Survival analysis in high-grade glioma: The role of salvage surgery.

OBJECTIVES: This study addresses the survival of consecutive patients with high-grade gliomas (HGG) treated at the same institution over a period of 10 years. We analyse the importance of associated factors and the role of salvage surgery at the time of progression. METHODS: We retrospectively analysed a series of patients with World Health Organization (WHO) grade III/IV gliomas treated between 2008 and 2017 at Hospital Gregorio Marañón (Madrid, Spain). Clinical, radiological, and anatomical pathology data were obtained from patient clinical histories. RESULTS: Follow-up was completed in 233 patients with HGG. Mean age was 62.2 years. The median survival time was 15.4 months. Of 133 patients (59.6%) who had undergone surgery at the time of diagnosis, 43 (32.3%) underwent salvage surgery at the time of progression. This subgroup presented longer overall survival and survival after progression. Higher Karnofsky Performance Status score at diagnosis, a greater extent of surgical resection, and initial diagnosis of WHO grade III glioma were also associated with longer survival. CONCLUSIONS: About one-third of patients with HGG may be eligible for salvage surgery at the time of progression. Salvage surgery in this subgroup of patients was significantly associated with longer survival.

Survival analysis in high-grade glioma: the role of salvage surgery. / Análisis de supervivencia en gliomas de alto grado: papel de la cirugía de rescate.

OBJECTIVES: This study addresses the survival of consecutive patients with high-grade gliomas treated at the same institution over a period of 10 years. We analyse the importance of associated factors and the role of salvage surgery at the time of progression. METHODS: We retrospectively analysed a series of patients with World Health Organization (WHO) grade III/IV gliomas treated between 2008 and 2017 at Hospital Gregorio Marañón (Madrid, Spain). Clinical, radiological, and anatomical pathology data were obtained from patient clinical histories. RESULTS: Follow-up was completed in 233 patients with HGG. Mean age was 62.2 years. The median survival time was 15.4 months. Of 133 patients (59.6%) who had undergone surgery at the time of diagnosis, 43 (32.3%) underwent salvage surgery at the time of progression. This subgroup presented longer overall survival and survival after progression. Higher Karnofsky Performance Status score at diagnosis, a greater extent of surgical resection, and initial diagnosis of WHO grade III glioma were also associated with longer survival. CONCLUSIONS: About one-third of patients with HGG may be eligible for salvage surgery at the time of progression. Salvage surgery in this subgroup of patients was significantly associated with longer survival.

Effects of radiotherapy on plasma energy metabolites in patients with breast cancer who received neoadjuvant chemotherapy.

PURPOSE: Neoadjuvant chemotherapy (NACT) is employed in patients with breast cancer (BC) with the aim of reducing tumor burden and improving surgical outcomes. We evaluated the levels of energy metabolites pre- and post-radiotherapy (RT) in breast cancer (BC) patients who previously received NACT and investigated the alterations of these metabolites in relation to the patient achieving a pathologic complete response to NACT. MATERIALS AND METHODS: We included 37 BC patients who were treated with NACT following surgery and analyzed the concentrations of energy balance-related metabolites using targeted metabolomics before and one month after the end of RT. The control group was composed of 44 healthy women. RESULTS: Pre-radiotherapy, patients had significant decreases in the plasma levels of 12 metabolites. RT corrected these alterations and the improvement was superior in patients with a pathologic complete response. CONCLUSION: Our results highlight the importance of metabolism in the outcomes of patients with BC.

Minimal impact of lenvatinib (Lenvima®) on muscle mass in advanced hepatocellular carcinoma and implications for treatment duration. Two cases from the REFLECT study.

