PROMIS scores of patients undergoing neoadjuvant and adjuvant radiation therapy for surgically excised soft tissue sarcoma.

INTRODUCTION: Few recent studies have examined patient reported outcomes (PROs) during pre- or post-operative radiation therapy (RT) for soft tissue sarcoma (STS), and none have used PROMIS. This study aims to examine PROMIS scores across peri-operative time points for patients receiving pre- or post-operative RT. METHODS: Anxiety, depression, pain interference, and physical function PROMIS domains were collected at the pre-operative (1), immediate post-operative (2), and post-treatment completion (3) timepoints for patients undergoing surgery and either pre-operative or post-operative RT. Median scores were compared between groups using the Kruskal-Wallis test. The reliable change index was used to determine minimum important change in PROMIS scores and to compare scores between timepoints. RESULTS: 95 patients were included (19 pre-operative, 76 post-operative). Both groups had significant decreases in function during treatment. Patients with wound complications were more likely to have significant increases in anxiety (36.4% vs. 8.3%; p = 0.020) and decreases in physical function (57.1% vs. 16.2%; p = 0.011) independent of RT timing. CONCLUSIONS: This study demonstrates minimum significant change thresholds to detect PROMIS changes in STS patients undergoing pre- and post-operative radiotherapy. As expected, more patients with pre-operative RT than post-operative RT had wound complications (p = 0.06), but patients with complications in both groups had worse anxiety and function at the completion of treatment compared with those that did not. The association of wound complications with worse anxiety and physical function at completion of treatment should be considered when making individualized treatment recommendations regarding the timing of RT.

Outcomes in patients ≥ 80 years with a diagnosis of a hepatopancreaticobiliary (HPB) malignancy.

Older patients are underrepresented in oncological clinical trials. The incidence of hepatopancreaticobiliary (HPB) malignancies is higher in older patients, but data on outcomes are lacking. This study assessed patient outcomes in those < 80 and ≥ 80 years with a HPB malignancy seen at a tertiary referral centre, The Christie NHS Foundation Trust. Data on patients with a HPB malignancy were collected retrospectively between 2012 and 2017 via on-line case-note review. Survival was calculated using the Kaplan-Meier method and prognostic factors using log-rank analysis. Of 1421 patients, 10% were ≥ 80 years. Of patients < 80 and ≥ 80 years, 56% and 57% had pancreas cancer, 39% and 36% biliary tract cancer, and 5% and 7% had hepatocellular carcinoma, respectively. Amongst patients ≥ 80 years, 75% had an Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Patients ≥ 80 years had higher rates of comorbidity; 28% received systemic anti-cancer therapy (SACT), compared with 62% of patients < 80 years. Best supportive care (BSC) was instituted in 44% of older patients, compared with 13% in those < 80 years. Of patients ≥ 80 years who received SACT, 82% received monotherapy. Median overall survival (OS) for patients receiving palliative SACT was 10.07 months (95% CI 8.89-11.08) and 10.10 months (95% CI 6.30-12.30) in patients < 80 and ≥ 80 years, respectively, p 0.41; ECOG PS (p < 0.001) was prognostic for OS in older patients but Adult Comorbidity Evaluation-27 comorbidity score (p = 0.07, when comparing groups of ACE score ≤ 1 and > 1) was not. Baseline factors were similar in both age cohorts, but more comorbidities were present in older patients. Older patients were less likely to receive SACT, but when they did, they had an equivalent benefit in OS to younger patients.

Comparison of clamping modalities in a rabbit model of normothermic renal ischemia.

