Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial.

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.

Oral hygiene motivational talks for parents or guardians of children aged 5 to 8 years and its influence on the duration of composite resin restorations: a clinical study with a 24 months follow-up in Ecuador / Motivación en higiene bucal dirigida a padres o responsables de niños de 5 a 8 años de edad y su influencia sobre la duración de las restauraciones de resina compuesta: estudio clínico con seguimiento a 24 meses en Ecuador

ABSTRACT. Introduction: tissue loss due to carious processes is usually resolved with restorations, requiring abundant patient collaboration in oral hygiene. The aim of the present study was to evaluate the effect of oral hygiene motivational talks addressed to parents or guardians of children aged 5 to 8 years on the duration of composite resins over 24 months. Methods: a prospective descriptive study was conducted in 31 children and their parents or guardians meeting the inclusion criteria. The parents and guardians were trained in oral hygiene techniques, and the participating children's cavitated teeth were restored with composite resin, providing dental cleaning devices every 6 months during the study period. Clinical evaluations were performed every 6 months during the study period, evaluating the deterioration of restorations and the presence of visible plaque (VPI) and gingival bleeding (GBI). The data obtained were submitted to ANOVA statistical analysis and Student t-test through the STATA software. Results: There was a close relationship between oral hygiene indexes (p = 0,2019 for VPI and p = 0,6243 for GBI) and the deterioration of restorations, especially those involving proximal sides. Survival analysis showed that failure is lower in the presence of nearby caries (42.9%), with p values of 0.0045 for the occlusal-distal surface and 0.0291 for the occlusal-mesial one. Conclusion: the oral hygiene motivational talks addressed to parents or guardians of participating children influence the durability of composite resins.

RESUMEN. Introducción: la pérdida de tejido relacionada con procesos cariosos suele ser resuelta con restauraciones, cuyo cuidado depende en gran medida de la higiene oral del paciente. El objetivo del presente estudio consistió en evaluar el efecto de la motivación en higiene bucal dirigida a padres o responsables de niños de 5 a 8 años de edad sobre la duración de resinas compuestas a lo largo de 24 meses. Métodos: se planteó un estudio descriptivo prospectivo, en el que participaron 31 niños y sus padres o responsables, que cumplieron los criterios de inclusión y exclusión previamente determinados. Los representantes fueron capacitados en técnicas de higiene bucal, y los dientes afectados por caries de los menores intervenidos fueron restaurados mediante resina compuesta, contando con acceso a dispositivos de aseo dental cada 6 meses durante el periodo del estudio. Se realizaron evaluaciones clínicas cada 6 meses durante el periodo de estudio, evaluando el deterioro de la restauración y la presencia de placa visible y de sangrado gingival. Los datos obtenidos fueron sometidos a análisis estadístico ANOVA y al test t-Student mediante el programa STATA. Resultados: se evidenció una estrecha relación entre los índices de higiene oral (p = 0,2019 para IPV y p= 0,6243 para ISG) y el deterioro de las restauraciones, en especial en aquellas que involucraban caras proximales. En la aplicación de las técnicas de supervivencia, el fracaso es menor en presencia de caries aledañas (42,9%), con valores p de 0,0045 para la superficie ocluso-distal y 0,0291 para la ocluso-mesial. Conclusión: la motivación a padres o responsables de los participantes sobre higiene bucal influyó sobre la durabilidad de las resinas compuestas.

A Randomized Phase II Study of Axitinib as Maintenance Therapy After First-line Treatment for Metastatic Colorectal Cancer.

INTRODUCTION: The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B). RESULTS: Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment. CONCLUSIONS: In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC.

Ionic Conductivity and Potential Application for Fuel Cell of a Modified Imine-Based Covalent Organic Framework.

We present the novel potential application of imine-based covalent organic frameworks (COFs), formed by the direct Schiff reaction between 1,3,5-tris(4-aminophenyl)benzene and 1,3,5-benzenetricarbaldehyde building blocks in m-cresol or acetic acid, named RT-COF-1 or RT-COF-1Ac/RT-COF-1AcB. The post-synthetic treatment of RT-COF-1 with LiCl leads to the formation of LiCl@RT-COF-1. The ionic conductivity of this series of polyimine COFs has been characterized at variable temperature and humidity, using electrochemical impedance spectroscopy. LiCl@RT-COF-1 exhibits a conductivity value of 6.45 × 10-3 S cm-1 (at 313 K and 100% relative humidity) which is among the highest values so far reported in proton conduction for COFs. The mechanism of conduction has been determined using 1H and 7Li solid-state nuclear magnetic resonance spectroscopy. Interestingly, these materials, in the presence of controlled amounts of acetic acid and under pressure, show a remarkable processability that gives rise to quasi-transparent and flexible films showing in-plane structural order as confirmed by X-ray crystallography. Finally, we prove that these films are useful for the construction of proton exchange membrane fuel cells (PEMFC) reaching values up to 12.95 mW cm-2 and 53.1 mA cm-2 for maximum power and current density at 323 K, respectively.