OBJECTIVE: Two case reports of advanced unresectable hepatocellular carcinoma (HCC) treated with lenvatinib (Lenvima®) are presented; the drug's effect on muscle loss and duration of treatment are discussed. PATIENTS AND METHODS: Between November 2014 and December 2017, at the Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy, two male patients with advanced HCC enrolled in the lenvatinib arm of the REFLECT trial received the drug over 24 cycles (almost 2 years). We reviewed the clinical charts from baseline, when lenvatinib was started, through 24 months of treatment. The changes in the skeletal mass area (SMA), as assessed by computed tomography (CT) at the third lumbar level (L3), between baseline and month 24 into treatment were recorded. RESULTS: Case 1: SMA decreased by 2.8 cm2 between baseline and month 24 (134 cm2 vs. 131.2 cm2), with a muscle loss of 2.13%. Case 2: SMA decreased by 13 cm2 between baseline and month 24 (133 cm2 vs. 120 cm2), with a muscle loss of 10.83%. CONCLUSIONS: The disease remained stable for over 2.5 years in both patients. A minimal loss of muscle mass was noted at 24 months of treatment. The minimum effect on muscle loss may be correlated with the positive clinical response and the drug's low toxicity. Our findings may help to elucidate the effect of lenvatinib on muscle mass and inform the development of the targeted nutritional support for HCC patients.

[Analysis of the clinical impact of the diagnostic reclassification of brain gliomas according to the World Health Organization classification (2016)]. / Análisis del impacto clínico de la reclasificación diagnóstica de gliomas cerebrales según la clasificación de la Organización Mundial de la Salud (2016).

INTRODUCTION: Since the introduction of genetic and molecular criteria in the 2016 World Health Organization (WHO) classification of brain tumours, there has been a diagnostic reclassification between certain astrocytomas and oligodendro-gliomas with histological and genetic discordances, the prognosis of which is unknown. AIM: To analyse the implications of the diagnostic reclassification of brain gliomas according to the 2016 WHO criteria, especially depending on isocitrate dehydrogenase (IDH) mutation and 1p19q codeletion. PATIENTS AND METHODS: We conducted a retrospective study of gliomas treated from 1 January 2012 to 31 December 2016, with analyses of clinicoradiological aspects and prognoses, and with available and complete follow-up until 31 March 2019. RESULTS: From a total of 147 brain gliomas, a molecular diagnosis and a diagnostic re-evaluation were carried out in 69 cases (grade II-IV astrocytomas or oligodendrogliomas). Twenty-four reclassified gliomas were detected, usually oligodendro-gliomas that became astrocytomas, and which showed greater survival, derived from their not being classified as grade IV. The reclassified gliomas, all grades II/III, mostly began with seizures, without focus, with single lesions, < 17 cm3 and with oedema, although with similar survival rates. The prognostic factors were: young age, focus, grade II and no contrast enhancement or necrosis, or multiplicity. No variations were detected according to the molecular pattern with IDH mutation or codeletion. CONCLUSION: The changes in diagnosis after the WHO classification of 2016 present specific clinical-radiological characteristics in this series, but no greater survival, although, due to the habitual survival in these cases, they would require a longer follow-up time.

TITLE: Análisis del impacto clínico de la reclasificación diagnóstica de gliomas cerebrales según la clasificación de la Organización Mundial de la Salud (2016).Introducción. Desde la introducción de los criterios genéticos y moleculares en la clasificación de la Organización Mundial de la Salud (OMS) de tumores cerebrales de 2016, se ha producido una reclasificación diagnóstica entre determinados astrocitomas y oligodendrogliomas con discordancias histológicas y genéticas, cuyo pronóstico se desconoce. Objetivo. Analizar las implicaciones de la reclasificación diagnóstica de los gliomas cerebrales según los criterios de la OMS de 2016, especialmente según la mutación de la isocitrato deshidrogenasa (IDH) y la codeleción 1p19q. Pacientes y métodos. Estudio retrospectivo de los gliomas tratados desde el 1 de enero de 2012 hasta el 31 de diciembre de 2016, con análisis de los aspectos clinicorradiológicos y pronósticos, y con seguimiento disponible y completo hasta el 31 de marzo de 2019. Resultados. De 147 gliomas cerebrales, en 69 (astrocitomas u oligodendrogliomas de grados II-IV) se realizaron un diagnóstico molecular y una reevaluación diagnóstica. Se detectaron 24 gliomas reclasificados, habitualmente oligodendrogliomas que pasaron a astrocitomas, y que mostraron mayores supervivencias, derivadas de la no reclasificación en grado IV. Los gliomas reclasificados, todos de grados II/III, comenzaron mayoritariamente con crisis, sin focalidad, con lesiones únicas, < 17 cm3 y con edema, aunque con similar supervivencia. Los factores pronósticos fueron: edad joven, focalidad, grado II y no captación de contraste o necrosis, o multiplicidad. No se detectaron variaciones según el patrón molecular con mutación en la IDH o codeleción. Conclusión. Los cambios diagnósticos tras la clasificación de la OMS de 2016 presentan características clinicorradiológicas específicas en esta serie, aunque no mayores supervivencias, si bien, por la supervivencia habitual en estos casos, precisarían un mayor tiempo de seguimiento.

