Reliability of the bony anatomy in image-guided stereotactic radiotherapy of brain metastases

PURPOSE: To evaluate whether the position of brain metastases remains stable between planning and treatment in cranial stereotactic radiotherapy (SRT). METHODS AND MATERIALS: Eighteen patients with 20 brain metastases were treated with single-fraction (17 lesions) or hypofractionated (3 lesions) image-guided SRT. Median time interval between planning and treatment was 8 days. Before treatment a cone-beam CT (CBCT) and a conventional CT after application of i.v. contrast were acquired. Setup errors using automatic bone registration (CBCT) and manual soft-tissue registration of the brain metastases (conventional CT) were compared. RESULTS: Tumor size was not significantly different between planning and treatment. The three-dimensional setup error (mean +/- SD) was 4.0 +/- 2.1 mm and 3.5 +/- 2.2 mm according to the bony anatomy and the lesion itself, respectively. A highly significant correlation between automatic bone match and soft-tissue registration was seen in all three directions (r >/= 0.88). The three-dimensional distance between the isocenter according to bone match and soft-tissue registration was 1.7 +/- 0.7 mm, maximum 2.8 mm. Treatment of intracranial pressure with steroids did not influence the position of the lesion relative to the bony anatomy. CONCLUSION: With a time interval of approximately 1 week between planning and treatment, the bony anatomy of the skull proved to be an excellent surrogate for the target position in image-guided SRT.     

Unmet needs and health care utilization in young adults with cerebral palsy

PURPOSE: To gain insight into the unmet needs and utilization of health care of young adults with cerebral palsy (CP) and to explore relations between unmet needs, health care utilization and subject characteristics. METHOD: A cross-sectional study was performed in 29 young adults with CP without severe learning disabilities (IQ > 70). Subject characteristics such as age, gender, limb distribution, level of gross motor functioning, level of education and perceived participation and autonomy were measured. Outcome measures were the Southampton Needs Assessment Questionnaire, Impact on Participation and Autonomy and a questionnaire on health care utilization. RESULTS: Young adults with CP reported unmet needs mostly on information (79%), mobility (66%) and health care (66%). About half of the participants visited a rehabilitation physician (52%) or a physical therapist (55%) in the past year. Participants with lower levels of gross motor functioning were found to have more unmet needs and visited various health care professionals more often than young adults with higher levels of gross motor functioning. However, participants with higher levels of gross motor functioning still reported several unmet needs. CONCLUSIONS: Although young adults with CP frequently receive treatment from health care professionals, they indicate unmet needs with respect to several areas such as information on diagnosis, functional mobility and formal health care. In the treatment of young adults with CP, attention should be paid to these aspects.     

Local hyperthermia in prostate cancer

We conducted a clinical trial evaluating the effects of hyperthermia in patients with carcinoma of the prostate, treating 20 patients with newly diagnosed carcinoma of the prostate with local microwave hyperthermia (915 MHz). Histological examination revealed hypoeremic effects and diffuse oedema with interstitial lymphoplasmatic cellular infiltration. However, necrotic tumour cells were not found in any of specimens. A second series consisted of 10 patients with metastasizing carcinoma of the prostate (n = 4 untreated; n = 6 hormone-resistant). For 8 weeks, epirubicin was administered once weekly, followed each time by local microwave hyperthermia 1 h later. The efficacy was evaluated according to the EORTC criteria. In 4 patients with untreated carcinoma no change was found in the size of the prostate or metastases. In 3 of the 6 patients with hormone-resistant carcinoma progressive disease was found, while the other 3 had stable disease. Only in 2 of the 10 patients did the grading of tumour regression reveal any improvement. Cytophotometric studies showed no change of DNA ploidy. Currently we consider hyperthermia unsuitable as monotherapy for carcinoma of the prostate, and the combination of epirubicin and hyperthermia is no more favourable than monotherapy with epirubicin alone. Further studies are necessary to evaluate other cytotoxic regimens and various patterns of application for hyperthermia.     

Exploring the reference point in prospect theory: gambles for length of life.

Attitude toward risk is an important factor determining patient preferences. Risk behavior has been shown to be strongly dependent on the perception of the outcome as either a gain or a loss. According to prospect theory, the reference point determines how an outcome is perceived. However, no theory on the location of the reference point exists, and for the health domain, there is no direct evidence for the location of the reference point. This article combines qualitative with quantitative data to provide evidence of the reference point in life-year certainty equivalent (CE) gambles and to explore the psychology behind the reference point. The authors argue that goals (aspirations) in life influence the reference point. While thinking aloud, 45 healthy respondents gave certainty equivalents for life-year CE gambles with long and short durations of survival. Contrary to suggestions from the literature, qualitative data argued that the offered certainty equivalent most frequently served as the reference point. Thus, respondents perceived life-year CE gambles as mixed. Framing of the question and goals set in life appeared to be important factors behind the psychology of the reference point. On the basis of the authors' quantitative and qualitative data, they argue that goals alter the perception of outcomes as described by prospect theory by influencing the reference point. This relationship is more apparent for the near future as opposed to the remote future, as goals are mostly set for the near future.     