PURPOSE: The objective of this study was to investigate the patterns of renal function recovery with different renal vessel clamping modalities during a prolonged warm ischemia (WI) condition in an experimental two-kidney rabbit model. MATERIALS AND METHODS: Twenty-eight rabbits were randomly clustered into four groups and underwent laparotomy with different types of renal pedicle clamping. Group 1 (n=4) was sham-operated. Group 2 (n=8) underwent 80 minutes of WI with artery only clamping. Group 3 (n=8) underwent arteriovenous clamping for 80 minutes, and group 4 (n=8) received an arteriovenous clamping for 80 minutes with 10-second declamping periods every 20 minutes. Serum levels of creatinine (SCr) were recorded preoperatively and on postoperative days (PODs) 1, 3, and 7. Renal function was evaluated by (99m)technetium-mercaptoacetyltriglycine scintigraphy. Afterward, the animals were euthanized, and the kidneys were harvested and evaluated microscopically. RESULTS: Renal function completely recuperated on POD 7 in the groups that underwent artery only and ateriovenous intermittent clamping, and both of these methods were superior to ateriovenous clamping (P<0.001). SCr showed a similar variation in all the clamping groups and did not demonstrate statistical differences among the groups. Histopathologic changes were similar among the ischemic groups. CONCLUSION: The less deleterious clamping modalities in this experimental model were the artery only and intermittent en bloc clamping methods.

Zinc, metallothioneins and immunosenescence.

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. The nutritional factor, zinc, may remodel these changes with subsequent healthy ageing, because zinc improves the inflammatory/immune response as shown by in vitro and in vivo studies. The intracellular zinc homeostasis is regulated by buffering metallothioneins (MT) and zinc transporters (ZnT and ZIP families) that mediate the intracellular zinc signalling assigning to zinc a role of 'second messenger'. In ageing, the intracellular zinc homeostasis is altered, because high MT are unable to release zinc and some zinc transporters deputed to zinc influx (ZIP family) are defective leading to low intracellular zinc content for the immune efficiency. Physiological zinc supplementation in the elderly improves these functions. However, the choice of old subjects for zinc supplementation has to be performed in relation to the specific genetic background of MT and IL-6, because the latter is involved both in MTmRNA and in intracellular zinc homeostasis. Old subjects carrying GG genotypes (C-carriers) in the IL-6-174G/C locus display high IL-6, low intracellular zinc content, impaired innate immunity and enhanced MT. Old subjects carrying GC and CC genotypes (C+carriers) display satisfactory intracellular zinc content, adequate innate immunity and are more prone to reach longevity. Zinc supplementation in old C-carriers restores natural killer cell cytotoxicity and zinc status. The genetic variations of the IL-6-174G/C locus when associated with those of the MT1A+647A/C locus are useful tools for the choice of old people for zinc supplementation.

Zinc, metallothioneins and longevity: interrelationships with niacin and selenium.

Ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. Some nutritional factors (zinc, niacin, selenium) may remodel these changes leading to a possible escaping of diseases, with the consequence of healthy ageing, because they are involved in improving immune functions, metabolic homeostasis and antioxidant defence. Experiments performed "in vitro" (human lymphocytes exposed to endotoxins) and "in vivo" (old mice or young mice with low zinc dietary intake) show that zinc is important for immune efficiency (both innate and adaptive), metabolic homeostasis (energy utilization and hormone turnover) and antioxidant activity (SOD enzyme). Niacin is a precursor of NAD+, the substrate for the activity of DNA repair enzyme PARP-1 and, consequently, may contribute to maintaining genomic stability. Selenium provokes zinc release by Metallothioneins (MT), via reduction of glutathione peroxidase. This fact is crucial in ageing because high MT may be unable to release zinc with subsequent low intracellular free zinc ion availability for immune efficiency, metabolic harmony and antioxidant activity. Taking into account the existence of zinc transporters (ZnT and ZIP family) for cellular zinc efflux and influx, respectively, the association between zinc transporters and MT is crucial in maintaining satisfactory intracellular zinc homeostasis in ageing. Improved immune performance, metabolic homeostasis, antioxidant defence occur in elderly after physiological zinc supplementation, which also induces prolonged survival in old, nude and neonatal thymectomized mice. The association "zinc plus selenium" improves humoral immunity in old subjects after influenza vaccination. The association "zinc plus niacin" in elderly is actually in progress.

Effects of interleukin-6 -174C/G and metallothionein 1A +647A/C single-nucleotide polymorphisms on zinc-regulated gene expression in ageing.