The role of antiangiogenic agents in the treatment of patients with advanced colorectal cancer according to K-RAS status.

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide. Recently, it has been found that about 40 % of patients with CRC have mutations in the K-RAS gene. Several clinical trials have showed that patients with metastatic colorectal cancer (mCRC) who present tumour-promoting mutations in signalling pathways involving the epidermal growth factor receptor (EGFR), which includes activating K-RAS mutations, do not respond to anti-EGFR drugs such as panitumumab and cetuximab. Hence, K-RAS status is now considered an important negative predictive factor for response to anti-EGFR drugs. Moreover, K-RAS status seems to have also a prognostic role in CRC, but this fact is somewhat controversial. Activity of antiangiogenic agents seems not to be influenced by K-RAS gene status. Tumour angiogenesis has attracted interest in attempts to improve the management of mCRC. The vascular endothelial growth factor (VEGF) pathway is fundamental to the regulation of angiogenesis, and research has focused on developing agents that selectively target it. In this way, the anti-VEGF antibody bevacizumab in combination with chemotherapy has provided important clinical benefits in terms of response rate, progression-free survival and overall survival to patients with mCRC. Efficacy data of bevacizumab in K-RAS wild-type patients seem to be comparable with the efficacy data observed with anti-EGFR therapies in a cross-trial comparison. Although there is a lack of prospective and randomized data in this setting, the combination of chemotherapy plus antiangiogenic agents could be considered as an effective alternative for the treatment of mCRC with independence of K-RAS gene status. Here, we review the available data we have in the literature of the use of antiangiogenic strategies in the treatment of mCRC nowadays.

Occupational therapy based on Ayres Sensory Integration in the treatment of retentive fecal incontinence in a 3-year-old boy.

OBJECTIVE. We present the case report of a 3-yr-old boy with retentive fecal incontinence and sensory overresponsivity. Sensory integration theory was used to address the overresponsivity affecting the child's ability to acquire age-appropriate toileting habits. We describe the 7 mo of treatment and 3 mo of follow-up in occupational therapy. METHOD. We analyzed a retrospective chart review of daily defecation log outcome data and parent interview. RESULTS. Notable improvements in acquiring age-appropriate toileting habits were documented and measured using daily defecation logs. Improvements in sensory processing were documented using the Sensory Profile and corroborated improvements in the child's ability to participate in toileting routines and parent report of improved quality of life. CONCLUSION. Occupational therapy using Ayres Sensory Integration(®) was a useful framework for addressing this child's toileting habits. This case explicates occupational therapy using data-driven intervention principles to address the relationship among sensory processing, behavior, and occupational performance.

[CAPS treatment]. / Tratamiento de los síndromes periódicos asociados a la criopirina (CAPS).

Non-steroidal anti-inflammatories, corticoids and antihistamines, as well as a great many other molecules, have classically been used to control the symptoms of cryopyrin-associated periodic syndromes (CAPS), with very few encouraging results. Knowledge of its genetic character, and its aetiopathogenesis associated with inflammasome and the production of interleukin-1 (IL-1) has led to the development of new therapeutic weapons that have not just obtained improvements of the symptoms and quality of life of the patients, but also managed to control the underlying inflammation. Results show that anakinra, an IL-1 receptor antagonist molecule, improved the clinical symptoms and the inflammatory markers of patients with CAPS has motivated research with other molecules directed against IL-1: rilonacept and canakinumab. It is likely that the use of these molecules could prevent the development of the late complications associated with chronic inflammation.

Genetic correction of PSA values using sequence variants associated with PSA levels.

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.

We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: approximately 25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor-positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5' end of TNRC9 , a high mobility group chromatin-associated protein whose expression is implicated in breast cancer metastasis to bone.

Gemcitabine/capecitabine in patients with metastatic breast cancer pretreated with anthracyclines and taxanes.

PURPOSE: Gemcitabine and capecitabine are 2 anticancer drugs with a mechanism of action involving metabolism of pyrimidine nucleotides. Both are among the few agents active in patients with metastatic breast cancer (MBC) progressing after therapy with anthracyclines and taxanes. We have conducted a phase II trial of gemcitabine/capecitabine in patients with disease progression after treatment with anthracyclines and taxanes. PATIENTS AND METHODS: Treatment included gemcitabine 2000 mg/m2 on day 1 every 3 weeks and capecitabine 2500 mg/m2 daily (divided into 2 doses) on days 1-14 every 3 weeks; treatment was administered until disease progression or unacceptable toxicity was documented. All patients received concomitant oral pyridoxine 300 mg twice daily to prevent hand-foot syndrome (HFS). Of 39 patients treated, 33 had received previous treatment with anthracyclines, 6 had medical contraindication to anthracyclines, 35 had previously received taxanes, and 23 had received vinorelbine. Fourteen patients had previous high-dose chemotherapy with stem cell rescue and 5 had previously received trastuzumab. Patients were 31-79 years of age (median, 55 years) and, altogether, were given 386 courses of therapy (range, 1-36 courses per patient; median, 6 courses). RESULTS: Grade 3/4 toxicities included HFS (11 courses, 6 patients), stomatitis (6 courses, 2 patients), diarrhea (5 courses, 4 patients), anemia (5 courses, 2 patients), thrombocytopenia (5 courses, 2 patients), and neutropenia (1 course, 1 patient). Response rate (all 39 patients were evaluable) was 48.7% (partial response, n = 19; stable disease, n = 7; progressive disease, n = 13). Thirty-six patients died because of disease progression, and 3 are alive with progressive disease. Median follow-up was 26 months or until death. Median duration of response was 15 months (range, 3-26 months). Median time to disease progression was 5 months (range, 1-26 months). Median overall survival duration was 10 months (range, 1-37 months). CONCLUSION: In this cohort of patients heavily pretreated with anthracyclines and taxanes, the response rate to gemcitabine/capecitabine is encouraging, although response duration is limited.

