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SummaryBackgroundThere is no standard second-line treatment after platinum–etoposide chemotherapy for gastroenteropancreatic neuroendocrine carcinoma. We aimed to evaluate the efficacy of FOLFIRI plus bevacizumab, and FOLFIRI alone, in this setting. MethodsWe did a randomised, non-comparative, open-label, phase 2 trial (PRODIGE 41-BEVANEC) at 26 hospitals in France. We included patients aged 18 years or older with locally advanced or metastatic gastroenteropancreatic neuroendocrine carcinoma or neuroendocrine carcinoma of unknown primary origin, documented progressive disease during or after first-line platinum–etoposide chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned (1:1; block size of three), without stratification, to receive FOLFIRI (irinotecan 180 mg/m 2, calcium folinate 400 mg/m 2 or levofolinate 200 mg/m 2, and fluorouracil 400 mg/m 2 bolus then 2400 mg/m 2 over 46 h) plus bevacizumab 5 mg/kg or FOLFIRI alone, intravenously, every 2 weeks until disease progression or unacceptable toxicity. Neither patients nor investigators were masked to group assignment. The primary outcome was overall survival at 6 months after randomisation, evaluated in the modified intention-to-treat population (all enrolled and randomly assigned patients who received at least one cycle of FOLFIRI). This study is now complete and is registered with ClinicalTrials.gov, NCT02820857. FindingsBetween Sept 5, 2017, and Feb 8, 2022, 150 patients were assessed for eligibility and 133 were enrolled and randomly assigned: 65 to the FOLFIRI plus bevacizumab group and 68 to the FOLFIRI group. 126 patients (59 in the FOLFIRI plus bevacizumab group and 67 in the FOLFIRI group) received at least one cycle of FOLFIRI and were included in the modified intention-to-treat population, 83 (66%) of whom were male and 43 (34%) were female, and the median age of the patients was 67 years (IQR 58–73). The primary tumour location was colorectal in 38 (30%) of 126 patients, pancreatic in 34 (27%), gastro-oesophageal in 22 (17%), and unknown in 23 (18%). After a median follow-up of 25·7 months (95% CI 22·0–38·2), 6-month overall survival was 53% (80% CI 43–61) in the FOLFIRI plus bevacizumab group and 60% (51–68) in the FOLFIRI group. Grade 3–4 adverse events that occurred in at least 5% of patients were neutropenia (eight [14%] patients), diarrhoea (six [10%]), and asthenia (five [8%]) in the FOLFIRI plus bevacizumab group, and neutropenia (seven [10%]) in the FOLFIRI group. One treatment-related death (ischaemic stroke) occurred in the FOLFIRI plus bevacizumab group. InterpretationThe addition of bevacizumab did not seem to increase the benefit of FOLFIRI with regard to overall survival. FOLFIRI could be considered as a standard second-line treatment in patients with gastroenteropancreatic neuroendocrine carcinoma. FundingFrench Ministry of Health and Roche SAS.

In this clinical trial involving patients with established cardiovascular disease, the addition of niacin to intensive statin therapy provided no additional clinical benefit over a period of 3 years, despite favorable changes in lipid levels. More than 18 million North Americans have coronary heart disease, and despite profound advances in both pharmacologic and interventional management, both morbidity and mortality remain appreciable. 1 , 2 Elevated low-density lipoprotein (LDL) cholesterol levels are an established predictor of the risk of coronary heart disease. Multiple primary and secondary prevention trials have shown a significant reduction of 25 to 35% in the risk of cardiovascular events with statin therapy 3 ; however, residual risk persists despite the achievement of target LDL cholesterol levels. Epidemiologic studies have shown that, in addition to elevated LDL cholesterol levels, low levels of high-density lipoprotein (HDL) cholesterol . . .

