Supportive Care in Pediatric Oncology: Opportunities and Future Directions.

The optimization of outcomes for pediatric cancer patients relies on the successful advancement of supportive care to ease the treatment burden and mitigate the long-term impacts of cancer therapy. Advancing pediatric supportive care requires research prioritization as well as the development and implementation of innovations. Like the prevailing theme throughout pediatric oncology, there is a clear need for personalized or precision approaches that are consistent, evidence-based, and guided by clinical practice guidelines. By incorporating technology and datasets, we can address questions which may not be feasible to explore in clinical trials. Now is the time to listen to patients' voices by using patient-reported outcomes (PROs) to ensure that their contributions and experiences inform clinical care plans. Furthermore, while the extrapolation of knowledge and approaches from adult populations may suffice in the absence of pediatric-specific evidence, there is a critical need to specifically understand and implement elements of general and developmental pediatrics like growth, nutrition, development, and physical activity into care. Increased research funding for pediatric supportive care is critical to address resource availability, equity, and disparities across the globe. Our patients deserve to enjoy healthy, productive lives with optimized and enriched supportive care that spans the spectrum from diagnosis to survivorship.

17 alpha-O-(aminoalkyl)oxime derivatives of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane as inhibitors of Na(+),K(+)-ATPase at the digitalis receptor.

The synthesis and binding affinities to the digitalis Na(+),K(+)-ATPase receptor of a series of 3 beta,14 beta-dihydroxy-5 beta-androstane and 3 beta-hydroxy-14-oxoseco-D-5 beta-androstane derivatives bearing a 17 alpha-(aminoalkoxy)imino chain are reported; some derivatives were also studied for their inotropic activity. Our recently proposed model of interaction of molecules with the digitalis receptor was used to design these compounds. On that basis, the possibility to design novel potent inhibitors of Na(+),K(+)-ATPase without being constrained by the stereochemistry of the classical digitalis skeleton in the D-ring region was predicted. The binding affinities of the most potent compounds in the two series, (EZ)-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-5 beta-androstane-3 beta,14 beta-diol (6f) and (EZ)-3 beta-hydroxy-17 alpha-[2-[(2-aminoethoxy)imino]ethyl]-14,15-seco-5 beta-androstan-14-one (24c) are higher than that of the potent natural compound digitoxigenin, despite the unusual alpha-exit of the substituent in position 17 of 6f or the disruption of the D-ring in 24c. These results further support the validity of our recently proposed model of binding at the digitalis receptor. Results of the inotropic tests on guinea pig atrium deserve further investigation on the pharmacological profile of these derivatives.

CHF-1024, a DA2/alpha2 agonist, blunts norepinephrine excretion and cardiac fibrosis in pressure overload.

We compared the effects of an ACE inhibitor, captopril, with those of a DA2-dopaminergic/alpha2-adrenergic receptor agonist (CHF-1024) on neuroendocrine activation and cardiac fibrosis in a model of pressure-overload hypertrophy. Interrenal aortic stenosis was performed in 89 rats, treated with CHF-1024 (0.33, 2 or 6 mg kg(-1) day(-1)), or captopril (1 g/L). Hemodynamic variables were recorded. Cardiac and renal weights, plasma aldosterone, renin activity and urinary catecholamine excretion were measured, as well as cardiac collagen. Blood pressure was lower in stenotic animals treated with CHF-1024 compared to vehicle (161 +/- 10 vs 219 +/- 10 mmHg, p < 0.01), but LV weight was similar. CHF-1024 elicited a marked dose-dependent attenuation of urinary norepinephrine excretion (1.80 +/- 0.18 in controls compared to 0.40 +/- 0.14 microg/24 h at the highest dose, p < 0.01) and of LV perivascular fibrosis. Captopril provoked a marked hypotension, reduced cardiac and body weights, plasma aldosterone concentration, dopamine excretion and perivascular collagen. The DA2/alpha2 agonist CHF-1024 effectively blunts adrenergic drive and cardiac fibrosis in a rat model of pressure overload.

Effects of a DA2/alpha2 agonist and a beta1-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion.

