Bone metastases are associated with worse prognosis in patients affected by metastatic colorectal cancer treated with doublet or triplet chemotherapy plus bevacizumab: a subanalysis of the TRIBE and TRIBE2 trials.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers; ∼20% of patients have metastases at diagnosis, and 50%-60% subsequently develop metachronous metastases. Bone involvement, despite being rare, is usually associated with higher disease burden, worse prognosis, impaired quality of life, and significant health-related cost. In the last few years, following the positive results of the TRIBE and TRIBE2 trials, the association of FOLFOXIRI plus bevacizumab has become the new standard of care for metastatic CRC. Despite being highly efficacious in all subgroups, little is known about the activity of this regimen in patients with bone metastases. PATIENTS AND METHODS: We carried out a pooled analysis of TRIBE and TRIBE2 studies focusing on patients with skeletal deposits. RESULTS: Our analyses on the whole population showed that patients with baseline bone involvement reported shorter overall survival [OS; 14.0 versus 26.2 months; hazard ratio (HR) 2.04, 95% confidence interval (CI) 1.46-2.87; P < 0.001] and progression-free survival (PFS; 6.2 versus 11.1 months; HR 1.96, 95% CI 1.42-2.69; P < 0.001) compared with those without bone metastases; no significant interaction with the treatment was reported for PFS (P = 0.094) and OS (P = 0.38). Bone metastases had a negative prognostic implication in the multivariate analysis (HR 2.24, 95% CI 1.54-3.26; P < 0.001). Furthermore, patients with bone lesions at first radiological progression (including those with baseline bone metastases) had a shorter OS compared with those who progressed in other sites (10.4 versus 13.2 months; HR 1.48, 95% CI 1.15-1.91; P = 0.002). A trend toward inferior OS (7.5 versus 11 months, HR 1.50, 95% CI 0.92-2.45; P = 0.10) appeared in patients with basal skeletal deposits compared with those with bone involvement at first radiological progression. CONCLUSIONS: Our study confirmed the negative prognostic impact of bone metastases in CRC. Furthermore, we demonstrated for the first time that the survival advantage of triplet chemotherapy plus bevacizumab is maintained even in this prognostically unfavorable subgroup.

Predictors of in-hospital mortality of COVID-19 patients and the role of telemetry in an internal medicine ward during the third phase of the pandemic.

OBJECTIVE: The first pandemic phase of COVID-19 in Italy was characterized by high in-hospital mortality ranging from 23% to 38%. During the third pandemic phase there has been an improvement in the management and treatment of COVID-19, so mortality and predictors may have changed. A prospective study was planned to identify predictors of mortality during the third pandemic phase. PATIENTS AND METHODS: From 15 December 2020 to 15 May 2021, 208 patients were hospitalized (median age: 64 years; males: 58.6%); 83% had a median of 2 (IQR,1-4) comorbidities; pneumonia was present in 89.8%. Patients were monitored remotely for respiratory function and ECG trace for 24 hours/day. Management and treatment were done following the timing and dosage recommended by international guidelines. RESULTS: 79.2% of patients necessitated O2-therapy. ARDS was present in 46.1% of patients and 45.4% received non-invasive ventilation and 11.1% required ICU treatment. 38% developed arrhythmias which were identified early by telemetry and promptly treated. The in-hospital mortality rate was 10%. At multivariate analysis independent predictors of mortality were: older age (R-R for≥70 years: 5.44), number of comorbidities ≥3 (R-R 2.72), eGFR ≤60 ml/min (RR 2.91), high d-Dimer (R-R for≥1,000 ng/ml:7.53), and low PaO2/FiO2 (R-R for <200: 3.21). CONCLUSIONS: Management and treatment adherence to recommendations, use of telemetry, and no overcrowding appear to reduce mortality. Advanced age, number of comorbidities, severe renal failure, high d-Dimer and low P/F remain predictors of poor outcome. The data help to identify current high-risk COVID-19 patients in whom management has yet to be optimized, who require the greatest therapeutic effort, and subjects in whom vaccination is mandatory.