Invited review: Plant polyphenols and rumen microbiota responsible for fatty acid biohydrogenation, fiber digestion, and methane emission: Experimental evidence and methodological approaches.

The interest of the scientific community in the effects of plant polyphenols on animal nutrition is increasing. These compounds, in fact, are ubiquitous in the plant kingdom, especially in some spontaneous plants exploited as feeding resources alternative to cultivated crops and in several agro-industry by-products. Polyphenols interact with rumen microbiota, affecting carbohydrate fermentation, protein degradation, and lipid metabolism. Some of these aspects have been largely reviewed, especially for tannins; however, less information is available about the direct effect of polyphenols on the composition of rumen microbiota. In the present paper, we review the most recent literature about the effect of plant polyphenols on rumen microbiota responsible for unsaturated fatty acid biohydrogenation, fiber digestion, and methane production, taking into consideration the advances in microbiota analysis achieved in the last 10 yr. Key aspects, such as sample collection, sample storage, DNA extraction, and the main phylogenetic markers used in the reconstruction of microbial community structure, are examined. Furthermore, a summary of the new high-throughput methods based on next generation sequencing is reviewed. Several effects can be associated with dietary polyphenols. Polyphenols are able to depress or modulate the biohydrogenation of unsaturated fatty acids by a perturbation of ruminal microbiota composition. In particular, condensed tannins have an inhibitory effect on biohydrogenation, whereas hydrolyzable tannins seem to have a modulatory effect on biohydrogenation. With regard to fiber digestion, data from literature are quite consistent about a general depressive effect of polyphenols on gram-positive fibrolytic bacteria and ciliate protozoa, resulting in a reduction of volatile fatty acid production (mostly acetate molar production). Methane production is also usually reduced when tannins are included in the diet of ruminants, probably as a consequence of the inhibition of fiber digestion. However, some evidence suggests that hydrolyzable tannins may reduce methane emission by directly interacting with rumen microbiota without affecting fiber digestion.

Impact of malnutrition on survival and infections among pediatric patients with cancer: a retrospective study.

OBJECTIVE: Recognizing and managing malnutrition among hospitalized children affected by cancer is a rising need. Awareness and consideration of malnutrition among clinicians are still largely insufficient. This can principally be explained by the lack of consciousness and the shortage of easy and objective tools to identify malnutrition status. The aim of this study is to explore the impact of malnutrition on survival and infections among a population of pediatric patients with cancer. PATIENTS AND METHODS: All children aged between 3 and 18 years, newly diagnosed with a malignancy between August 2013 and April 2018, were included in our study. We assessed nutritional risk at diagnosis (with STRONGkids), then we evaluated anthropometric measurements (BMI Z-scores and weight loss), data about survival and number of hospitalization for febrile neutropenia (FN) in the first year after diagnosis. Cut-off values for malnourishment were chosen as BMI Z-score ≤-2.0. RESULTS: One hundred twenty-six pediatric cancer patients were included in the study. At diagnosis 36 pediatric cancer patients (28.6%) were at high risk of malnutrition (STRONGkids 4 or 5), whereas 6 (4.7%) others were malnourished (BMI Z-score≤-2.0). The risk of mortality and the rate of infections (≥3 hospitalizations for FN episodes) were significantly increased by malnutrition and rapid weight loss in the initial phase of treatment (3-6 months after diagnosis). Multivariate analysis confirmed the independent effect of weight loss≥ 5% at 3 months on both survival and infections, and the independent impact of a high risk of malnutrition at diagnosis on infections. CONCLUSIONS: A personalized evaluation of nutritional risk at diagnosis and a close monitoring of nutritional status during the initial phase of treatment are crucial for ensuring a timely and personalized nutritional intervention, which may potentially improve tolerance to chemotherapy and survival, and prevent prolonged hospitalization for infections in childhood cancer patients.