Renin-angiotensin-aldosterone and sympathetic nervous systems overactivity play a major role in worsening the extent of heart failure. Attenuation of neurohumoral activation with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers has proven beneficial in congestive heart failure. Because ACE inhibition is a recommended treatment for heart failure, this study was designed to test the effects on neurohumoral activation, hemodynamics, and left ventricular (LV) volume of the combination of an ACE inhibitor (delapril) with a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) or a beta1-adrenoceptor antagonist (metoprolol) after a moderate to large myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 134 rats, and six were not operated on. After 2 months, the animals with ECG evidence of MI were treated for 1 more month with CHF- 1024, 0.33 mg/kg/day or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps, in addition to delapril (6 mg/kg/day) in the drinking water. Daily urinary excretion of norepinephrine (NE) and circulating concentration were measured. Hemodynamic variables were measured, and three-dimensional morphometric analysis was done on the diastole-arrested hearts to quantify infarct size and LV geometry. In conscious animals, delapril alone or with CHF-1024 or metropolol did not modify heart rate or systolic blood pressure. Both combination treatments, however, significantly reduced heart rate in anesthetized animals compared with the group receiving vehicle. Infarct size was not different between treatments, averaging 20-22% of LV volume. The threefold increase of LV chamber volume in infarcted rats was significantly attenuated by delapril alone or with CHF-1024 or metoprolol (-37 to -44%, p<0.05). Treatment with a combination of the ACEi and CHF-1024 tended to normalize the shape of the LV cavity. Urinary NE excretion was unaffected by delapril alone but was reduced by the addition of CHF-1024 or metoprolol. In conclusion, 1 month of treatment with doses of delapril having no hemodynamic effect, reduced LV volume in a model of chronic heart failure. When CHF-1024 or metoprolol was given with delapril, sympathetic activation decreased with no unwanted effects, such as excessive hypotension.

Within-patient variability of hormone and cytokine concentrations in heart failure.

Several studies on disease and treatment effects on neurohormones have been conducted with small numbers of patients, using one blood sample as representative of their states. The aim of this study was to assess the within-patient variability of plasma concentrations of several hormones and cytokines of recent interest, in patients with moderate heart failure and controlled stable background therapy over 3 weeks. Blood for neurohormone and cytokine assays was sampled in duplicate from 18 patients with moderate heart failure. After an initial visit, the patients were kept on stable therapy until the second blood sampling 21 +/- 3 days later. The plasma concentrations of several neurohormones (endothelin, renin, angiotensin II, aldosterone, norepinephrine) and cytokines (interleukin-6 (IL-6), interleukin-13 (IL-13), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF) and soluble receptor type I of tumour necrosis factor-alpha, (sTNF-RI) were measured with immunochemical methods. Some cytokines (IL-13, CNTF and LIF) were not detected. Despite clinically satisfactory ACE inhibition, circulating angiotensin II and aldosterone levels were still elevated in some patients, suggesting aldosterone escape. The between-visit agreement of plasma concentrations measured in duplicate was less than 35% for all circulating factors, except renin which showed a higher variability throughout the 3-week study period.

Comparative efficacy of a DA2/alpha2 agonist and a beta-blocker in reducing adrenergic drive and cardiac fibrosis in an experimental model of left ventricular dysfunction after coronary artery occlusion.

Attenuation of neuroendocrine activation may be beneficial in congestive heart failure. Sympathetic nervous system overactivity can be reduced by receptors blockade or by reducing norepinephrine (NE) spillover. This study evaluated and compared the effects of a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) and a beta1-adrenoreceptor antagonist in terms of hemodynamics, ventricular remodeling, beta-adrenergic drive, and cardiac fibrosis after myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 213 rats, whereas 12 were left unoperated on. After 2 months, the operated-on animals were treated for 1 more month with CHF-1024 at either 0.33 mg/kg/day (low dose) or 1 mg/kg/day (high dose) or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps. Plasma concentration and urinary excretion of NE were measured before the rats were killed. Hemodynamic variables were measured and morphometric analysis was done on the diastole-arrested hearts to quantify left ventricular remodeling and interstitial collagen density. Metoprolol treatment tended to normalize LV end-diastolic pressure (LVEDP). CHF-1024 at either dose, and metoprolol, significantly reduced collagen deposition in LV of infarcted animals (from 8.8 +/- 0.5% LV area in vehicle-treated rats to 6.6 +/- 0.2% or 6.4 +/- 0.2% after the low or high dose of CHF-1024, respectively; p < 0.05). Similarly, CHF-1024 at either dose reduced the plasma concentration of NE (from 224 +/- 53 pg/ml to 60 +/- 7 pg/ml or 87 +/- 13 pg/ml; p < 0.05) and urinary excretion of NE in rats with MI, whereas beta-blockade did not affect these variables. In conclusion, CHF-1024 infused for 1 month to rats with LV dysfunction reduced heart rate, NE spillover, and collagen deposition, without unwanted effects, only appearing at the higher dose. Effective beta-blockade with metoprotol reduced LVEDP with no effects on heart function. Neither DA2/alpha2 stimulation nor beta-blockade altered LV remodeling after coronary artery ligation.