Elevated plasma free fatty acid concentrations do not modify cardiac repolarization in patients treated by electrolyte-glucose-insulin infusion.

Fat emulsion infusion is routinely used as a source of calories and essential fatty acids for critically ill patients who may be at risk for acquired ventricular repolarization alterations due either to drugs or electrolyte disturbances. The aim of this study was to evaluate whether acute elevations of plasma free fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion and sympathetic nervous system activity in patients requiring parenteral nutrition. Thirty hospitalized patients (mean +/- SD: 62 +/- 17 yr of age) requiring total parenteral nutrition received an infusion of 10% (500 ml) triacylglycerol emulsion as a source of calories (450 Kcal); on another occasion, and in random order, the same patients received an infusion of 20% (500 ml) triacylglycerol emulsion (900 Kcal). The infusion lasted 8 h and was preceded by a sc injection of heparin (5,000 U). Infusions of both 10% and 20% triacylglycerol emulsion increased plasma free fatty acid (p<0.00 1) and triacylglycerol (p<0.01) concentrations, and was associated with no significant change in mean BP, heart rate, and plasma catecholamines. At baseline, Q-Tc and Q-Tc dispersion were within the normal range (<440 milliseconds for QTc and <40 ms for QTc-d) and did not show any significant change at any time during infusion of triacylglycerol emulsion at both concentrations. In the setting of a balanced parenteral nutrition, acute elevation of plasma free fatty acid concentrations in critically ill patients do not modify ventricular repolarization.

Myocardial infarction in diabetic rats: role of hyperglycaemia on infarct size and early expression of hypoxia-inducible factor 1.

AIMS/HYPOTHESIS: This study aimed to evaluate the effects of hyperglycaemia on the evolution of myocardial infarction and the expression of the transcriptional factor for angiogenesis hypoxia-inducible factor 1alpha (HIF-1alpha) in the rat. METHODS: We studied the effects of streptozotocin induced diabetes on infarct size and HIF-1 alpha gene expression. These parameters were also evaluated in isolated hearts of non-diabetic rat, in condition of high glucose concentration. RESULTS: In streptozotocin (STZ)-diabetic rats (in vivo study), myocardial infarct size was greater (p<0.01) in hyperglycaemic rats (22 mmol/l) than in normoglycaemic (7 mmol/l) or non-diabetic rats. In euglycaemic conditions, basal expression of HIF-1alpha mRNA was not appreciable, but increased steadily after ischaemia (762+/-86%, p<0.001); this response was blunted in hyperglycaemic STZ-rats (6.8+/-6% of the control, p<0.001) and improved in euglycaemic STZ-rats (58+/-10%). The changes in myocardial Rac1 mRNA expression paralleled those of HIF-1alpha. In isolated hearts from non-diabetic rats (in vitro study), perfusion with high glucose (33 mmol/l) produced an infarct size (58+/-2% of the area at risk) not different from that obtained in hyperglycaemic STZ-rats (57+/-2%). Similar changes in the expression of HIF-1alpha and Rac1, which were prevented by glutathione infusion (0.3 mmol/l) were also observed. CONCLUSION/INTERPRETATION: Both hyperglycaemia and high glucose concentrations increased basal HIF-1alpha and Rac1 expression, suggesting a state of pseudohypoxia. These findings show that myocardial infarct size in the rat is increased in hyperglycaemic conditions and is associated with a reduced expression of the HIF-1alpha gene. These changes are reversed, totally or partially, by normoglycaemia or glutathione suggesting a role for reactive oxygen species generation brought about by hyperglycaemia.

Erectile and endothelial dysfunction in Type II diabetes: a possible link.

AIMS/HYPOTHESIS: The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. METHODS: We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the L-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. RESULTS: Mean erectile score and HbA1c were 10.5+/-5.8 and 8.3+/-1.6% in patients with erectile dysfunction, and 24.0+/-0.7 and 6.8+/-1.4% in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA1c and erectile function score in patients with erectile dysfunction (r = -0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to L-arginine was lower (p < 0.05-0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05-0.02). Indices of coagulation activation (F1 + 2 and D-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds. as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA1c, MBP response to L-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. CONCLUSION/INTERPRETATION: Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation.