Surgery information reduces anxiety in the pre-operative period.

PURPOSE: Patients preparing to undergo surgery should not suffer needless anxiety. This study aimed to evaluate anxiety levels on the day before surgery as related to the information known by the patient regarding the diagnosis, surgical procedure, or anesthesia. METHOD: Patients reported their knowledge of diagnosis, surgery, and anesthesia. The Spielberger State-Trait Anxiety Inventory (STAI) was used to measure patient anxiety levels. RESULTS: One hundred and forty-nine patients were selected, and 82 females and 38 males were interviewed. Twenty-nine patients were excluded due to illiteracy. The state-anxiety levels were alike for males and females (36.10 +/- 11.94 vs. 37.61 +/- 8.76) (mean +/- SD). Trait-anxiety levels were higher for women (42.55 +/- 10.39 vs. 38.08 +/- 12.25, P = 0.041). Patient education level did not influence the state-anxiety level but was inversely related to the trait-anxiety level. Knowledge of the diagnosis was clear for 91.7% of patients, of the surgery for 75.0%, and of anesthesia for 37.5%. Unfamiliarity with the surgical procedure raised state-anxiety levels (P = 0.021). A lower state-anxiety level was found among patients who did not know the diagnosis but knew about the surgery (P = 0.038). CONCLUSIONS: Increased knowledge of patients regarding the surgery they are about to undergo may reduce their state-anxiety levels.

Prognostic value of serum S-100B in malignant melanoma.

AIMS AND BACKGROUND: Although there is no established tumor marker of proven value for patients with melanoma, high serum levels of S-100B protein have been found in patients with melanoma and distant metastases. This study was performed to assess the prognostic value of this marker. METHODS AND STUDY DESIGN: Serum S-100B protein was measured by means of the LIA-mat System 300 (Sangtec S-100B LIA, AB Sangtec Medical, Bromma, Sweden) in 85 patients with melanoma. RESULTS: Mean serum S-100B protein was 0.075 microg/L (range, 0.001-0.470) in 66 patients with non-metastatic melanoma (stage I-III) versus 0.441 microg/L (range, 0.001-16.840) in 19 patients with metastatic melanoma (stage IV) (P <0.001, Mann Whitney U test). The median follow-up time was 329 days. Serum levels above 0.150 microg/L were found in 10 of patients with non-metastatic melanoma (15.2%) and in 17 of 19 patients with metastatic disease (89.4%). Median survival was 256 days for the 27 patients with serum S-100B levels above 0.150 microg/L versus 561 days for the 58 patients with normal values (P <0.3973). CONCLUSION: Serum S-100B is a useful tumor marker in melanoma.

Surgery information reduces anxiety in the pre-operative period

PROPÓSITO: Pacientes que vão ser operados não devem sofrer ansiedade. Este estudo tem por objetivo comparar o grau de ansiedade no dia anterior à cirurgia entre pacientes que têm informação sobre seu diagnóstico, cirurgia e anestesia. MÉTODOS: Pacientes referiram seu conhecimento sobre o diagnóstico, a cirurgia e a anestesia. O inventário de Spielberger, State-Trait Anxiety Inventory (STAI), mediu a ansiedade. RESULTADOS: Cento e quarenta e nove pacientes foram selecionados, 82 mulheres e 38 homens foram entrevistados. Vinte e nove pacientes foram excluídos do estudo por analfabetismo. A ansiedade-estado foi semelhante para homens e mulheres, (36,10 ± 11,94 vs. 37,61 ± 8,76) (mean ± SD). A ansiedade-traço foi maior entre mulheres (42,55 ± 10,39 vs. 38,08 ± 12,25, P = 0,041). O nível de educação não influenciou a ansiedade-estado mas mostrou-se inversamente relacionado à ansiedade-traço. O diagnóstico fora claro para 91,7 por cento dos pacientes entrevistados, cirurgia para 75 por cento e anestesia para 37,5 por cento. O desconhecimento da cirurgia elevou a ansiedade-estado (P = 0,021) cujo menor índice foi encontrado entre pacientes que não conheciam seu diagnóstico, mas sabiam sobre a cirurgia (P = 0,038). CONCLUSÕES: O conhecimento sobre a cirurgia a ser realizada pode reduzir o estado de ansiedade.