Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: toxicity analysis of RTOG 95-17

PURPOSE: Accelerated partial breast irradiation (APBI) can be delivered with brachytherapy within 4-5 days compared with 5-6 weeks for conventional whole breast external beam radiotherapy. Radiation Therapy Oncology Group 95-17 is the first prospective phase I-II cooperative group trial of APBI alone after lumpectomy in select patients with breast cancer. The toxicity rates are reported for low-dose-rate (LDR) and high-dose-rate (HDR) APBI on this trial. METHODS AND MATERIALS: The inclusion criteria for this study included invasive nonlobular tumors < or =3 cm after lumpectomy with negative surgical margins and axillary dissection with zero to three positive axillary nodes without extracapsular extension. The patients were treated with either LDR APBI (45 Gy in 3.5-5 days) or HDR APBI (34 Gy in 10 twice-daily fractions within 5 days). Chemotherapy (> or =2 weeks after APBI) and/or tamoxifen could be given at the discretion of the treating physicians. RESULTS: Between August 1997 and March 2000, 100 women were enrolled in this study, and 99 were evaluated. Of the 99 women, 33 were treated with LDR and 66 with HDR APBI. The median follow-up for all patients was 2.7 years (range, 0.6-4.4 years) and was 2.9 years for LDR and 2.7 years for HDR patients. Toxicities attributed to APBI included erythema, edema, tenderness, pain, and infection. Of the 66 patients treated with HDR APBI, 2 (3%) had Grade 3 or 4 toxicity. Of the 33 patients treated with LDR, 3 (9%) had Grade 3 or 4 toxicity during brachytherapy. Late toxicities included skin thickening, fibrosis, breast tenderness, and telangiectasias. No patient experienced late Grade 4 toxicity; the rate of Grade 3 toxicity was 18% for the LDR and 4% for the HDR groups. CONCLUSION: Acute and late toxicity for this invasive breast radiation technique was modest and acceptable. Patients receiving chemotherapy, a nonprotocol therapy, had a greater rate of Grade 3 toxicity. The study design did not allow for this to be tested statistically.     

Molecular, Microscopic, Microstructural and Mechanical Methods of Analyzing Pseudoneointimal Linings within Partial Artificial Hearts in Man and the Calf

Ex vivo molecular, microscopic (cellular), microstructural and mechanical methods have been utilized to evaluate biologic, blood-interfacing linings (pseudneointima) formed on textured, fibril-flocked pumping surfaces within abdominal left ventricular assist devices (ALVADs) or partial artificial hearts. Thus far, seventeen human and twenty bovine pseudoneointimal linings (1–28 day pumping durations) have been evaluated by these methods. The results indicate that pseudoneointima begins developing within 24 hours after contact of the pumping surface with blood and is well developed at five days. The linings exhibit surface immunofluorescent fibrinogen activity, viable surface macrophages and histiocytes and scattered erythrocytes at ALVAD removal. Structurally similar linings (20 μ to 500 μ in thickness) develop in calves and in man. Mechanically, pseudoneointima is a stable, adherent, highly compliant, isotropic structural material. It is linearly elastic and strain-rate independent, with small viscous energy losses under physiologic strains. The methods employed for the evaluation of pseudoneointima provide useful information to determine the suitability of textured or rough surfaces for blood interfacing. The cumulative results indicate that the textured surface approach is useful for intermediate-term clinical ALVAD utilization.     

Non-inferiority trials: the 'at least as good as' criterion with dichotomous data

The 'at least as good as' criterion, introduced by Laster and Johnson for a continuous response variate, is developed here for applications with dichotomous data. This approach is adaptive in nature, as the margin of non-inferiority is not taken as a fixed difference; it varies as a function of the positive control response. When the non-inferiority margin is referenced as a high fraction of the positive control response, the procedure is seen to be uniformly more efficient than the fixed margin approach, yielding smaller sample sizes when sizing non-inferiority trials under identically specified conditions. Extending this method to proportions is straightforward, but highlights special considerations in the design of non-inferiority trials versus superiority trials, including potential trade-offs in statistical efficiency and interpretability.     

Incorporating time-dependent covariates in survival analysis using the LVAR method

In survival analysis, use of the Cox proportional hazards model requires knowledge of all covariates under consideration at every failure time. Since failure times rarely coincide with observation times, time-dependent covariates (covariates that vary over time) need to be inferred from the observed values. In this paper, we introduce the last value auto-regressed (LVAR) estimation method and compare it to several other established estimation approaches via a simulation study. The comparison shows that under several time-dependent covariate processes this method results in a smaller mean square error when considering the time-dependent covariate effect.     