Decreased zinc ion availability in ageing is associated with altered immune response. One of the main regulators of zinc availability is metallothionein. Metallothionein induction is under the control of interleukin-6, a pro-inflammatory cytokine whose production is associated with poor ageing. The production of interleukin-6 is controlled, in part, by variability in the -174 nucleotide position. Under conditions of chronic inflammation, such as in ageing, zinc release by metallothionein is limited and may reduce zinc availability. Understanding the precise nature of the interactions between interleukin-6 and metallothioneins will aid in identifying individuals who are at risk of zinc deficiency. In the current study, we used gene arrays to investigate the effects of in vitro zinc supplementation on gene expression in elderly donors with described interleukin-6 and metallothionein 1a polymorphisms. Ingenuity Pathway Analysis identified several zinc-responsive genetic networks uniquely regulated only in elderly individuals with the pro-inflammatory interleukin-6 polymorphism. These include zinc-dependent decreased transcription of pro-inflammatory cytokines and alterations in metabolic regulatory pathways. The genomic effects of zinc increased in significance in the presence of the metallothionein 1a +647 C/A transition, suggesting that the interleukin-6 and metallothionein 1a genes act in a concerted manner to control zinc-regulated gene expression.

+647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications.

Diabetes mellitus is a chronic disease characterized by an overproduction of reactive oxygen species, which perturbs zinc metabolism and promotes the onset of cardiovascular disease (CVD) in diabetic patients. Metallothioneins (MT) are cysteine-rich metal-binding proteins which, by means of their antioxidant and zinc-buffering properties, might prevent the development of diabetic cardiovascular complications. A recent investigation shows that a polymorphism (+647 A/C) in the human MT-1A gene, affects the intracellular zinc ion release (iZnR) from the proteins and is associated with longevity in Italian population. The aim of the present study is to assess the involvement of +647 A/C and +1245 A/G MT1A polymorphisms with the susceptibility to type 2 diabetes (DM2) and cardiovascular complications. The study included 694 old individuals: 242 old healthy controls, 217 DM2 patients without clinical evidence of CVD (DNC) and 235 diabetic patients with diagnosis of CVD (DCVD). +647 A/C MT1A polymorphism, but not the second SNP, was associated with DM2. C allele carriers were more prevalent in DNC and DCVD patients than in control group (OR=1.37, p=0.034; OR=1.54, p=0.002, respectively). C+ carriers was associated with higher glycemia and glycosylated hemoglobin in DCVD patients, but not in DNC or control subjects. No differences in plasma zinc, but a modulation of MT levels and iZnR in PBMCs were observed in DCVD cohort when related to +647 A/C MT1A polymorphism. In summary, this work provides novel evidence on the association of the +647 A/C MT1A polymorphism with DM2. Moreover, C+ carriers in DCVD patients presented a worse glycemic control, a reduced iZnR and a higher MT levels, suggesting a possible role of MT in diabetic cardiovascular complications.

Differential effects of in vitro zinc treatment on gene expression in peripheral blood mononuclear cells derived from young and elderly individuals.

Mild zinc deficiency, which is prevalent in vegetarians, diseased individuals, and the general aging population, depresses immunity and increases risk of disease in later life. However, human zinc intervention trials have produced conflicting results, perhaps because many of these trials included young or zinc-sufficient subjects. Since heterogeneity of the adult population may impact on response to dietary zinc, nutrigenomic approaches aimed at understanding the impact of zinc on modulation of gene and protein activities may aid in identifying subsets of the population-in particular the aging population-with increased risk of zinc deficiency who might receive benefit from a dietary zinc intervention and in this way may influence the success of the intervention. In the current study we used nutrigenomic approaches to investigate the impact of age on zinc-regulated gene expression in peripheral blood mononuclear cells. Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA) identified several genetic networks and functional canonical pathways which appeared responsive to zinc that were differentially regulated in young and elderly individuals. These include tryptophan metabolism, eicosanoid signaling, p38 mitogen-activated protein kinase (MAPK) signaling, integrin signaling, purine metabolism, G-protein-coupled receptor signaling, and most significantly, peroxisome proliferator-activated receptor (PPAR) signaling. These data suggest that age impacts strongly on the transcriptional effects of zinc and provides evidence to support the hypothesis that young and elderly individuals may respond differentially to zinc intervention.

Carotid intima-media thickness is slightly increased over time in HIV-1-infected patients.

