Rudolf Steiner

The effect of perfluorocarbon-based artificial oxygen carriers on tissue-engineered trachea.

The biological effect of the perfluorocarbon-based artificial oxygen carrier (Oxygent) was investigated in tissue-engineered trachea (TET) construction. Media supplemented with and without 10% Oxygent were compared in all assessments. Partial tissue oxygen tension (PtO(2)) was measured with polarographic microprobes; epithelial metabolism was monitored by microdialysis inside the TET epithelium perfused with the medium underneath. Chondrocyte-DegraPol constructs were cultured for 1 month with the medium before glycosaminoglycan assessment and histology. Tissue reaction of TET epithelial scaffolds immersed with the medium was evaluated on the chick embryo chorioallantoic membrane. Oxygent perfusion medium increased the TET epithelial PtO(2) (51.2 +/- 0.3 mm Hg vs. 33.4 +/- 0.3 mm Hg at 200 microm thickness; 12.5 +/- 0.1 mm Hg vs. 3.1 +/- 0.1 mm Hg at 400 microm thickness, p < 0.01) and decreased the lactate concentration (0.63 +/- 0.08 vs. 0.80 +/- 0.06 mmol/L, p < 0.05), lactate/pyruvate (1.87 +/- 0.26 vs. 3.36 +/- 10.13, p < 0.05), and lactate/glucose ratios (0.10 +/- 0.00 vs. 0.29 +/- 0.14, p < 0.05). Chondrocyte-DegraPol in Oxygent group presented lower glycosaminoglycan value (0.03 +/- 0.00 vs. 0.13 +/- 0.00, p < 0.05); histology slides showed poor acid mucopolysaccharides formation. Orthogonal polarization spectral imaging showed no difference in functional capillary density between the scaffolds cultured on chorioallantoic membranes. The foreign body reaction was similar in both groups. We conclude that Oxygent increases TET epithelial PtO(2), improves epithelial metabolism, does not impair angiogenesis, and tends to slow cartilage tissue formation.

Report on the international colloquium on cardio-oncology (rome, 12-14 march 2014).

Cardio-oncology is a relatively new discipline that focuses on the cardiovascular sequelae of anti-tumour drugs. As any other young adolescent discipline, cardio-oncology struggles to define its scientific boundaries and to identify best standards of care for cancer patients or survivors at risk of cardiovascular events. The International Colloquium on Cardio-Oncology was held in Rome, Italy, 12–14 March 2014, with the aim of illuminating controversial issues and unmet needs in modern cardio-oncology. This colloquium embraced contributions from different kind of disciplines (oncology and cardiology but also paediatrics, geriatrics, genetics, and translational research); in fact, cardio-oncology goes way beyond the merging of cardiology with oncology. Moreover, the colloquium programme did not review cardiovascular toxicity from one drug or the other, rather it looked at patients as we see them in their fight against cancer and eventually returning to everyday life. This represents the melting pot in which anti-cancer therapies, genetic backgrounds, and risk factors conspire in producing cardiovascular sequelae, and this calls for screening programmes and well-designed platforms of collaboration between one key professional figure and another. The International Colloquium on Cardio-Oncology was promoted by the Menarini International Foundation and co-chaired by Giorgio Minotti (Rome), Joseph R Carver (Philadelphia, Pennsylvania, United States), and Steven E Lipshultz (Detroit, Michigan, United States). The programme was split into five sessions of broad investigational and clinical relevance (what is cardiotoxicity?, cardiotoxicity in children, adolescents, and young adults, cardiotoxicity in adults, cardiotoxicity in special populations, and the future of cardio-oncology). Here, the colloquium chairs and all the session chairs briefly summarised what was said at the colloquium. Topics and controversies were reported on behalf of all members of the working group of the International Colloquium on Cardio-Oncology.

Increasing exercise in long-term survivors of pediatric cancer and their siblings: should treatment be a family affair?