High glucose induces ventricular instability and increases vasomotor tone in rats.

AIMS/HYPOTHESIS: To investigate cardiac repolarization time in streptozotocin-induced diabetic rats and isolated hearts perfused with high glucose concentration. METHODS: We studied the effects of streptozotocin-induced diabetes on the cardiac repolarisation time (Q-T interval) in Sprague-Dawley rats during a 4-day period of hyperglycaemia and a subsequent 4-day period of normoglycaemia. The Q-T interval was also evaluated in isolated hearts of non-diabetic rats, in condition of high glucose concentration. RESULTS: Hyperglycaemia in streptozotocin rats increased mean blood pressure and led to a significant (p < 0.001) prolongation of Q-T values, which normalized after 4 days of normoglycaemia with intravenous insulin infusion. Perfusion of isolated hearts in condition of high glucose concentration caused a significant prolongation of Q-T values and increased coronary perfusion pressure (p < 0.001). The effects of high glucose were completely prevented by glutathione and almost completely by L-arginine, the natural precursor of nitric oxide. In a condition of normal glucose, L-NAME, an inhibitor of endogenous nitric oxide synthesis, increased both Q-T and CPP values to levels similar to those induced by high glucose (p < 0.001). Verapamil completely prevented Q-T lengthening and reduced by about two-thirds CPP values (p < 0.001). CONCLUSION/INTERPRETATION: Streptozotocin-diabetes in rats produces significant haemodynamic and electric perturbations that are reversed by normoglycaemia. Moreover, high glucose increases Q-T and CPP values in the isolated hearts of non-diabetic rats. The latter effects are reversed by glutathione and L-arginine, partially reversed by verapamil and mimicked by L-NAME. By increasing the production of free radicals, high glucose could reduce nitric oxide availability to target cells inducing a state of increased vasomotor tone and ventricular instability.

Elevated plasma fatty acid concentrations prolong cardiac repolarization in healthy subjects.

BACKGROUND: High fatty acid concentrations have been shown to stimulate sympathetic nervous system activity, which may modify ventricular repolarization and thus the Q-T interval on electrocardiogram recordings. OBJECTIVE: The aim of this study was to investigate whether acute elevations of plasma fatty acid concentrations influence the corrected Q-T interval (Q-Tc), Q-Tc dispersion, and sympathetic nervous system activity in healthy nonobese subjects. DESIGN: Thirty-two healthy subjects (x +/- SD: 48+/-7 y of age) received an infusion of 10% triacylglycerol emulsion plus heparin (a bolus of 200 U followed by 0.2 U min(-1) * kg body wt(-1) for 180 min); on another occasion and in random order, the same subjects received a saline infusion. RESULTS: Compared with the saline infusion, infusion of 10% triacylglycerol emulsion increased plasma fatty acids (P<0.001) and was associated with an increase in mean blood pressure (P<0.05), heart rate (P<0.05), Q-Tc (P<0.01), Q-Tc dispersion (P<0.01), and plasma epinephrine (P<0.005). Furthermore, individual changes in plasma epinephrine correlated with changes in Q-Tc (r = 0.60, P<0.001) and Q-Tc dispersion (r = 0.53, P< 0.02) even after adjustment for age, sex, and body mass index (P<0.03 for all correlations). Only changes in plasma fatty acids (P = 0.04) and plasma epinephrine (P = 0.006) concentrations were significantly and independently associated with the lengthening of the Q-T interval. CONCLUSION: Our study showed that elevated plasma fatty acid concentrations might affect cardiac repolarization, at least in part because of an increase in plasma catecholamines.

Hemodynamic effects of acute hyperglycemia in type 2 diabetic patients.