OBJECTIVES: HIV-infected patients are at risk of atherosclerosis and cardiovascular diseases. In a 12-month follow-up study, we aimed to investigate changes in carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, and its determinants in HIV-1-infected patients. METHODS: Our multicentre prospective longitudinal cohort study included 346 HIV-infected patients, for each of whom two IMT measurements were taken by B-mode ultrasonography at baseline (M0) and 1 year later (M12). RESULTS: We observed a significant but moderate increase in the common carotid artery (CCA) median IMT, from 0.54 to 0.56 mm (P<10(-4)), i.e. an increase of 0.020 mm (95% confidence interval 0.012-0.029). There was a significant association between cross-sectional CCA IMT measures at M12 and conventional cardiovascular risk factors (higher CCA IMT with older age, P<10(-4); male gender, P=0.02; tobacco consumption, P=0.05), as well as higher CD4 cell count at M12 (>median 455 cells/microL, P=0.01). Only CD4 cell count at M0 was strongly and positively associated with the variation in IMT between M0 and M12 (P=4 x 10(-3)). IMT progression was +0.0020 mm for the lowest quartile of CD4 cell count distribution at M0, i.e. 3-253 cells/microL, +0.010 mm for 253-402 cells/microL, +0.043 mm for 402-590 cells/microL, and +0.028 mm for 590-2270 cells/microL. No association was found with type or duration of antiretroviral exposure. CONCLUSIONS: Conventional cardiovascular risk factors are major determinants of IMT evolution. The link between immunological status and carotid IMT requires further study.

The -308G/A polymorphism of TNF-alpha influences immunological parameters in old subjects affected by infectious diseases.

Abnormal increments of pro-inflammatory cytokines (IL-6 and TNF-alpha) characterize the outbreak of infectious diseases, which are the major cause of death in the elderly. A counterbalance to the inflammation is exerted by IL-10 with an inhibitory role on TNF-alpha production. As is well known, some cytokine gene polymorphisms influence the cytokine production, playing a role as susceptibility or resistance factors against immune-mediated and infectious disease. Genetic variations in the -308A/G locus for TNF-alpha seems to affect the clinical outcome of some infectious diseases. In fact, the -308A allele is associated with severe septic shock and death. On this basis, we have screened healthy old subjects, nonagenarians and old patients affected by the acute phase of chronic obstructive bronchitis and bronchopneumonia of bacteria origin for the -308G/A locus (PCR-RFLP). Subjects are grouped in A+ (AG, AA genotypes) and A- (GG genotype) and data on IL-6, TNF-alpha, IL-10, NK cell cytotoxicity, zinc and metallothioneins (MTs) gene expression (RT-PCR) were stratified according to different TNF-alpha genotypes. The frequency of the A allele was increased in infected patients in comparison with healthy old controls. No differences existed between A+ and A- young adult, old and nonagenarian controls in tested parameters. Conversely, A+-infected patients displayed elevated IL-6, TNF-alpha and MTmRNA, low IL-10 coupled with impaired NK cell cytotoxicity and lower zinc ion than A- patients. However, the data reported are gender independent. Therefore, the -308A polymorphism at the locus of TNF-alpha may be one of the susceptibility factor for infectious diseases in old persons, particularly considering its association to the increased release of pro-inflammatory cytokines and to the reduction of zinc release and MTs synthesis involved in the control of the inflammatory response. These data strongly suggest that the genetic screening of the -308G/A polymorphism may be a valid tool for identification of subjects needing a more appropriate therapy when affected by acute and/or recurrent infectious diseases.

Common carotid intima-media thickness: does it matter how it is measured.

AIM: Intima media thickness (IMT) has proved to be a useful tool in predicting cardiovascular morbidity. However, methods are not well standardized, and several software packages softwares are available although they have never been compared with one other. Thus, the extrapolation of data from large studies might be questionable on routine practice. Our objective was to compare 2 software packages largely used for semi-automatic measurement of IMT. METHODS: We have measured IMT on left and right common carotid in 97 patients in standardized conditions. RESULTS: The same image was processed through the 2 software (Metris and Iôdp). There was no difference for IMT measured at various times by the same investigator, although the number of measurable points increased as the operator became more experienced. The number of measurable points was significantly greater with Iôdp. IMT was lower with Iôdp than Metris (mean difference 0.066 mm on the right side). CONCLUSION: These results suggest that the same software must be used for repeated measurements in 1 patient. One must be careful in using data from large studies or normality values. At the individual level, the use of IMT to determine vascular risk is dependent upon the software used. It is urgent to standardize the methods of IMT measurement.

