapeutic and pharmacoeconomic perspectives

Background. Oral etoposide administration is a suitable alternative to the intravenous route; therefore, commercial capsules have been developed. Before these capsules were available in Mexico, we studied drug bioavailability after oral administration of the intravenous etoposide solution (IVES). Methods. Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and blood samples were collected over a period of 24 h. plasma etoposide concentration was determined by high-performance liquid chromatography, plasma concentration against time curves were constructed, and biovailability parameters were calculated. Results. Oral IVES yielded an adequate bioavailability profile because Cmax was 2.38 ñ 0.30 µg/mL, AUC was 12.87 ñ 2.02 µg/mL and half-life was 6.72 ñ 0.97 h. Conclusions. Considering that the pharmacokinetic aim is to maintain plasm concentrations between 0.5 and 1.0 µg/mL for several hours while avioding high concentrations, i.e., of 10 µg/mL or higher, oral administration of 50-mg etoposide as IVES appears to be a suitable dosing option. In addition, oral IVES is considerably less expensive than intravenous administration in terms of both drug presentation and administration