OBJECTIVE: The aim of the present study was to evaluate the hemodynamic effects of acute hyperglycemia in type 2 diabetic patients and to see whether these effects are related to changes in nitric oxide (NO) availability. RESEARCH DESIGN AND METHODS: Twenty newly diagnosed complication-free diet-treated type 2 diabetic patients participated in the study. All patients underwent 3 hyperglycemic glucose clamps in random order: 1) the control study was performed with plasma glucose clamped at 18 mmol/l for 2 h; 2) the octreotide study with plasma insulin blocked at basal levels during the clamp; and 3) the L-arginine study with L-arginine (1 g/min) infused during the last 30 min of the clamp. A group of 8 patients also underwent a glutathione infusion (600 mg as an intravenous bolus followed by 5 mg/min infusion) during the clamp. RESULTS: During hyperglycemia, there were significant increments of systolic (sBP) (from 115.5 +/- 9.1 to 120.3 +/- 8.2 mmHg, P < 0.01) and diastolic (dBP) (from 70.3 +/- 7.8 to 79.7 +/- 5.3 mmHg, P < 0.01) blood pressure, as well as heart rate (from 75.2 +/- 7.8 to 80.8 +/- 5.4 beats/min, P < 0.01) and plasma catecholamines (P < 0.05). Squatting ratios, a measure of the baroreflex activity, significantly deteriorated after hyperglycemia (P < 0.01). The infusion of octreotide, used to avoid the possible confounding influence of insulin, did not change the hemodynamic effects of hyperglycemia. Glutathione, a free radical scavenger, completely prevented the vascular effects of hyperglycemia. L-Arginine produced a fall in sBP and dBP to baseline values and normalized squatting ratios. CONCLUSIONS: Acute hyperglycemia in newly diagnosed type 2 diabetic patients causes significant hemodynamic changes that are independent of endogenous insulin and are prevented by glutatione and reversed by L-arginine, suggesting an interference with endogenous NO availability. These observations could help explain the adverse cardiovascular effects of hyperglycemic spikes.

The effect of acute hyperglycaemia on QTc duration in healthy man.

AIMS/HYPOTHESIS: Prolongation of heart rate-adjusted QT (QTc) is associated with an increased risk of coronary heart disease and sudden death. The objective of this study was to investigate whether acute increases of plasma glucose concentrations in healthy subjects could influence QTc and QTc dispersion. METHODS: Plasma glucose concentrations were quickly raised to 15 mmol/l in 20 healthy subjects (10 men/10 women) and maintained for 2 h. On another occasion, and in random order, all subjects underwent the same hyperglycaemic clamp as above and an infusion of the somatostatin analogue octreotide (25 microg as iv bolus followed by a 0.5 g/min infusion) to block the release of endogenous insulin. RESULTS: Systolic and diastolic blood pressures, heart rate and plasma catecholamine concentrations showed significant increases (p < 0.05) starting after 60 min of hyperglycaemia. QTc, QTc dispersion and PR interval also showed significant increments at 120 min of the hyperglycaemic clamp. The infusion of octreotide did not influence QTc duration, QTc dispersion, PR interval and the haemodynamic effects of acute hyperglycaemia. CONCLUSION/INTERPRETATION: The results show that acute hyperglycaemia produces significant increments of QTc and QTc dispersion in normal subjects. In this context, endogenously released insulin during acute hyperglycaemia seems to play a minor part.

Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins.

CONTEXT: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. OBJECTIVE: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. DESIGN AND SETTING: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. SUBJECTS: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. INTERVENTIONS: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. MAIN OUTCOME MEASURES: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. RESULTS: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) micromol/L at baseline to 27.1 (6.7) micromol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] micromol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] micromol/L; P=.75). Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=.009) and blood viscosity (-3.0% [1.2%]; P=.04) declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=.24). CONCLUSION: Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism.

Hemodynamic and metabolic effects of transdermal clonidine in patients with hypertension and non-insulin-dependent diabetes mellitus.