[Epidemiology of atherosclerotic cardiovascular risk in HIV-1 infected patients]. / Epidémiologie du risque vasculaire d'origine athéroscléreuse chez les patients infectés par le VIH-1.

OBVIOUS EFFICACY, BUT ALSO RISKS: The administration of combinations of highly active antiretroviral since 1996 has greatly decreased morbidity and mortality in HIV-1 infected patients. Side effects associated with these treatments were rapidly described. Other than abnormal distribution of fat, the dyslipidemia and insulin-resistance leads to a pro-atherogenic profile in these patients. Since 1998, the publication of several observations of acute cardio-vascular events in HIV-1 infected patients most often treated by antiretrovirals has raised the question of the increased risk of atherosclerosis in these patients. Today, some studies have been published and several are ongoing to evaluate the cardiovascular risk in HIV-1 infected patients. TWO FUNDAMENTAL QUESTIONS: The purpose of this review was to critically report the results of published studies in order to answer the two major questions: do HIV-1 infected patients have an increased cardiovascular risk compared to non infected subjects, and what are these cardiovascular risk factors? REPLY ELEMENTS: The review of available published results is in favour of an increased risk in HIV-1 infected patients compared to the general population. However, it is difficult to evaluate the importance of the absolute risk compared to the benefits of antiretroviral treatments and also the inherent effect of antiretroviral molecules. The main risk factors seem to be classical risk factors such as smoking habits, age and dyslipidemia that are partly due themselves to highly active antiretroviral treatments

[Sensitivity and specificity of criteria of left ventricular hypertrophy for predicting cardiovascular complications in the Bordeaux cohort of hypertensive patients]. / Sensibilité et spécificité des différents critères d'hypertrophie ventriculaire gauche pour la prédiction des complications cardiovasculaires dans une cohorte d'hypertendus bordelais.

Left ventricular hypertrophy (LVH) is associated with an increased risk of cardiovascular complications independently of other known risk factors. Since 1983, we have followed up a cohort of initially untreated hypertensive patients with echocardiographic measurements of left ventricular mass (LVM). We analyzed the data on 474 patients with more than five years' follow-up to assess the prognostic value of LVM and the sensitivity and specificity of the different ways to index for LVM through ROC curves. Forty patients were lost to follow-up. The mean follow-up period was 89 +/- 31 months. A cardiovascular complication was recorded in 40 individuals. There was a strong link between increased LVM and the occurrence of complications. Indexation by body surface area or height to the power 2.7 give the [table: see text] greatest area under the curve (AUC) to discriminate between patient with or without cardiovascular events. To get the same sensitivity in females and in males for the prediction of future events, lower cut-off must be used in females.

Zinc-bound metallothioneins as potential biological markers of ageing.

Metallothioneins (MTs) (I+II) play pivotal roles in metal-related cell homeostasis because of their high affinity for metals forming clusters. The main functional role of MTs is to sequester and/or dispense zinc participating in zinc homeostasis. Consistent with this role, MT gene expression is transcriptionally induced by a variety of stressing agents to protect cells from reactive oxygen species. In order to accomplish this task, MTs induce the secretion of pro-inflammatory cytokines by immune and brain cells, such as astrocytes, for a prompt response against oxidative stress. These cytokines are in turn involved in new synthesis of MTs in the liver and brain. Such protective mechanism occurs in the young-adult age, when stresses are transient. Stress-like condition is instead constant in the old age, and this causes continuous stealing of intracellular zinc by MTs and consequent low bioavailability of zinc ions for immune, endocrine, and cerebral functions. Therefore, a protective role of zinc-bound MTs (I+II) during ageing can be questioned. Because free zinc ions are required for optimal efficiency of the immune-endocrine-nervous network, zinc-bound MTs (I+II) may play a different role during ageing, switching from a protective to a deleterious one in immune, endocrine, and cerebral activities. Physiological zinc supply, performed cautiously, can correct deficiencies in the immune-neuroendocrine network and can improve cognitive performances during ageing and accelerated ageing. Altogether these data indicate that zinc-bound MTs (I+II) can be considered as novel potential markers of ageing.

