Background
This study was designed to assess patterns of recurrence and long-term outcomes of patients undergoing surgery for localized retroperitoneal sarcoma (RPS) after neoadjuvant high dose ...long-infusion ifosfamide (HLI) and radiotherapy (RT).
Methods
Patients received three cycles of HLI (14 g/m
2
). RT was started in combination with II cycle up to a total dose of 50.4 Gy. Surgery was scheduled 4–6 weeks after the end of RT. The primary endpoint was relapse-free survival (RFS) after surgery. Secondary endpoints were overall survival (OS), crude cumulative incidence of local recurrence (CCI-LR), and distant metastases (CCI-DM). For patients who relapsed, progression-free survival (PFS) and post-relapse OS were estimated. The trial was registered with ITASARC_*II_2004_003.
Results
Between 2003 and 2010, 83 patients were recruited. At a median follow-up of 91.7 months, 42 (56%) of 75 operated patients developed LR (
n
= 27) or DM (
n
= 10) or both LR and DM (
n
= 5) relapse. Seven-year RFS was 46.6% 95% confidence interval (CI) 29.6–52.4. Thirty-two patients died. Seven-year OS rate was 63.2% (95% CI 42.7–66.0). The corresponding CCI of LR and DM were 37.4% standard error (SE) 5.5% and 20.0% (SE 12.6%), respectively. The only factor significantly associated with LR was FNCLCC grading, whereas histological subtype resulted associated with DM. At recurrence, 24 patients (57%) underwent surgery. Two-year post-relapse PFS and OS rates for patients developing LR or DM were 14.8, 41.0, 27.3, and 63.6%, respectively.
Conclusions
LR after neoadjuvant CT-RT for RPS were predominantly infield. While almost one half of relapsed patients underwent further surgery, prognosis was poor.
We examined whether endurance performance and neuromuscular fatigue would be affected by caffeine ingestion during closed- and open-loop exercises. Nine cyclists performed a closed-loop (4,000-m ...cycling time trial) and an open-loop exercise (work rate fixed at mean power of the closed-loop trial) 60 min after ingesting caffeine (CAF, 5 mg/kg) or placebo (PLA, cellulose). Central and peripheral fatigue was quantified via pre- to post-exercise decrease in quadriceps voluntary activation and potentiated twitch force, respectively. Test sensitivity for detecting caffeine-induced improvements in exercise performance was calculated as the mean change in time divided by the error of measurement. Caffeine ingestion reduced the time of the closed-loop trial (PLA: 375.1±14.5 s vs CAF: 368.2±14.9 s, P=0.024) and increased exercise tolerance during the open-loop trial (PLA: 418.2±99.5 s vs CAF: 552.5±106.5 s, P=0.001), with similar calculated sensitivity indices (1.5, 90%CI: 0.7-2.9 vs 2.8, 90%CI: 1.9-5.1). The reduction in voluntary activation was more pronounced (P=0.019) in open- (-6.8±8.3%) than in closed-loop exercises (-1.9±4.4%), but there was no difference between open- and closed-loop exercises for the potentiated twitch force reduction (-25.6±12.8 vs -26.6±12.0%, P>0.05). Caffeine had no effect on central and peripheral fatigue development in either mode of exercise. In conclusion, caffeine improved endurance performance in both modes of exercise without influence on post-exercise central and peripheral fatigue, with the open-loop exercise imposing a greater challenge to central fatigue tolerance.
Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic ...variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.
A large proportion of the elderly population complains of depressive symptoms. The ideal antidepressant for these patients, who often suffer from numerous concomitant diseases, should not worsen ...their cognitive functions and should be free of contraindications.
To assess the effects of 2 selective serotonin reuptake inhibitors on cognitive functions in elderly depressed patients (ICD-10 criteria), we conducted a double-blind, randomized, parallel-group, multicenter study comparing paroxetine (20-40 mg daily) and fluoxetine (20-60 mg daily) treatment for 1 year. Cognitive performance was evaluated by means of the Buschke Selective Reminding Test, the Blessed Information and Memory Test, the Clifton Assessment Schedule, the Cancellation Task Test, and the Wechsler Paired Word Test; the Hamilton Rating Scale for Depression (HAM-D) and the Clinical Anxiety Scale were administered to assess the course of depressive and anxiety symptoms, respectively.
