An "in silico" clinical trial comparing free breathing, slow and respiration correlated computed tomography in lung cancer patients.

BACKGROUND AND PURPOSE: To determine which method of internal target volume (ITV) definition based on a respiration correlated CT (RCCT) allows optimal tumor coverage. MATERIAL AND METHODS: A free breathing CT (CT(fb)) and an RCCT scan were acquired in 41 lung cancer patients. For 12 patients with a motion >7 mm in any direction, a detailed analysis was made. The RCCT scan was used to measure tumor motion and to reconstruct a CT at 10 phases (CT(10ph)), amongst which the half ventilation CT (CT(hv)). By averaging the CT(10ph), a slow CT (CT(slow)) was reconstructed. Based on those scans ITVs were delineated and treatments were planned, where for the ITV(hv) an internal margin of (motion amplitude)/4 was used. The treatment plans for the ITVs were projected on the 10 respiration phases. Doses were calculated and averaged over the 10 phases to estimate the actual CTV coverage. RESULTS: The 3D motion was on average 8.1+/-1.0 mm (1 SD) for all patients; no statistical difference was found between lower and upper lobe tumors. The ITV(slow) was the smallest volume on average (142+/-38 cm(3)), followed by the ITV(hv) (160+/-40 cm(3)), the ITV(10ph) (161+/-41 cm(3)) and the ITV(fb) (250+/-63 cm(3)). Mean CTV doses were between 95% and 107% of the prescribed dose for nearly all patients and treatment plans. Analysis of the CTV coverage suggested that underdosage may occur when the CT(slow) is used and a geographic miss occurred using the CT(fb), due to uncorrect localization of the average tumor position. CONCLUSIONS: The CT(hv) seems to be the optimal dataset for delineation, using an adequate anisotropic internal margin of (motion amplitude)/4.     

Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: A phase II trial

PURPOSE: To evaluate the patterns of recurrence when elective node irradiation was omitted in patients with limited disease small cell lung cancer (LD-SCLC). METHODS: A prospective phase II study was undertaken in 27 patients with LD-SCLC without detectable distant metastases on CT scan. Chest radiotherapy to a dose of 45 Gy in 30 fractions in 3 weeks (1.5 Gy BID with 6 - 8 h interval) was delivered concurrently with carboplatin and etoposide chemotherapy. Chest radiation started after a mean time of 17.7 days +/- 9.7 days (SD) (range: 0-33 days) after the beginning of chemotherapy. Only the primary tumour and the positive nodal areas on the pre-treatment CT scan were irradiated. A total of five chemotherapy cycles were administered, followed by prophylactic cranial irradiation (PCI) in patients without disease progression. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. RESULTS: After a median time of 18 months post-radiotherapy, 7 patients (26%, 95% CI 19.5-42.5%) developed a local recurrence. Three patients (crude rate 11%, 95% CI 2.4-29%), developed an isolated nodal failure, all of them in the ipsilateral supraclavicular fossa. The median actuarial overall survival was 21 months (95% CI 15.3-26.7), and the median actuarial progression free survival was 16 months (95% CI 6.5-25.5). Eight patients developed an acute, reversible grade 3 (CTC 3.0) radiation oesophagitis (30%, 95% CI 14-50%). CONCLUSIONS: Because of the small sample size, no definitive conclusions can be drawn. However, the omission of elective nodal irradiation on the basis of CT scans in patients with LD-SCLC resulted in a higher than expected rate of isolated nodal failures in the ipsilateral supraclavicular fossa. The incidence of acute, reversible oesophagitis was in the same range as reported with elective nodal fields. The safety of selective nodal irradiation in NSCLC should not be extrapolated to patients with LD-SCLC until more data are available. In the mean time, elective nodal irradiation should only be omitted in clinical trials.     

Resting muscle pain as the first clinical symptom in children carrying the MTTK A8344G mutation.

The characteristic clinical presentation, especially the appearance of muscle symptoms, is quite unique in children carrying the mtA8344G mutation. The diagnosis of MERRF syndrome is seldom made in the pediatric age. Fatigue is a common finding in children of pubertal age. Fatigue in combination with recurrent resting muscle pain occurs frequently in the initial phase of various hereditary muscle disorders and in several autoimmune, endocrine and metabolic syndromes. In the absence of obvious biochemical/metabolic abnormalities and in the lack of neurological symptoms the complaints are frequently labelled as fibromyalgia or chronic fatigue syndrome. In patients with behavioural or psychiatric abnormalities one might even start to question the organic etiology of the complaints. We describe a family carrying the classic MTTK mutation with a variable degree of heteroplasmy, presenting in childhood as isolated recurrent muscle pain as the first symptom of the disease.     

Effects of flavonoid mixtures on the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers: an in vitro and kinetic modeling approach to predict the combined effects on transporter inhibition.

