Optimal control of set-up margins and internal margins for intra- and extracranial radiotherapy using stereoscopic kilovoltage imaging.

In this paper the clinical introduction of stereoscopic kV-imaging in combination with a 6 degrees-of-freedom (6 DOF) robotics system and breathing synchronized irradiation will be discussed in view of optimally reducing interfractional as well as intrafractional geometric uncertainties in conformal radiation therapy. Extracranial cases represent approximately 70% of the patient population on the NOVALIS treatment machine (BrainLAB A.G., Germany) at the AZ-VUB, which is largely due to the efficiency of the real-time positioning features of the kV-imaging system. The prostate case will be used as an example of those target volumes showing considerable changes in position from day-to-day, yet with negligible motion during the actual course of the treatment. As such it will be used to illustrate the on-line target localization using kV-imaging and 6 DOF patient adjustment with and without implanted radio-opaque markers prior to treatment. Small lung lesion will be used to illustrate the system's potential to synchronize the irradiation with breathing in coping with intrafractional organ motion.

Course of neuropsychological recovery from moderate-to-severe head injury: a 2-year follow-up.

Neuropsychological outcome and recovery of a group of 91 patients with moderate-to-severe head injuries were prospectively investigated over a 2 year period, with evaluations at acute hospital discharge at 6 months and 2 years post-injury. A group of 39 trauma patients with injuries to parts of the body other than the head were used as controls. The head injured group performed significantly worse than the control group at baseline, 6 months and 2 years post-injury. Significant improvement was found during the first 6 months, but also between 6 months and 2 years post-injury. Trauma controls also performed significantly better at 6 months post-injury compared to baseline. Differential practice effects between groups cause difficulties in determining recovery. Within the head injured group, three distinct recovery groups were identified varying as a function of coma-length and coma-duration. The first group is comparable with the trauma controls. The other two groups demonstrate significant neuropsychological impairments at baseline, with one group showing a marked improvement over the 2 year period, and the other group showing only small improvement over this time period.

Early predictors of mortality and morbidity after severe closed head injury.

Mortality and morbidity of 158 patients with severe head injury were studied in relation to age, and early (24-h) clinical and computed tomography data. For comparison of outcome data in survivors, a group of 32 patients with traumatic injuries to parts of the body other than the head was used as controls. Within the head-injured group, the mortality rate was 51%. Logistic regression analyses combined 13 out of 16 predictors into a model with an accuracy of 93%, a sensitivity of 90%, and a specificity of 95%. These include age, Glasgow Coma Scale (GCS) score, pupillary reactivity, blood pressure, intracranial pressure, blood glucose, platelet count, body temperature, cerebral lactate, and subdural, intracranial, subarachnoid, and ventricular hemorrhage. At 6 months postinjury, head-injury survivors and trauma controls were evaluated with the Glasgow Outcome Scale (GOS), a neuropsychological test battery and the Sickness Impact Profile (SIP). Head-injury survivors had a higher proportion of disabilities and neuropsychological dysfunctions than trauma controls. They also report more quality of life-related functional limitations on the SIP scales for mobility, intellectual behavior, communication, home management, eating, and work. Linear regression analysis resulted in age being the only important predictor of outcome on the GOS, the GCS score being the best predictor of neuropsychological functioning, and pupillary reactivity being the most predictive for self-reported quality of life as measured by SIP. Those factors important for predicting mortality (clinical variables such as ICP or blood glucose level, and CT observations) failed to show any significant relationship with morbidity.

Adjuvant radiotherapy for breast cancer significantly improves overall survival: the missing link.

BACKGROUND AND PURPOSE: The influence of surgical adjuvant radiotherapy on overall survival of patients with operable breast cancer is still a controversial subject. The negative result of the EBCTCG meta-analysis (Early breast cancer trialists', collaborative group. Effects of radiotherapy and surgery in early breast cancer. An overview of the randomised trials. N. Engl. J. Med. 1995;333:1444-1455) of clinical randomized trials on adjuvant radiotherapy in breast cancer is in strong contrast with the Danish 82B, 82C and British Columbia trials (Overgaard M, Hanse PS, Overgaar J, et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. N. Engl. J. Med. 1997;337:949-955; Overgaard M, Jensen MB, Overgaard J, et al. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 1999;353:1641-1648; Ragaz J, Jackson S, Le N, et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N. Engl. J. Med. 1997;337:956-962) showing an impressive survival benefit. This paper tries to fill in the gap between the conflicting results. MATERIALS AND METHODS: The 36 trials of the EBCTCG (Early breast cancer trialists', collaborative group, 1995) were prospectively screened for a number of objective parameters that are usually not analyzed in review papers. The odds of death data (and its variance) were borrowed from the original meta-analysis (Early breast cancer trialists', collaborative group, 1995) to check whether the objective features were significant predictors for overall survival benefit. RESULTS: A significant survival benefit for the radiotherapy arm was found for recent trials (2P<0.05), large trials (2P<0.03), trials that used standard fractionation (2P<0.02), and trials with a favourable crude survival (2P<0.03). For these four parameters clear parameter-effect relations were found. In recent and large trials the odds reduction was 12.4% (2P=0.004). CONCLUSIONS: Surgical adjuvant radiotherapy significantly improves overall survival of breast cancer patients provided that current techniques are used and treatment is given with standard fractionation. For the best subgroups we observed an odds of death reduction of more than 20%. The results of this study stress the importance of reducing cardiovascular and other late toxicity in adjuvant radiotherapy for breast cancer.