The aim of this study was to evaluate the effect of transdermal clonidine on hemodynamic and metabolic parameters in patients who have elevated blood pressure and non-insulin-dependent diabetes mellitus (NIDDM). After a 2-week run in placebo period, 20 NIDDM patients who had diastolic blood pressure in the range of 90 to 105 mm Hg underwent a randomized, single blind, placebo controlled, cross-over study of 4 week treatment with clonidine (transdermal patch 2.5 mg/week) or placebo (inactive patch). Compared with placebo, clonidine significantly reduced systolic (153 +/- 6 v 163 +/- 8) and diastolic (88 +/- 2 v 98 +/- 3.5 mm Hg, P = .001) blood pressure, left ventricular mass (94 +/- 11 v 99 +/- 12 g/m2, P < .01) and fasting glucose levels. Total glucose disposal (glucose clamp) was 6.5 +/- 1.5 with placebo and 7.1 +/- 1.6 mg/kg/min with clonidine (P < .01). Oxidative glucose disposal (indirect calorimetry) was also greater after clonidine. Plasma glucose, insulin, and C-peptide responses following oral glucose (75 g) were significantly lower after clonidine, as well as urinary albumin excretion. Transdermal clonidine is effective in reducing blood pressure in hypertensive NIDDM patients and is well tolerated. It may be useful to reduce the cardiovascular impact of hypertension in diabetes mellitus.

L-arginine for testing endothelium-dependent vascular functions in health and disease.

The objective of this study was to assess the role of L-arginine, the natural precursor of nitric oxide, for testing endothelial function in physiological and pathophysiological conditions. In an initial study of 20 healthy subjects, mean blood pressure decreases in response to increasing doses of L-arginine (1, 2, 3, and 5 g) were 1.1 +/- 1.3, 2.6 +/- 1.5, 7.6 +/- 1.3, and 7.7 +/- 2 mmHg, respectively, P < 0.01. The enantiomer D-arginine (3 g) did not produce any change in mean blood pressure and platelet aggregation (n = 10), whereas the infusion of the L-arginine analog NG-monomethyl-L-arginine (6 mg/min) reduced by 70% the vascular effects of L-arginine. In the whole population of 52 healthy subjects, there was an inverse correlation between age and blood pressure or platelet aggregation changes after L-arginine. Compared with matched controls (n = 20), the changes in mean blood pressure and platelet aggregation after L-arginine were significantly lower in non-insulin-dependent diabetic (n = 20) and hypercholesterolemic (n = 16), but not in hypertensive (n = 20), subjects. Changes in blood viscosity were significantly lower only in hypercholesterolemic subjects. Our findings suggest that an intravenous bolus of 3 g L-arginine may be a simple and useful tool to assess the endothelial control of blood pressure and platelet activity in health and disease.

Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia.

BACKGROUND: Acute hyperglycemia may increase vascular tone in normal humans via a glutathione-sensitive, presumably free radical-mediated pathway. The objective of this study was to investigate whether or not the vascular effects of hyperglycemia are related to reduced availability of nitric oxide. METHODS AND RESULTS: Acute hyperglycemia (15 mmol/L, 270 mg/dL) was induced in 12 healthy subjects with an artificial pancreas. Systolic and diastolic blood pressures, heart rate, and plasma catecholamines showed significant increases (P < .05) starting after 30 minutes of hyperglycemia; leg blood flow decreased significantly (15%; P < .05) at 60 and 90 minutes. Platelet aggregation to ADP and blood viscosity also showed significant increments (P < .05). The infusion of L-arginine (n = 7, 1 g/min) but not D-arginine (n = 5, 1 g/min) or L-lysine (n = 5, 1 g/min) in the last 30 minutes of the hyperglycemic clamp completely reversed all hemodynamic and rheological changes brought about by hyperglycemia. Infusion of NG-monomethyl-L-arginine (L-NMMA; 2 mg/min) to inhibit endogenous nitric oxide synthesis in 8 normal subjects produced vascular effects qualitatively similar to those of hyperglycemia but quantitatively higher (P < .05); however, heart rate and plasma catecholamine levels decreased during L-NMMA infusion, presumably as a consequence of baroreflex activation. Infusion of L-NMMA during hyperglycemia produced changes not different from those obtained during infusion of L-NMMA alone. CONCLUSIONS: The results show that acute hyperglycemia in normal subjects causes significant hemodynamic and rheological changes that are reversed by L-arginine. Moreover, the effects of hyperglycemia are mimicked to a large extent, but not entirely, by infusion of L-NMMA. This suggests that hyperglycemia may reduce nitric oxide availability in humans.