Role of phase angle in the evaluation of effect of an immuno-enhanced formula in post-surgical cancer patients: a randomized clinical trial.

OBJECTIVE: Neoplastic disease is frequently associated with poor nutritional status or severe malnutrition. Diet and nutritional intervention are becoming increasingly important for prognosis and quality of life in cancer patients. Accessible and repeatable tools for assessing nutritional status with body composition techniques seems to be fundamental. The aim of this study was to evaluate the effects of immunonutrition on body composition parameters, inflammatory response and nutritional status in patients at stage III of head and neck squamous carcinoma (HNSCC). PATIENTS AND METHODS: In our work, 50 malnourished subjects with HNSCC staging III were recruited and treated with oral diet (OD) or enteral nutrition (EN). Patient under EN followed, for the first three days, enteral standard nutrition (ESN) and then enteral immunonutrition (EIN). Nutrition state was evaluated on days 0, 3, and 8 through body composition and biochemical analyses. RESULTS: After 8 days, the EIN treatment showed a significant improvement in phase angle, pre-albumin, retinol binding protein and transferrin compared to the OD treatment. CONCLUSIONS: Our results showed that immunonutrition treatment improves the nutritional status of neoplastic patients, supporting chemotherapy. The phase angle is not only a predictor of cancer survival, but has also proved to be useful in the surveillance of nutritional status improvement as well as biochemical indices.

Germline promoter hypermethylation in BRCA1 and BRCA2 genes is not present in hereditary breast cancer patients.

PURPOSE: Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome. METHODS: We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. RESULTS: Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed. CONCLUSIONS: Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assay for the detection of germline hypermethylation as an effective pre-screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA.

Quality, storability, and essential oil content of Ligularia fischeri during modified atmosphere packaging storage.

Modified atmosphere packaging (MAP) enhanced the quality and storability of Ligularia fischeri. Oxygen transmission rate (OTR) films were used as a MAP. MAP storage displayed lower fresh weight loss than perforated film. The oxygen, carbon dioxide, and ethylene concentration were properly maintained by a 10,000 cc OTR packaging film at 8 °C and 30,000 cc OTR packaging film at 24 °C. On the last day of storage, the off-odor, such as the acetaldehyde and ethanol concentration, was the lowest in the 10,000 cc OTR film at 8 °C and 30,000 cc OTR film at 24 °C treatments. The 10,000 cc OTR film treatment at 8 °C and 30,000 cc OTR film treatments at 24 °C had the highest chlorophyll content, total phenolic content, leaf toughness, antioxidant activity, vitamin C, and less off-flavor. The shelf life of 10,000 cc OTR film was 13 days, at 8 °C storage temperature. At 24 °C storage temperature, the shelf life of 30,000 cc OTR film was 4 days. The MAP storage of the Ligularia treated with 10,000 cc OTR film at 8 °C and 30,000 cc OTR film at 24 °C had the highest essential oil content. These results suggest that the best MAP film for cold-chain distribution was the 10,000 cc OTR film, and the 30,000 cc OTR film was a more suitable MAP film for local distribution without the cold-chain system of L. fischeri.

Factors affecting variations in the detailed fatty acid profile of Mediterranean buffalo milk determined by 2-dimensional gas chromatography.