242 patients were enrolled (mean +/- SD age = 75.4 +/- 6.6 years). During the study, no deterioration of cognition was observed; on the contrary, most of the tested cognitive functions improved. Good antidepressant efficacy was maintained for over 1 year with both drugs, based on the percentage of responders to treatment (patients achieving a HAM-D total score < 10; 60%). Both drugs showed a good tolerability and safety profile.
The 2 antidepressants proved to be suitable for the long-term treatment of depression in the elderly and to be devoid of detrimental effects on the tested cognitive functions.
Thermal and hydrotime requirements for seed germination can vary with the species, environment in which the seeds developed and/or seed mass. We investigated seed germination responses to temperature ...and water potential of Aspidosperma quebracho‐blanco, Bulnesia retama, Parasenegalia visco, Parkinsonia praecox and Tecoma stans, all of which are native tree species of Chaco seasonally dry forests in northwest Argentina. We determined inter‐and intraspecific variability in seed germination through thermal and hydrotime models and correlated model parameters with environmental variables of seed provenance and seed mass. Seeds of all species germinated to high percentage over a range of temperatures. Seeds of A. quebracho‐blanco, P. praecox and T. stans were more tolerant to water stress than those of B. retama and P. visco. Thermal and hydrotime parameters for germination varied amongst species and populations. There was a negative correlation between thermal (θT(50)) and hydrotime (θH) constants and base temperature (Tb) and water potential (Ψb(50)). Seed mass correlated negatively with Tb and positively with θT(50). Species and populations were grouped according to thermal and hydrotime parameters and seed mass but not according to seed provenance. These results suggest that seed germination traits related to temperature, water potential and seed mass are species specific, and the variations within a species are probably due to a high phenotypic plasticity. These species showed a complex set of germination strategies that give them a competitive advantage in different environments, depending on dispersal time, seed mass and local environmental conditions during the germination period.
A high-fat diet increases the risk of insulin resistance, type-2 diabetes, and non-alcoholic steato-hepatitis. Here we identified two heat-shock proteins, Heat-Shock-Protein70 and Glucose-Regulated ...Protein78, which are increased in the jejunum of rats on a high-fat diet. We demonstrated a causal link between these proteins and hepatic and whole-body insulin-resistance, as well as the metabolic response to bariatric/metabolic surgery. Long-term continuous infusion of Heat-Shock-Protein70 and Glucose-Regulated Protein78 caused insulin-resistance, hyperglycemia, and non-alcoholic steato-hepatitis in rats on a chow diet, while in rats on a high-fat diet continuous infusion of monoclonal antibodies reversed these phenotypes, mimicking metabolic surgery. Infusion of these proteins or their antibodies was also associated with shifts in fecal microbiota composition. Serum levels of Heat-Shock-Protein70 and Glucose-Regulated Protein78were elevated in patients with non-alcoholic steato-hepatitis, but decreased following metabolic surgery. Understanding the intestinal regulation of metabolism may provide options to reverse metabolic diseases.
Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients.
A phase 3, multicenter, randomized, ...double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control.
The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo,
= 0.99) and day 365 (24 on reparixin vs. 15 on placebo,
= 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%,
= 0.09) when antithymocyte globulin was used as induction immunosuppression.
In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.
Bone marrow–derived mesenchymal stem cells (BM-MSCs) are stromal cells with the ability to proliferate and differentiate into many tissues. Although they represent powerful tools for several ...therapeutic settings, mechanisms regulating their migration to peripheral tissues are still unknown. Here, we report chemokine receptor expression on human BM-MSCs and their role in mediating migration to tissues. A minority of BM-MSCs (2% to 25%) expressed a restricted set of chemokine receptors (CXC receptor 4 CXCR4, CX3C receptor 1 CX3CR1, CXCR6, CC chemokine receptor 1 CCR1, CCR7) and, accordingly, showed appreciable chemotactic migration in response to the chemokines CXC ligand 12 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3), and CCL19. Using human pancreatic islets as an in vitro model of peripheral tissue, we showed that islet supernatants released factors able to attract BM-MSCs in vitro, and this attraction was principally mediated by CX3CL1 and CXCL12. Moreover, cells with features of BM-MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)–positive BM. A population of bona fide MSCs that also expressed CXCR4, CXCR6, CCR1, and CCR7 could be isolated from normal adult human pancreas. This study defines the chemokine receptor repertoire of human BM-MSCs that determines their migratory activity. Modulation of homing capacity may be instrumental for harnessing the therapeutic potential of BM-MSCs.
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