Prediction of drug clearance in children from adults: a comparison of several allometric methods

AIMS: In recent years with the advent of paediatric exclusivity and requirements to conduct clinical studies in children, the current emphasis is to find a safe and efficacious dose of a drug in children. It has been suggested that one can predict the clearance of a drug in children according to the equation: CL in the child=adult CLx(weight of the child/70)0.75. Considering the controversy surrounding the exponent of 0.75 for the prediction of clearance and lack of any systematic evaluation of the aforementioned proposal, the objectives of the study were as follows: (i) to determine if indeed the exponent 0.75 is the most suitable exponent for the prediction of clearance in children from adult data; (ii) to explore and search for other exponents that are more accurate or as good as 0.75; and (iii) to propose a new approach (if any) based on the findings of the current evaluation. METHODS: Six methods were used to predict clearance of drugs in children from adult data. Besides evaluating the exponent of 0.75, exponents of 0.80, 0.85 and 1.0 were also evaluated. An empirical approach based on kidney and liver weights was also examined. Based on the results of five methods, a sixth method was introduced. RESULTS: The results of the study indicate that no single method is suitable for all drugs or for all age groups. The exponents 0.75, 0.80, and 0.85 provided the same degree of accuracy or error in the prediction of clearance in children. CONCLUSIONS: Since no single method is suitable for all drugs or for all age groups. A combination of approaches is suggested which may help in improving the prediction of clearance in children from adult data.     

The role of tissue oxygen monitoring in patients with acute brain injury

Cerebral ischaemia is implicated in poor outcome after braininjury, and is a very common post-mortem finding. The inabilityof the brain to store metabolic substrates, in the face of highoxygen and glucose requirements, makes it very susceptible toischaemic damage. The clinical challenge, however, remains thereliable antemortem detection and treatment of ischaemic episodesin the intensive care unit. Outcomes have improved in the traumaticbrain injury setting after the introduction of progressive protocol-driventherapy, based, primarily, on the monitoring and control ofintracranial pressure, and the maintenance of an adequate cerebralperfusion pressure through manipulation of the mean arterialpressure. With the increasing use of multi-modal monitoring,the complex pathophysiology of the injured brain is slowly beingunravelled, emphasizing the heterogeneity of the condition,and the requirement for individualization of therapy to preventsecondary adverse hypoxic cerebral events. Brain tissue oxygenpartial pressure (     

Reactive oxygen species derived from NADPH oxidase system is not essential for liver regeneration after partial hepatectomy

BACKGROUND: There is suggestive evidence that reactive oxygen species may play a role in the initiation of liver regeneration via a kupffer cell-mediated mechanism involving TNFa and NF-kappa B. In mammalian cells, a major source of reactive oxygen species derives from the membrane-bound NADPH oxidase system (no protein de novo synthesis is required) and it is known that the low levels of oxidants produced through NADPH oxidase play a role in liver cell proliferation because of peroxisome proliferators. METHODS: We used knockout mice lacking Cybb: subunit of NADPH oxidase to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves reactive oxygen species produced through NADPH oxidase and to analyze in more detail the abnormalities caused by lack of its component, which is required for the initiation of liver regeneration. RESULTS: Lack of Cybb had little effect on NF-kappa B and STAT3 binding, and no effect in TNFa and interleukin-6 production after PH. Cybb KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. CONCLUSIONS: We conclude that NADPH oxidase is not necessary for liver regeneration after PH. It is likely that there is a potential pathway not including NADPH oxidase to activate NF-kappa B and STAT3 binding for the initiation of liver regeneration after PH.     

Complex Partial Seizures in Childhood

Abstract. A clinical and electroencephalographic study was undertaken on 215 children with complex partial seizures as selected on the basis of the International Classification of Epileptic Seizures (1981).

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  Complex partial seizures were noted in 7.8% of the epileptic children.
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  The ictal symptoms of complex partial seizures closely resembled those of psychomotor triad described by Lennox.
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  Interictal EEG revealed seizure discharges from the temporal or frontal focus in 57.2%.
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  There existed a group with automatism as a main symptom having both diffuse slow spike-waves and focal temporal spikes. This type should be interpreted to be one of secondary generalized epilepsies and be a variant of the Lennox syndrome.