Effects of consumption of Brussels sprouts on intestinal and lymphocytic glutathione S-transferases in humans

A high intake of glucosinolate-containing cruciferous vegetables,such as Brussels sprouts (Brassica oleraceae), has been linkedto a decreased cancer risk, but the underlying mechanism isstill unclear. The aim of this study was to reveal possiblemodulating effects of consumption of Brussels sprouts on duodenal,rectal and lymphocytic (i) glutathione S-transferase (GST) enzymeactivity, (ii) GST isozyme levels and (iii) glutathione (GSH)content. Ten healthy non-smoking volunteers were randomly assignedto two groups in a cross-over design. Five persons started ona glucosinolate-free diet (control period), while the otherfive consumed 300 g/day cooked Brussels sprouts, at the expenseof 300 g glucosinolate-free vegetables (sprouts period). After7 days the regimen was changed for a further week. At the endof both periods blood samples and duodenal and rectal biopsieswere taken. Mean GST activity showed marked differences betweenduodenal, rectal and lymphocytic cytosols (737 54, 321 29and 154 14 nmol/min/mg protein respectively), but was uninfluencedby the dietary regimen. Isozyme distribution varied greatlybetween the tissues. In duodenum GST-     

Increased vascular alpha1-adrenergic sensitivity in patients with renal failure: receiving recombinant erythropoeitin

End stage renal disease (ESRD) is associated with altered hemodynamic regulation as a result of the pathophysiology or treatment of renal failure. Hypertension, common among dialysis patients, is a recognized complication of recombinant human erythropoietin (rHuEPO) therapy. We determined vascular adrenergic and nitric-oxide-mediated responsiveness in 7 patients with established ESRD on rHuEPO treatment and in 13 healthy volunteers using the dorsal hand vein technique. Sensitivity to the alpha1-adrenergic selective agonist phenylephrine was significantly increased in patients with ESRD on rHuEPO. The mean dose of phenylephrine producing 50% venoconstriction (ED50) was 38 +/- 1.6 ng/min in patients with ESRD and 135 +/- 1.3 ng/min in healthy volunteers-almost a 4-fold increase in dose, P = 0.01. In contrast, maximal venodilation mediated by bradykinin, an endothelium-dependent vasodilator, was not different in the 2 groups. To determine whether rHuEPO has a direct vasoconstrictor effect, we studied venous responsiveness to local infusions of rHuEPO in healthy volunteers. Increasing concentrations of rHuEPO produced no vasoconstriction in hand veins of healthy volunteers. These results suggest that vascular responsiveness to alpha-adrenergic stimulation in patients with ESRD on rHuEPO is increased whereas bradykinin-mediated venodilation remains intact. This increase in vascular alpha-adrenergic responsiveness may contribute to the increased peripheral vascular resistance and hypertension seen in patients with ESRD on rHuEPO.     

Classification of anti-estrogens according to intramolecular FRET effects on phospho-mutants of estrogen receptor alpha

Anti-estrogen resistance is a major clinical problem in the treatment of breast cancer. In this study, fluorescence resonance energy transfer (FRET) analysis, a rapid and direct way to monitor conformational changes of estrogen receptor alpha (ERalpha) upon anti-estrogen binding, was used to characterize resistance to anti-estrogens. Nine different anti-estrogens all induced a rapid FRET response within minutes after the compounds have liganded to ERalpha in live cells, corresponding to an inactive conformation of the ERalpha. Phosphorylation of Ser(305) and/or Ser(236) of ERalpha by protein kinase A (PKA) and of Ser(118) by mitogen-activated protein kinase (MAPK) influenced the FRET response differently for the various anti-estrogens. PKA and MAPK are both associated with resistance to anti-estrogens in breast cancer patients. Their respective actions can result in seven different combinations of phospho-modifications in ERalpha where the FRET effects of particular anti-estrogen(s) are nullified. The FRET response provided information on the activity of ERalpha under the various anti-estrogen conditions as measured in a traditional reporter assay. Tamoxifen and EM-652 were the most sensitive to kinase activities, whereas ICI-182,780 (Fulvestrant) and ICI-164,384 were the most stringent. The different responses of anti-estrogens to the various combinations of phospho-modifications in ERalpha elucidate why certain anti-estrogens are more prone than others to develop resistance. These data provide new insights into the mechanism of action of anti-hormones and are critical for selection of the correct individual patient-based endocrine therapy in breast cancer.     

Effect of phentolamine on the hyperemic response to adenosine in patients with microvascular disease

For accurate measurement of the fractional flow reserve (FFR) of the myocardium, the presence of maximum hyperemia is of paramount importance. It has been suggested that the hyperemic effect of the conventionally used hyperemic stimulus, adenosine, could be submaximal in patients who have microvascular dysfunction and that adding alpha-blocking agents could augment the hyperemic response in these patients. We studied the effect of the nonselective alpha-blocking agent phentolamine, which was administered in addition to adenosine after achieving hyperemia, in patients who had microvascular disease and those who did not. Thirty patients who were referred for percutaneous coronary intervention were selected. Of these 30 patients, 15 had strong indications for microvascular disease and 15 did not. FFR was measured using intracoronary adenosine, intravenous adenosine, and intracoronary papaverine before and after intracoronary administration of the nonselective alpha blocker phentolamine. In patients who did not have microvascular disease, no differences in hyperemic response to adenosine were noted, whether or not alpha blockade was given before adenosine administration; FFR levels before and after phentolamine were 0.76 and 0.75, respectively, using intracoronary adenosine (p = 0.10) and 0.75 and 0.74, respectively, using intravenous adenosine (p = 0.20). In contrast, in patients who had microvascular disease, some increase in hyperemic response was observed after administration of phentolamine; FFR levels decreased from 0.74 to 0.70 using intracoronary adenosine (p = 0.003) and from 0.75 to 0.72 using intravenous adenosine (p = 0.04). Although statistically significant, the observed further decrease in microvascular resistance after addition of phentolamine was small and did not affect clinical decision making in any patient. In conclusion, when measuring FFR, routinely adding an alpha-blocking agent to adenosine does not affect clinical decision making.