Buffalo milk is the world's second most widely produced milk, and increasing attention is being paid to its composition, particularly the fatty acid profile. The objectives of the present study were (1) to characterize the fatty acid composition of Mediterranean buffalo milk, and (2) to investigate potential sources of variation in the buffalo milk fatty acid profile. We determined the profile of 69 fatty acid traits in 272 individual samples of Mediterranean buffalo milk using gas chromatography. In total, 51 individual fatty acids were identified: 24 saturated fatty acids, 13 monounsaturated fatty acids, and 14 polyunsaturated fatty acids. The major individual fatty acids in buffalo milk were in the order 16:0, 18:1 cis-9, 14:0, and 18:0. Saturated fatty acids were the predominant fraction in buffalo milk fat (70.49%); monounsaturated and polyunsaturated fatty acids were at 25.95 and 3.54%, respectively. Adopting a classification based on carbon-chain length, we found that medium-chain fatty acids (11-16 carbons) represented the greater part (53.7%) of the fatty acid fraction of buffalo milk, whereas long-chain fatty acids (17-24 carbons) and short-chain fatty acids (4-10 carbons) accounted for 32.73 and 9.72%, respectively. The n-3 and n-6 fatty acids were 0.46 and 1.77%, respectively. The main conjugated linoleic acid, rumenic acid, represented 0.45% of total milk fatty acids. Herd/test date and stage of lactation were confirmed as important sources of variation in the fatty acid profile of buffalo milk. The percentages of short-chain and medium-chain fatty acids in buffalo milk increased in early lactation (+0.6 and +3.5%, respectively), whereas long-chain fatty acids decreased (-4.2%). The only exception to this pattern was butyric acid, which linearly decreased from the beginning of lactation, confirmation that its synthesis is independent of malonyl-CoA. These results seem to suggest that in early lactation the mobilization of energy reserves may have less influence on the fatty acid profile of buffalo milk than that of cow milk, probably due to a shorter and less severe period of negative energy balance. Parity affected the profiles of a few traits and had the most significant effects on branched-chain fatty acids. This work provided a detailed overview of the fatty acid profile in buffalo milk including also those fatty acids present in small concentrations, which may have beneficial effects for human health. Our results contributed also to increase the knowledge about the effects of some of the major factors affecting buffalo production traits and fatty acid concentrations in milk, and consequently its technological and nutritional properties.

Effects of candidate gene polymorphisms on the detailed fatty acids profile determined by gas chromatography in bovine milk.

Association analyses between candidate genes and bovine milk fatty acids can improve our understanding of genetic variation in milk fatty acid profiles and reveal potential opportunities to tailor milk fat composition through selection strategies. In this work, we investigated the association of 51 single nucleotide polymorphisms (SNP) selected from 37 candidate genes using a functional and positional approach, with 47 fatty acids, 9 fatty acid groups, and 5 Δ(9)-desaturation indices in milk samples from Brown Swiss cows. Individual milk samples were collected from 1,158 Italian Brown Swiss cows, and gas chromatography was used to obtain detailed milk fatty acid compositions. A GoldenGate assay system (Illumina, San Diego, CA) was used to perform genotype 96 selected SNP located in 54 genes across 22 chromosomes. In total, 51 polymorphic SNP in 37 candidate genes were retained for the association analysis. A Bayesian linear animal model was used to estimate the contribution of each SNP. A total of 129 tests indicated relevant additive effects between a given SNP and a single fatty acid trait; 38 SNP belonging to 30 genes were relevant for a total of 57 fatty acid traits. Most of the studied fatty acid traits (~81%) were relevantly associated with multiple SNP. Relevantly associated SNP were mainly found in genes related to fat metabolism, linked to or contained in previously identified quantitative trait loci for fat yield or content, or associated with genes previously identified in association analyses with milk fatty acid profiles in other cow breeds. The most representative candidate genes were LEP, PRL, STAT5A, CCL3, ACACA, GHR, ADRB2, LPIN1, STAT1, FABP4, and CSN2. In particular, relevant associations with SNP located on bovine chromosome 19 (BTA19) were found. Two candidate genes on BTA19 (CCL3 and ACACA) were relevantly associated with de novo short- and medium-chain fatty acids, likely explaining the high heritability values found for these fatty acids (with the exception of C6:0). Two additional genes on BTA19 (CCL2 and GH1) showed associations with saturated and branched-chain fatty acids. Our findings provide basic information on genes and SNP affecting the milk fatty acid composition of dairy cows. These results may support the possibility of using genetic selection to modify milk fatty acid profiles to promote beneficial health-related effects.

Genetic and environmental relationships of detailed milk fatty acids profile determined by gas chromatography in Brown Swiss cows.