Key Points Hypoglycaemia, a common adverse effect of treatment of diabetes mellitus with insulin and sulphonylureas, is associated with impairment of cognitive function, which can have important consequences on everyday behaviour Adults with type 1 diabetes mellitus have ∼2 episodes of mild hypoglycaemia per week; the annual prevalence of severe hypoglycaemia is ∼30%, with several factors, such as long disease duration, increasing its incidence Adults with insulin-treated type 2 diabetes mellitus experience a lower frequency of mild and severe hypoglycaemia episodes than those with type 1 diabetes mellitus, but frequency rises progressively with increasing duration of insulin therapy Sympathoadrenal activation in response to hypoglycaemia has haemodynamic, haemostatic, haemorrheological and electrophysiological effects, all of which can affect cardiovascular function and potentially lead to myocardial ischaemia, cardiac arrhythmias or sudden death Hypoglycaemia provokes neurophysiological, electrical activity and regional vascular flow changes in the brain, which can lead to coma, seizures, vascular events such as hemiplegia, and cognitive dysfunction in young children and elderly people Prevention of hypoglycaemia depends on effective patient education, diet, exercise, frequent glucose monitoring and appropriate adjustment of therapies; new technologies, such as real-time continuous glucose monitoring and insulin pumps, might also help Hypoglycaemia is a frequent adverse effect of some therapies for diabetes mellitus, and can have serious consequences. This Review describes the epidemiology of hypoglycaemia in adults with diabetes mellitus, principally in those treated with insulin. The consequences of hypoglycaemia are discussed, with particular focus on the cardiovascular and neurological morbidities that can occur. Hypoglycaemia is a frequent adverse effect of treatment of diabetes mellitus with insulin and sulphonylureas. Fear of hypoglycaemia alters self-management of diabetes mellitus and prevents optimal glycaemic control. Mild (self-treated) and severe (requiring help) hypoglycaemia episodes are more common in type 1 diabetes mellitus but people with insulin-treated type 2 diabetes mellitus are also exposed to frequent hypoglycaemic events, many of which occur during sleep. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and leisure pursuits. In addition to accidents and physical injury, the morbidity of hypoglycaemia involves the cardiovascular and central nervous systems. Whereas coma and seizures are well-recognized neurological sequelae of hypoglycaemia, much interest is currently focused on the potential for hypoglycaemia to cause dangerous and life-threatening cardiac complications, such as arrhythmias and myocardial ischaemia, and whether recurrent severe hypoglycaemia can cause permanent cognitive impairment or promote cognitive decline and accelerate the onset of dementia in middle-aged and elderly people with diabetes mellitus. Prevention of hypoglycaemia is an important part of diabetes mellitus management and strategies include patient education, glucose monitoring, appropriate adjustment of diet and medications in relation to everyday circumstances including physical exercise, and the application of new technologies such as real-time continuous glucose monitoring, modified insulin pumps and the artificial pancreas.

Air pollution exposure increases cardiovascular morbidity and mortality and is a major global public health concern. We investigated the benefits of reducing personal exposure to urban air pollution in patients with coronary heart disease. In an open randomized crossover trial, 98 patients with coronary heart disease walked on a predefined route in central Beijing, China, under different conditions: once while using a highly efficient face mask, and once while not using the mask. Symptoms, exercise, personal air pollution exposure, blood pressure, heart rate, and 12-lead electrocardiography were monitored throughout the 24-hr study period. Ambient air pollutants were dominated by fine and ultrafine particulate matter (PM) that was present at high levels [74 μg/m³ for PM(2.5) (PM with aerodynamic diamater <2.5 µm)]. Consistent with traffic-derived sources, this PM contained organic carbon and polycyclic aromatic hydrocarbons and was highly oxidizing, generating large amounts of free radicals. The face mask was well tolerated, and its use was associated with decreased self-reported symptoms and reduced maximal ST segment depression (-142 vs. -156 μV, p = 0.046) over the 24-hr period. When the face mask was used during the prescribed walk, mean arterial pressure was lower (93 ± 10 vs. 96 ± 10 mmHg, p = 0.025) and heart rate variability increased (high-frequency power: 54 vs. 40 msec², p = 0.005; high-frequency normalized power: 23.5 vs. 20.5 msec, p = 0.001; root mean square successive differences: 16.7 vs. 14.8 msec, p = 0.007). However, mask use did not appear to influence heart rate or energy expenditure. Reducing personal exposure to air pollution using a highly efficient face mask appeared to reduce symptoms and improve a range of cardiovascular health measures in patients with coronary heart disease. Such interventions to reduce personal exposure to PM air pollution have the potential to reduce the incidence of cardiovascular events in this highly susceptible population.