A method for assessing catheter patency in implanted pumps for long-term intraperitoneal insulin delivery.

Catheter complications are a common problem during long-term insulin therapy with implanted pumps. The purpose of this study was to test the feasibility of imaging intraperitoneal catheters with technetium (Tc) 99m in implantable devices for insulin delivery. Testing physical stability of an insulin/Tc 99 mixture did not show formation of insulin aggregates during a period up to 48 h on a rotating wheel. Five hundred microCurie (equal to 18 MBq) of Tc 99m were injected in the flush port of a pump for intraperitoneal insulin delivery implanted in patients with type I (insulin dependent) diabetes mellitus, and gamma camera images were obtained for 30 min. In patent catheters the tracer rapidly imaged the whole length of the catheter while in occluded catheters the tracer remained in the flush port, imaging only the portion of the catheter before the occlusion. In patent catheters in which insulin absorption was impaired, the tracer rapidly imaged the whole length of the catheter, but its removal from the peritoneum was delayed. Tc 99m imaging of intraperitoneal catheters for insulin delivery can be used to assess catheter patency and impaired delivery into the peritoneal cavity.

Spectral analysis of 24 h blood pressure monitoring in the assessment of trough: peak ratio. A randomized, placebo-controlled, cross-over comparison of ramipril and enalapril.

BACKGROUND: The ratio between the magnitude of blood pressure reduction during the steady-state dosage interval (trough) and the maximum blood pressure reduction (peak) is an integrated in-vivo index both of the pharmacokinetic properties and of pharmacodynamic activity of an antihypertensive drug. Angiotensin converting enzyme inhibitors are often characterized by a low (often lower than 50%) trough: peak ratio but no direct drug comparisons are available. OBJECTIVE: To compare the absolute blood pressure reduction and the trough: peak ratio of daily doses of two angiotensin converting enzyme inhibitors, 5 mg ramipril and 10 mg enalapril. METHOD: After a 1-month wash-out and a 2-week placebo run-in, 25 mild hypertensives aged 47 +/- 4 years (17 men and eight women) were randomly assigned to treatments separated by a 2-week interval. Ambulatory blood pressure monitoring was performed and trough: peak ratio was calculated by the fast Fourier transform analysis of placebo-effect-subtracted data. RESULTS: After 1 month of ramipril treatment, 24 h blood pressure decreased from 139 +/- 10 to 129 +/- 11 mmHg for systolic (P < 0.05) and from 89 +/- 8 to 81 +/- 5 mmHg for diastolic blood pressure (P < 0.01). Also enalapril treatment caused a significant 24 h reduction in blood pressure both for systolic (to 132 +/- 7 mmHg, P < 0.05) and for diastolic blood pressure (to 84 +/- 5 mmHg, P < 0.05). Placebo caused a 24 h reduction in blood pressure (to 136 +/- 8 mmHg for systolic and 87 +/- 5 mmHg for diastolic blood pressure, NS, versus wash-out period). The two drugs were equally effective in reducing ambulatory blood pressure, but ramipril produced a trough: peak ratio significantly higher than that with enalapril both for systolic (48 +/- 11%, range 34-74%, versus 38 +/- 11%, range 21-67%, P < 0.005)and for diastolic blood pressure (47 +/- 11%, range 30-79 %, versus 37 +/- 12%, range 21-68%, P < 0.05). CONCLUSION: The low trough : peak ratios could have been due to the daily pattern of blood pressure of mild hypertensives, many of whom are normotensives at night-time, so that the main antihypertensive effect is exerted during daytime rather than during the night or early morning.

Digitalis-like compounds: synthesis and biological evaluation of seco-D and D-homo derivatives.