Automatic on-line electronic portal image analysis with a wavelet-based edge detector.

A fully automatic method for on-line electronic portal image analysis is proposed. The method uses multiscale edge detection with wavelets for both the field outline and the anatomical structures. An algorithm to extract and combine the information from different scales has been developed. The edges from the portal image are aligned with the edges from the reference image using chamfer matching. The reference is the first portal image of each treatment. The matching is applied first to the field and subsequently to the anatomy. The setup deviations are quantified as the displacement of the anatomical structures relative to the radiation beam boundaries. The performance of the algorithm was investigated for portal images with different contrast and noise level. The automatic analysis was used first to detect simulated displacements. Then the automatic procedure was tested on anterior-posterior and lateral portal images of a pelvic phantom. In both sets of tests the differences between the measured and the actual shifts were used to quantify the performance. Finally we applied the automatic procedure to clinical images of pelvic and lung regions. The output of the procedure was compared with the results of a manual match performed by a trained operator. The errors for the phantom tests were small: average standard deviation of 0.39 mm and 0.26 degrees and absolute mean error of 0.31 mm and 0.2 degrees were obtained. In the clinical cases average standard deviations of 1.32 mm and 0.6 degrees were found. The average absolute mean errors were 1.09 mm and 0.39 degrees. Failures were registered in 2% of the phantom tests and in 3% of the clinical cases. The algorithm execution is approximately 5 s on a 168 MHz Sun Ultra 2 workstation. The automatic analysis tool is considered to be a very useful tool for on-line setup corrections.

Assessment of the uncertainties in dose delivery of a commercial system for linac-based stereotactic radiosurgery.

PURPOSE: Linac-based stereotactic radiosurgery (SRS) was introduced in our department in 1992, and since then, more than 200 patients have been treated with this method. An in-house-developed algorithm for target localization and dose calculation has recently been replaced with a commercially available system. In this study, both systems have been compared, and positional accuracy, as well as dose calculation, have been verified experimentally. METHODS AND MATERIALS: The in-house-developed software for target localization and dose calculation is an extension to George Sherouse's GRATIS(R) software for radiotherapy treatment planning, and has been replaced by a commercial (BrainSCAN version 3.1; BrainLAB, Germany) treatment planning system (TPS) for SRS. The positional accuracy for the entire SRS procedure (from image acquisition to treatment) has been investigated by treatment of simulated targets in the form of 0.2-cm lead beads inserted into an anthropomorphic phantom. Both dose calculation algorithms have been verified against manual calculations (based on basic beam data and CT data from phantom and patients), and measurements with the anthropomorphic phantom applying ionization chamber, thermoluminescent detectors, and radiographic film. This analysis has been performed on a variety of experimental situations, starting with static beams and simple one-arc treatments, to more complex and clinical relevant applications. Finally, 11 patients have been evaluated with both TPS in parallel for comparison and continuity of clinical experience. RESULTS: Phantom studies evaluating the entire SRS procedure have shown that a target, localized by CT, can be irradiated with a positional accuracy of 0.08 cm in any direction with 95% confidence. Neglecting the influence of dose perturbation when the beam passes through bone tissue or air cavities, the calculated dose values obtained from both TPSs agreed within 1% (SD 1%) for phantom and patient studies. The application of a one-dimensional path length correction for tissue heterogeneity influences the treatment prescription 4% on average (SD 1%), which is in compliance with theoretical predictions. The phantom measurements confirmed the predicted dose at isocenter within uncertainty for the different treatment schedules in this study. CONCLUSION: The full SRS procedure applied to an anthropomorphic phantom has been used as a comprehensive method to assess the uncertainties involved in dose delivery and target positioning. The results obtained with both TPSs are in agreement with AAPM Report 54, TG 42 and clinical continuity is assured. However, the use of a one-dimensional path length correction will result in an increase of 4% in dose prescription, which is slightly more than that predicted in the literature.

Subjective complaints versus neuropsychological test performance after moderate to severe head injury.