This study describes and kinetically models the effect of flavonoid mixtures on PhIP transport through Caco-2 monolayers. Previously it was shown that quercetin, luteolin, naringenin and myricetin increase the apical to basolateral PhIP transport in Caco-2 monolayers. In this study, apigenin was shown to exert a similar effect with an apparent K(i) value of 10.8 microM. Additional experiments revealed that several binary flavonoid mixtures and one mixture containing all five model flavonoids increased the apical to basolateral PhIP transport through the Caco-2 monolayer. Assuming competitive inhibition of the apparent active transporter by the flavonoids and concentration-additivity for their inhibiting effect, the kinetic model previously developed to describe the effect of the individual flavonoids on PhIP transport, could be extended and adequately describes the experimental values obtained for the flavonoid mixtures. We conclude that combinations of flavonoids increase the transport of PhIP and do so by interacting in an additive way with the active transport of PhIP. This flavonoid-mediated increase in PhIP transport through Caco-2 monolayers may point at a possible increased bioavailability of PhIP in the presence of flavonoid mixtures in the in vivo situation. This would imply an adverse effect of these supposed beneficial food ingredients.     

The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group

BACKGROUND: Cardiovascular complications are the most important causes of perioperative morbidity and mortality among patients undergoing major vascular surgery. METHODS: We performed a randomized, multicenter trial to assess the effect of perioperative blockade of beta-adrenergic receptors on the incidence of death from cardiac causes and nonfatal myocardial infarction within 30 days after major vascular surgery in patients at high risk for these events. High-risk patients were identified by the presence of both clinical risk factors and positive results on dobutamine echocardiography. Eligible patients were randomly assigned to receive standard perioperative care or standard care plus perioperative beta-blockade with bisoprolol. RESULTS: A total of 1351 patients were screened, and 846 were found to have one or more cardiac risk factors. Of these 846 patients, 173 had positive results on dobutamine echocardiography. Fifty-nine patients were randomly assigned to receive bisoprolol, and 53 to receive standard care. Fifty-three patients were excluded from randomization because they were already taking a beta-blocker, and eight were excluded because they had extensive wall-motion abnormalities either at rest or during stress testing. Two patients in the bisoprolol group died of cardiac causes (3.4 percent), as compared with nine patients in the standard-care group (17 percent, P=0.02). Nonfatal myocardial infarction occurred in nine patients given standard care only (17 percent) and in none of those given standard care plus bisoprolol (P<0.001). Thus, the primary study end point of death from cardiac causes or nonfatal myocardial infarction occurred in 2 patients in the bisoprolol group (3.4 percent) and 18 patients in the standard-care group (34 percent, P<0.001). CONCLUSIONS: Bisoprolol reduces the perioperative incidence of death from cardiac causes and nonfatal myocardial infarction in high-risk patients who are undergoing major vascular surgery.     

Cardiac evaluation in hypotension-prone and hypotension-resistant hemodialysis patients

BACKGROUND: Hypotension during hemodialysis occurs frequently, but the precise mechanism remains unclear. In this study, the presence of myocardial ischemia and myocardial contractile reserve during infusions of the beta-adrenergic receptor agonist dobutamine was assessed by means of dobutamine-atropine stress echocardiography (DSE) in hypotension-prone (HP) and hypotension-resistant (HR) hemodialysis patients. METHODS: Eighteen HP patients (age 53 +/- 6 years) were compared with 18 HR patients (age 53 +/- 3 years), matched with respect to the duration of hemodialysis and cardiovascular history. New wall abnormalities during dobutamine stress reflect the presence of myocardial ischemia, whereas the increase in stroke index and cardiac index reflects myocardial contractile reserve. RESULTS: Wall motion score at rest (1.42 +/- 0.53 vs. 1.44 +/- 0.57) and dobutamine-induced new wall motion abnormalities (4 vs. 3 patients) between HP and HR patients were similar, but responses of cardiac index, stroke index, and systolic blood pressure to do butamine between the two groups were different. Not withstanding a similar cardiac index at rest (2.4 +/- 1.1 liter/min/m2 in HP and 2.8 +/- 1.2 liter/min/m2 in HR patients), dobutamine-induced increments in the cardiac index were considerably smaller in the former (0.8 +/- 1.3 liter/min/m2) than in the latter patients (2.3 +/- 1.6 liter/min/m2, P = 0.002), predominantly because of a progressive decrease in the stroke index in the HP patients. CONCLUSION: Impaired myocardial contractile reserve rather than ischemia is predominant in HP patients. This impaired myocardial contractile reserve may play a role in the development of hemodialysis-induced hypotension.     

Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA.

AIMS: Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events. METHODS AND RESULTS: Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab. CONCLUSION: Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.