The synthesis of seco-D and D-homo digitalis derivatives, from the carda-14,20(22)-dienolide 1, is described. Selective ozonolysis gave the seco-D 14-ketoaldehyde 2a. Modification of the two carbonyl groups and of the alpha, beta-unsaturated lactone ring of the seco-D 14-ketoaldehyde 2a allowed preparation of derivatives with a broad range of binding affinity to the Na+, K(+)-ATPase receptor. Some of the seco-D derivatives (10, 11b, and 13b) showed a binding affinity similar to that of digitoxigenin, demonstrating that the D-ring is not essential for recognition by the digitalis receptor. In the class of D-homo derivatives the highest binding value, about 15 times lower than that of digitoxigenin, was that of the C/D cis compound 29b; the C/D trans analog 28b showed a 7-fold decrease in binding affinity, indicating that the C/D configuration plays an important role in D-homo derivatives as in the classical digitalis compounds.

Efficacy of femoral intra-arterial administration of teicoplanin in gram-positive diabetic foot infections.

In this study the efficacy and safety femoral intra-arterial administration of teicoplanin in the treatment of diabetic foot infections caused by gram-positive bacteria were evaluated. Twenty-five hospitalized diabetic patients with foot ulcers or with foot ulcers and metatarsophalangeal osteomyelitis were included in the study. In the ulcers Staphylococcus aureus was present alone in 16 patients and was associated with Pseudomonas aeruginosa in 2 patients, with Candida albicans in 2, and with coagulase-negative Staphylococcus in 1 patient. In 4 patients other gram-positive bacteria were isolated. All isolated strains were resistant to various antibiotics tested. Teicoplanin, 200 mg, was administered once a day by femoral intra-arterial injection for an average period of 14.72 +/- 7.16 days (range ten to thirty-six days). Six patients were treated with an additional antibiotic intramuscularly or intravenously because of a mixed infection. At the end of the therapy microbiological assessment confirmed that gram-positive infection was eliminated in all patients. Clinical outcome demonstrated that healing occurred in 18 patients (72%) and improvement in 7 patients (28%). No adverse drug reactions were observed during the treatment. The results demonstrate that femoral intra-arterial administration of teicoplanin was highly effective in skin- and bone-infected lesions in the diabetic foot. This method may represent a further advantage in management of this severe diabetic complication.

Intraperitoneal insulin absorption after long-term intraperitoneal insulin therapy.

OBJECTIVE: To evaluate insulin absorption through the peritoneal membrane after long-term intraperitoneal insulin therapy using an implanted programmable device. RESEARCH DESIGN AND METHODS: Seven insulin-dependent diabetes mellitus (IDDM) patients implanted with a programmable pump were studied after 3 and 30 months of intraperitoneal insulin therapy. A 20-min square wave infusion of 15 IU of insulin was administered in the peritoneal space, and plasma glucose and plasma free insulin levels were monitored for 180 min. Hypoglycemia was prevented by intravenous glucose infusion. RESULTS: After 30 months of intraperitoneal insulin therapy, plasma free insulin profiles following the administration of insulin in the peritoneal space were similar to those observed at the beginning of this mode of therapy. CONCLUSIONS: In IDDM patients, intraperitoneal insulin absorption does not change after long-term intraperitoneal insulin therapy using an implanted device.

[Hemodynamic consequences of paracentesis, evaluated by a bloodless method, in liver cirrhosis]. / Conseguenze emodinamiche della paracentesi, valutate con metodica incruenta, nella cirrosi epatica.

Haemodynamic changes caused by paracentesis in cirrhosis of the liver with ascites have been studied, using systolic times in 11 patients. The use of a non-surgical technique made it possible to repeat the test after a 24 hour interval. The basal TCI and PEP, expressed as percentage variation of the normal frequency value, were significantly lowered, but the TET was substantially unchanged. The PEP/TET ratio was also reduced. The PEP and TCI tend to increase 24 hours after paracentesis, though not to a uniform degree, while the TET increases slightly and diminishes 24 hours later. The PEP/TET ratio gets significantly worse (P = 0.05) compared to values 24 hours after the end of paracentesis, but not in comparison to initial values. These data reveal that cardiac capacity and myocardial contractility undergo no significant variations either immediately after the end of paracentesis or 24 hours later. This procedure is therefore indicated in cases where ascites interferes with cardiorespiratory function. In addition to haemodynamic changes, significant variations in potassaemia and ammoniaemia needing accurate monitoring were observed in individual cases.