Background It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson’s disease (PD) has not been studied. Objective Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD. Methods We performed a nested case–control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified. Results The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95–1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists. Conclusions This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.

On July 30, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the FDA concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with an increased risk of myocardial ischemic events. Dr. Clifford Rosen reports. On July 30, 2007, the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee of the Food and Drug Administration (FDA) convened to discuss the myocardial ischemic risk associated with rosiglitazone treatment in patients with type 2 diabetes mellitus. The joint committee, which I chaired, consisted of 24 experts in cardiovascular disease, epidemiology, biostatistics, and endocrinology. After lengthy discussions, we concluded that the use of rosiglitazone for the treatment of type 2 diabetes was associated with a greater risk of myocardial ischemic events than placebo, metformin, or sulfonylureas. That conclusion was based primarily on . . .

The angiogenic mechanism and therapeutic potential of PDGF-CC, a recently discovered member of the VEGF/PDGF superfamily, remain incompletely characterized. Here we report that PDGF-CC mobilized endothelial progenitor cells in ischemic conditions; induced differentiation of bone marrow cells into ECs; and stimulated migration of ECs. Furthermore, PDGF-CC induced the differentiation of bone marrow cells into smooth muscle cells and stimulated their growth during vessel sprouting. Moreover, delivery of PDGF-CC enhanced postischemic revascularization of the heart and limb. Modulating the activity of PDGF-CC may provide novel opportunities for treating ischemic diseases.

In patients undergoing regadenoson SPECT myocardial perfusion imaging (MPI), it is unknown how soon and at which dose intravenous aminophylline can be administered to reverse regadenoson-related adverse effects without blunting stress-induced myocardial ischemia. We analyzed the pooled database of the ASSUAGE and ASSUAGE-CKD trials (n = 548). These were double-blinded, placebo-controlled, randomized clinical trials in which 75 mg of aminophylline or placebo was administered intravenously 90 seconds following 99mTc-tetrofosmin injection. There were no statistically significant differences in summed difference score (SDS) burden (P = .87) and in the rates of myocardial ischemia (SDS ≥ 2) (P = .93) between the aminophylline (n = 274) and placebo (n = 274) groups. There was no interaction between aminophylline use and SDS as a determinant of the composite endpoint of cardiac death or MI (P = .32) or the composite endpoint of cardiac death, MI, or coronary revascularization (P = .92). In patients undergoing regadenoson-stress SPECT-MPI, the intravenous administration of 75 mg of aminophylline as early as 90 seconds after radioisotope injection does not seem to attenuate the burden of myocardial ischemia.

Ischemia-reperfusion injury (I/R injury) is a common feature of ischemic stroke which occurs when blood supply is restored after a period of ischemia. Although stroke is an important cause of death in the world, effective therapeutic strategies aiming at improving neurological outcomes in this disease are lacking. Various studies have suggested the involvement of different mechanisms in the pathogenesis of I/R injury in the nervous system. These mechanisms include oxidative stress, platelet adhesion and aggregation, leukocyte infiltration, complement activation, blood-brain barrier (BBB) disruption, and mitochondria-mediated mechanisms. Curcumin, an active ingredient of turmeric, can affect all these pathways and exert neuroprotective activity culminating in the amelioration of I/R injury in the nervous system. In this review, we discuss the protective effects of curcumin against I/R injury in the nervous system and highlight the studies that have linked biological functions of curcumin and I/R injury improvement.

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).