Prognostic significance of blood pressure measured on rising.

Previous works using ambulatory blood pressure (BP) monitoring demonstrated that independently of the mean level of BP, the variability in BP, or the day-night range, could have prognostic significance. We have also found that the value of BP on rising in the morning is strongly correlated with left ventricular mass of hypertensive individuals independently of the 24-h value. In the present study, we sought its predictive value for cardiovascular complications in a cohort of hypertensive patients. The population studied belongs to a cohort of initially untreated hypertensive patients recruited since 1983 and followed for more than 5 years. Patients were then treated and followed by their family doctor. At entry, all patients were equipped with a device to measure ambulatory BP. They were requested to trigger a measurement manually on rising in the morning (arising BP). The data on their outcome were collected by a physician unaware of the initial state of the patients. A total of 256 patients have been followed up for 5 years or more, 19 were lost to follow-up. The mean follow-up period was 84 +/- 29 months. Cardiovascular complications were recorded in 23 individuals. The arising systolic BP (SBP) was significantly higher in the group who presented a complication. In a stepwise discriminant analysis including age, office, fitting, arising and 24-h average SBPs only age and arising SBP entered the equation. In conclusion, the single BP value measured by an ambulatory device on rising in the morning seems more discriminant of future cardiovascular events than the value of BP measured on fitting the device or the average of three measurements taken under standardised conditions in the hospital or office.

Prognostic value of left ventricular mass and its evolution during treatment in the Bordeaux cohort of hypertensive patients.

Left ventricular hypertrophy (LVH) is associated with an increased risk of cardiovascular complications independently of other known risk factors, but so far the predictive value of its evolution under treatment has been studied relatively little. Since 1983 we have followed up a cohort of initially untreated hypertensive patients with echocardiographic measurements of left ventricular mass (LVM). We analyzed the data on 474 patients with more than 5 years of follow-up to assess the prognostic value of LVM and its evolution during treatment for high blood pressure. A total of 40 patients were lost to follow-up. The mean follow-up period was 89 +/- 31 months. A cardiovascular complication was recorded in 40 individuals. There was a strong link between increased LVM and the occurrence of complications (P < .001). At least a second determination of LVM was performed in 311 patients, and the last value before the occurrence of any complication (60 +/- 38 months after the initial examination) was retained. In this subgroup, 28 patients presented with a cardiovascular event. There was a trend toward a reduction of the incidence of events in the group with a regression of LVH as compared to the group with persistent LVH, but there was no difference when patients were split into quartiles according to LVM evolution between baseline and follow-up. Thus, the reduction of LVM on treatment was not a good marker of future cardiovascular events and its seems at least premature to say that LVM fulfils all conditions for a surrogate end point in the evaluation of morbidity/ mortality in the hypertensive.

[Homocysteinemia: role in vascular disease]. / Homocystéinémie: rôle en pathologie vasculaire.

HEREDITARY DISEASE: Hereditary anomalies of homocysteine metabolism are quite uncommon and manifest by very high homocysteine levels (> 100 mumol/l) and associated homocysteinuria. The risk of premature cardiovascular disease is high. Clinical, biological and epidemiological data accumulated since the 70 s have demonstrated that a moderately elevated serum homocysteine level favors the development of atherothrombosis. PROVEN RISK: The risk of coronary or cerebral events is 1.5 to 3-fold higher for fasting homocysteine levels above 15 mumol/l. These data show that moderately elevated homocysteine level is a powerful cardiovascular risk factor. Further information is however needed to ascertain its frequency in the population and determine whether it is a truly independent risk factor. THERAPEUTIC OPTIONS: Most cases of moderately elevated homocysteine can probably be explained by gene-environment interactions. Homocysteine levels can be lowered by oral administration of vitamin cofactors implicated in homocystein metabolisms: folic acid, vitamin B6, vitamin B12.