The aim of this study was to characterize the profile of 47 fatty acids, including conjugated linoleic acid (CLA), 13 fatty acid groups, and 5 Δ(9)-desaturation indices in milk samples from Brown Swiss cows. The genetic variation was assessed and the statistical relevance of the genetic background for each trait was evaluated using the Bayes factor test. The additive genetic, herd-date, and residual relationships were also estimated among all single fatty acids and groups of fatty acids. Individual milk samples were collected from 1,158 Italian Brown Swiss cows and a detailed analysis of fat percentages and milk fatty acid compositions was performed by gas chromatography. Bayesian animal models were used for (co)variance components estimation. Exploitable genetic variation was observed for most of the de novo synthesized fatty acids and saturated fatty acids, except for C4:0 and C6:0, whereas long-chain fatty acids and unsaturated fatty acids (including CLA) were mainly influenced by herd-date effects. Herd-date effect explained large portions of the total phenotypic variance for C18:2 cis-9,cis-12 (0.668), C18:3 cis-9,cis-12,cis-15 (0.631), and the biohydrogenation and elongation products of these fatty acids. The desaturation ratios showed higher heritability estimates than the individual fatty acids, except for CLA desaturation index (0.098). Among the medium-chain fatty acids, C12:0 had greater heritability than C14:0 (0.243 vs. 0.097, respectively). Both C14:0 and C16:0 showed negative additive genetic correlations with the main monounsaturated and polyunsaturated fatty acids of milk fat, suggesting that their synthesis in the mammary gland may be influenced by the presence of unsaturated fatty acids. No correlation was observed between C4:0 and the other short-chain fatty acids (except for C6:0), confirming the independence of C4:0 from de novo mammary fatty acid synthesis. Among the genetic correlations dealing with potentially beneficial fatty acids, C18:0 was positively correlated with vaccenic and rumenic acids and negatively with linoleic acid. Finally, fatty acids C6:0 through C14:0 showed relevant correlations due to unknown environmental effects, suggesting the potential existence of genetic variances in micro-environmental sensitivity. This study allowed us to acquire new knowledge about the genetic and the environmental relationships among fatty acids. Likewise, the existence of genetic variation for most of de novo synthetized fatty acids and saturated fatty acids was also observed. Overall, these results provide useful information to combine feeding with genetic selection strategies for obtaining a desirable milk fatty acids profile, depending on the origin of fatty acids in milk.

Conjugated linoleic acid isomers strongly improve the redox status of bovine mammary epithelial cells (BME-UV1).

Some studies have shown the protective effects of conjugated linoleic acid (CLA) isomers against oxidative stress and lipid peroxidation in animal models, but no information is available about CLA and changes in oxidative status of the bovine mammary gland. The objectives of the study were to assess in vitro the effect of CLA on the cellular antioxidant response of bovine mammary cells, to examine whether CLA isomers could play a role in cell protection against the oxidative stress, and to study the molecular mechanism involved. For the study, BME-UV1 cells, a bovine mammary epithelial cell line, were used as the experimental model. The BME-UV1 cells were treated with complete medium containing 50 µM cis-9,trans-11 CLA (c9,t11 CLA), trans-10,cis-12 CLA (t10,c12 CLA), and CLA mixture (1:1, cis-9,trans-11: trans-10,cis-12 CLA). To monitor cellular uptake of CLA isomers, cells and culture medium were collected at 0, 3, and 48 h from CLA addition for lipid extraction and fatty acid analyses. To assess the cellular antioxidant response, glutathione (GSH/GSSH), NADPH, and γ-glutamyl-cysteine ligase activity was measured after 48 h from addition of CLA. Cytoplasmic superoxide dismutase, glutathione peroxidase, glutathione S-transferase, and glutathione reductase activities and mRNA were also determined. Intracellular reactive oxygen species and thiobarbituric acid reactive substance production were assessed in cells supplemented with CLA isomers. Cell viability after 3h to H2O2 exposure was assessed to evaluate and to compare the potential protection of different CLA isomers against H2O2-induced oxidative stress. Mammary cells readily picked up all CLA isomers, their accumulation was time dependent, and main metabolites at 48 h are two 18:3 isomers. The CLA treatment induced an intracellular GSH increase, matched by high concentration of NADPH, and an increase of γ-glutamyl-cysteine ligase activity mainly in cells treated with the t10,c12 CLA isomer. The CLA isomer treatment of bovine mammary cells increased superoxide dismutase, glutathione peroxidase, and glutathione S-transferase activity and decreased glutathione reductase activity, but no changes in gene expression of these antioxidant enzymes were observed. Cells supplemented with CLA isomers showed a reduction in intracellular reactive oxygen species and thiobarbituric acid reactive substance levels. All CLA isomers were able to enhance cell resistance against H2O2-induced oxidative stress. These suggest an antioxidant role of CLA, in particular of t10,c12 CLA, by developing a significantly high redox status in cells.

Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study.

Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 4 weeks for four cycles, followed by 80 mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65 years, 64 % suffered from hypertension, and 10 % had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32 % (95 % CI 19.5-46.7 %) and pCR in breast and axilla was 24 % (95 % CI 12.1-35.8 %). At diagnosis only, 26 % of patients were candidates for breast conservative surgery, which increased to 58.7 % after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.

Effect of dietary starch concentration and fish oil supplementation on milk yield and composition, diet digestibility, and methane emissions in lactating dairy cows.

The aim of this study was to evaluate the effects of diets with different starch concentrations and fish oil (FO) supplementation on lactation performance, in vivo total-tract nutrient digestibility, N balance, and methane (CH4) emissions in lactating dairy cows. The experiment was conducted as a 4×4 Latin square design with a 2×2 factorial arrangement: 2 concentrations of dietary starch [low vs. high: 23.7 and 27.7% on a dry matter (DM) basis; neutral detergent fiber/starch ratios: 1.47 and 1.12], the presence or absence of FO supplement (0.80% on a DM basis), and their interaction were evaluated. Four Italian Friesian cows were fed 1 of the following 4 diets in 4 consecutive 26-d periods: (1) low starch (LS), (2) low starch plus FO (LSO), (3) high starch (HS), and (4) high starch plus FO (HSO). The diets contained the same amount of forages (corn silage, alfalfa and meadow hays). The starch concentration was balanced using different proportions of corn meal and soybean hulls. The cows were housed in metabolic stalls inside open-circuit respiration chambers to allow measurement of CH4 emission and the collection of separate urine and feces. No differences among treatments were observed for DM intake. We observed a trend for FO to increase milk yield: 29.2 and 27.5kg/d, on average, for diets with and without FO, respectively. Milk fat was affected by the interaction between dietary starch and FO: milk fat decreased only in the HSO diet. Energy-corrected milk (ECM) was affected by the interaction between starch and FO, with a positive effect of FO on the LS diet. Fish oil supplementation decreased the n-6:n-3 ratio of milk polyunsaturated fatty acids. High-starch diets negatively influenced all digestibility parameters measured except starch, whereas FO improved neutral detergent fiber digestibility (41.9 vs. 46.1% for diets without and with FO, respectively, and ether extract digestibility (53.7 vs. 67.1% for diets without and with FO, respectively). We observed a trend for lower CH4 emission (g/d) and intensity (g/kg of milk) with the high-starch diets compared with the low-starch diets: 396 versus 415g/d on average, respectively, and 14.1 versus 14.9g/kg of milk, respectively. Methane intensity per kilogram of ECM was affected by the interaction between starch and FO, with a positive effect of FO for the LS diet: 14.5 versus 13.3g of CH4/kg of ECM for LS and LSO diets, respectively.

Antihypertensive and neuroprotective effects of catestatin in spontaneously hypertensive rats: interaction with GABAergic transmission in amygdala and brainstem.

The chromogranin A-derived peptide catestatin (CST) exerts sympathoexcitatory and hypertensive effects when microinjected into the rostral ventrolateral medulla (RVLM: excitatory output); it exhibits sympathoinhibitory and antihypertensive effects when microinjected into the caudal ventrolateral medulla (CVLM: inhibitory output) of vagotomized normotensive rats. Here, continuous infusion of CST into the central amygdalar nucleus (CeA) of spontaneously hypertensive rats (SHRs) for 15 days resulted in a marked decrease of blood pressure (BP) in 6-month- (by 37 mm Hg) and 9-month- (by 65 mm Hg)old rats. Whole-cell patch-clamp recordings on pyramidal CeA neurons revealed that CST increased both spontaneous inhibitory postsynaptic current (sIPSC) amplitude plus frequency, along with reductions of sIPSC rise time and decay time. Inhibition of GABAA receptors (GABAARs) by bicuculline completely abolished CST-induced sIPSC, corroborating that CST signals occur through this major neuroreceptor complex. Hypertension is a major risk factor for cerebrovascular diseases, leading to vascular dementia and neurodegeneration. We found a marked neurodegeneration in the amygdala and brainstem of 9-month-old SHRs, while CST and the GABAAR agonist Muscimol provided significant neuroprotection. Enhanced phosphorylation of Akt and ERK accounted for these neuroprotective effects through anti-inflammatory and anti-apoptotic activities. Overall our results point to CST exerting potent antihypertensive and neuroprotective effects plausibly via a GABAergic output, which constitute a novel therapeutic measure to correct defects in blood flow control in disorders such as stroke and Alzheimer's disease.