I n this issue of Pediatric Blood & Cancer, Miller et al. report that exercise capacity was significantly lower in survivors of pediatric cancer—particularly in females—regardless of the type of cancer than in their siblings, whose fitness was also well below normal. Older age, higher percentages of body fat, methotrexate exposure, and extremes of left ventricular mass and function were associated with lower VO2 max, the maximum volume of oxygen that the body can use during exercise. The authors conclude that survivors of childhood cancer should be encouraged to exercise regularly to improve exercise capacity, weight, mental status, and cardiometabolic risk. However, these patients, especially those with chemotherapyor radiation-induced restrictive cardiomyopathy, should be closely monitored during exercise because they may be limited by low cardiac reserves and non-cardiac exertional symptoms. Exercise capacity is one of the most important aspects of children’s health because physical activity is the most common stress placed on the body. Exercise requires coordinated activity over time with inputs from multiple organ systems. Exercise capacity can be reduced by cancer and other diseases, by therapies and their side effects, and by deconditioning from a sedentary lifestyle [1–3]. Despite the increasing number of pediatric cancer survivors reaching adulthood (at present, more than 300,000 in the US), with considerable diseaseand treatment-related co-morbidities, few studies have compared long-term survivors of different types of pediatric cancer and treatments with their siblings on exercise capacity and risk factors for reduced physical capacity. These studies are small, single-centered, and without long-term follow-up. Miller et al. compared measures of physical fitness—VO2 max, time to anaerobic threshold and time to peak exercise—from 72 survivors with those of 32 siblings without cancer at a mean of 13.4 years after cancer diagnosis (range, 4.5–31.6 years). Survivors were similar in age at diagnosis, time since diagnosis, and chemotherapeutic agents received. Importantly, they had a mix of cancer diagnoses, which should improve the generalizability of the results. The use of sibling controls also strengthens the validity of the results. The study provides compelling evidence that survivors had significantly lower exercise capacity, less endurance, and lower anaerobic thresholds than did their siblings. The study also confirms other reports that VO2 max is lower in young adult survivors than in their siblings, even years after treatment, and that it is lower in women [3,4]. Among other implications, these findings emphasize the importance of including controls in trials of physical fitness interventions or outcomes to avoid confounding sociodemographic influences. In some women, elevated concentrations of NT-proBNP, consistent with cardiomyopathy were not associated with lower VO2 max possibly, because lower VO2 max had non-cardiac causes [3]. Abnormal left ventricular mass was related to lower VO2 max in some men, several of whom had restrictive cardiomyopathy resulting from chemotherapy or chest irradiation with left ventricular diastolic dysfunction and reduced cardiac output. Surprisingly, among all survivors, anthracycline chemotherapy was not associated with reduced VO2 max, but it was associated with reduced VO2 max in males, although not significantly so. One study of long-term survivors reported that exercise capacity was reduced after anthracycline exposure in almost all of 23 patients and that this reduction was associated with abnormal cardiac function, leading to a restrictive cardiomyopathy, rhythm disturbances, and ischemic changes [5]. Anthracycline cardiotoxicity can now be prevented by dexrazoxane, especially in girls [6], suggesting the value in determining whether dexrazoxane can also prevent an anthracycline-induced decline in exercise capacity. Can exercise training, initiated during or after treatment, increase dexrazoxane-mediated protection against delayed-onset, anthracycline-induced cardiotoxicity? Such questions can be answered with controlled trials. In both the bivariate and multivariate models, the authors report a significant association between greater body fat and lower exercise capacity, with survivors carrying more body fat, which confirms and extends previous reports [7]. The fact that exercise capacity for survivors and siblings was well below normal for age and sex may reflect, in part, the current epidemic of obesity—as the authors suggest—but may also indicate that psychological factors in the families concerned may be important. The limitations of this seminal study are clearly presented (discordant numbers of survivors and siblings, unmatched research design, only non-Hispanic white survivors, exclusion of subjects after sub-maximal tests), but they should not detract from the key findings, which should stimulate the creation of innovative, tailored physical activity programs to improve both nutritional and cardiac conditions for long-term survivors and their

Feto-maternal interface of human placenta inhibits angiogenesis in the chick chorioallantoic membrane (CAM) assay.

The rapidly growing chorionic villi of the human placenta characteristically show constant blood vessel growth and differentiation. In contrast, the underlying decidua reveals tissue remodeling without apparent angiogenesis. Using the chick chorioallantoic membrane (CAM) assay, we found marked inhibition of angiogenesis by the feto-maternal interface tissue derived from nine human placentas obtained minutes after delivery. Inhibition was prevented by the addition of monensin, which blocks the release of synthesized cell products, and was markedly reduced by drying or freezing the tissue before the assay. Histology, combined with statistical analysis of the constituent cell types, correlated inhibition of angiogenesis with the number of fetally-derived extravillous trophoblasts in the feto-maternal interface tissue. Electron microscopy revealed endothelial cell damage in preexisting small (but not large) CAM vessels. We conclude that decidual tissue inhibited angiogenesis by releasing a water soluble factor which was under apparent constant production by viable trophoblast on the CAM. The extravillous trophoblast population resembles tumor cells in its migratory and invasive properties but, in contrast to tumor induced angiogenesis, it is angiostatic, perhaps to counteract angiogenic proteins leaking from the intervillous space which could be detrimental to the maternal organism if active.

Dexrazoxane Prevention of Anthracycline Cardiomyopathy

not sure of its relevance when the more detailed measure of average nausea, which was our primary outcome, and peak nausea were each significantly improved by the addition of dexamethasone on days 2 and 3. Rather than using a simple dichotomous measure of yes or no to assess nausea rates, we used average nausea on the basis of 11 assessment points, each on a 7-point scale. The peak nausea variable in our analyses was the highest nausea reported at any of these 11 reporting points. Celio and Aapro raise an important point regarding aprepitant for control of vomiting. In our discussion of vomiting in the online-only Appendix, we noted that although aprepitant was not more effective than prochlorperazine in controlling DN when both were combined with palonosetron and dexamethasone, this lack of a statistically significant difference could be moderated with what might be a clinically relevant benefit for patients receiving aprepitant. That is, patients receiving aprepitant had a nearly statistically significant lower incidence of DV than patients receiving prochlorperazine (8% v 14%), and also had significantly less DN if DV did occur. Concerning the assessment of Celio and Aapro that our “data indicate that prochlorperazine may play a specific role in DN when acute emesis is well controlled,” we concur, provided that the word “delayed” is substituted for the word “acute.” However, we think a better way to conceptualize our findings is to say that aprepitant may be more helpful than prochlorperazine in approximately 14% of patients, either by providing more effective control of DV or by helping to control nausea when DV does occur. Given that we found no benefit of palonosetron compared with granisetron in any of our analyses and, for 86% of patients, there was no benefit of aprepitant compared with prochlorperazine, we suggest that the widespread use of palonosetron be reconsidered, and a more targeted approach be used for aprepitant. We are also pleased with the positive comments on our article by Ishiguro et al. They raise important issues not addressed in our article concerning the substantially greater costs of the newer antiemetics compared with the older generic ones, and concerning the financial support and design of large antiemetic trials. Their points are well taken.