Pancreatic injury during AAA repair: a comparison between EVAR and open repair.

OBJECTIVES: Enzymatic pancreatic injury (EPI) in abdominal aortic aneurysm (AAA) treatment has been scarcely studied in the literature. Aim of this work was to compare perioperative EPI in AAA patients treated by endovascular repair (EVAR) or open repair (OR). METHODS: Forty AAA patients consecutively treated with either EVAR (GI, 20 pts) or OR (GII, 20 pts) were prospectively evaluated in terms of epidemiology, comorbidities and technical details. Serum levels of amylase, lipase and pancreatic isoamylase were assessed before treatment (T0), before aortic clamping/endograft deployment (T1), 1, 2, and 6 hours after aortic declamping/endograft deployment (T2, T3, T4) and 24, 48, and 72 hours after the procedure (T5, T6, T7). GI and GII were compared by Mann Whitney test with significance set at p < 0.05. RESULTS: GI patients were significantly older and with higher frequency of preoperative renal insufficiency than GII ones (p = 0.001 and 0.047 respectively). Other characteristics were not significantly different. Pancreatic enzymes values at T0 were within normal parameters in all patients. Total serum amylase was significantly greater at T4 (p = 0.003), T5 (p = 0.010), T6 (p = 0.003), T7 (p = 0.011) and isoamylase at T3 (p = 0.052), T4 (p = 0.037), T5 (p = 0.016) and T6 (p = 0.014) in GII compared with GI. Amylase and isoamylase peak occurred 24 hours after the procedure. Lipase was significantly different in the two groups only in T4 (p = 0.028). No acute pancreatitis occurred in the whole study group. CONCLUSIONS: EVAR significantly reduces EPI compared with OR in the AAA treatment.

Nutritional counselling and oral nutritional supplements in head and neck cancer patients undergoing chemoradiotherapy.

BACKGROUND: The role of nutritional counselling (NC) with or without oral nutritional supplements (ONS) in patients receiving chemoradiotherapy (CRT) for head and neck cancer (HNC) still remains to be clearly defined, particularly with regard to CRT-related toxicity. METHODS: Patients undergoing CRT for HNC received NC by the dietitian within the first 4 days of radiotherapy and weekly for the course of radiotherapy (approximately 6 weeks). A weekly supply of oral nutrition supplements [1560 kJ (373 kcal) per 100 g] for up to 3 months was provided to all patients. RESULTS: Twenty-one patients completed CRT. Mucositis G3 developed in seven (33.3%) patients, whereas mucositis G4 was absent. Dysphagia was present before the start of treatment in four patients. In the remaining 17 patients, dysphagia G3 developed during/at the end of treatment in five cases. The percentage of patients interrupting anti-neoplastic treatment for was 28% for ≥6 days, 28% for 3-5 days and 44% for 0-2 days. Mucositis G3 frequency was lower in patients with a baseline body mass index (BMI, kg m(-2) ) ≥25 (two out of 12; 16.6%) than in patients with BMI <25 (five out of nine; 55.5%) (P = 0.161) and in patients with a baseline mid arm circumference >30 cm than in those with a mid arm circumference in the range 28.1-30 cm and <28 cm, and higher in patients with a greater weight loss and a greater reduction of serum albumin and mid arm circumference. CONCLUSIONS: Nutritional counselling and ONS are associated with relatively low CRT-related toxicity and with mild deterioration of nutritional parameters.