Neuropsychological test performance and subjective complaints of 85 patients with moderate to severe head injury were investigated at 6 months postinjury. The neuropsychological test battery included 10 measures of attention, memory, mental flexibility, reaction time, visuoconstruction and verbal fluency. Subjective complaints were assessed using a self-report questionnaire subdivided into four subscales (somatic, cognitive, emotional and behavioural). Ratings were obtained for the pre-injury and current status. Thirty-three trauma patients with injuries to other parts of the body than the head were used as controls. For the head injured, relatives also completed the questionnaire. Head injured patients performed significantly below trauma control patients on nearly all test measures. Head injured patients and their relatives reported a significant increase in subjective complaints since the injury on all four subscales, with no differences between patients' and relatives' reports. These changes were also reported by the trauma controls, but they report fewer changes in somatic and cognitive functioning. Exploratory canonical correlation analyses revealed no correlations between any of the four scales of the questionnaire and the test measures, nor for the head injured, the trauma controls, or the relatives, indicating no relevant relationship between subjective complaints and neuropsychological test performance.

Cerebral perfusion pressure and intracranial pressure in relation to neuropsychological outcome.

OBJECTIVE: The study attempted to examine the relationship between neuropsychological functioning and reduced cerebral perfusion pressure (CPP), raised intracranial pressure (ICP), and reduced mean arterial pressure (MAP), monitored during intensive care treatment. DESIGN: This prospective follow-up study included consecutive patients and evaluated outcome at 6 months postinjury by the administration of a neuropsychological test battery. SETTING: The study was conducted at the University Hospital of Gent, Belgium. PATIENTS AND PARTICIPANTS: Over a 30-month period, 43 patients were included. Inclusion criteria were the following: hospital admission following closed head injury. ICP monitoring, no medical history of central nervous system disease or mental retardation, survival for at least 6 months, and informed consent for participation. INTERVENTIONS: All patients received the hospital's standard treatment for head injury, which remained unchanged during the study period. MEASUREMENTS AND RESULTS: Reduced CPP was analyzed using the number of observed values below 70 mmhg, raised ICP using the number of values above 20 mmHg, and MAP using the number of values below 80 mmHg. The neuropsychological test battery included 11 measures of attention, information processing, motor reaction time, memory, learning, visuoconstruction, verbal fluency, and mental flexibility. No linear relationships were found between overall neuropsychological impairment and episodes of reduced CPP, raised ICP, or reduced MAP. CONCLUSIONS: Although reduced CPP and raised ICP are frequent, often fatal, complications of head injury, in survivors they do not seem to be related to later neuropsychological functioning.

Personality change following head injury: assessment with the NEO Five-Factor Inventory.

We evaluated personality change following head injury in 68 patients at 6 months postinjury using the NEO Five-Factor Inventory to assess the five personality dimensions of the Five-Factor Model of Personality. All items had to be rated twice, once for the preinjury and once for the current status. Twenty-eight trauma patients with injuries to other parts of the body than the head were used as controls. For the head-injured group, 63 relatives also completed the questionnaire. The results showed no differences between the ratings of head-injured patients and the ratings of trauma control patients. Both groups showed significant change in the personality dimensions Neuroticism, Extraversion, and Conscientiousness. Compared to their relatives, head-injured patients report a smaller change in Extraversion and Conscientiousness. Changes were not reported on the Openness and Agreeableness scales, by neither the head-injured or their relatives, nor by the trauma controls.

A feasibility study of high dose rate brachytherapy in solitary urinary bladder cancer.

PURPOSE: To determine the feasibility of high dose rate brachytherapy in the treatment of T1-T3 solitary bladder cancer and to compare results and side-effects to those obtained by others using conventional, i.e., low dose rate regimens. METHODS AND MATERIALS: Between July 1992 and 1995, 16 patients entered the study. Median age at diagnosis was 64 years (range: 45-79 years). Diagnostic transurethral resection showed four T1, five T2, and seven T3 lesions, all proven solitary by random biopsies. Radiotherapy consisted of low-dose preoperative external beam irradiation (3 x 3.5 Gy on the 3 consecutive days prior to implantation), followed by high dose rate brachytherapy (15 x 3 Gy during the 8 consecutive days thereafter). Median follow-up from the date of implantation was 23 months (range: 6-43 months). In 15 patients, cystoscopy was systematically performed during follow-up, whereas the 16th patient was followed on a clinical basis only. RESULTS: Recurrences have occurred in 2 of 15 evaluable patients (both stage T3): metastasis in 1 and combined local plus distant failure in the other patient. Cystoscopic evaluation showed persisting alterations of the implanted portion of the bladder mucosa in 11 of 15 evaluable patients (ulceration, calcifications, and/or punctiform bleedings). Symptomatic radiation cystitis was mild and transient in 14 but persisting and severe in 2 patients. CONCLUSION: This study documents the feasibility of high dose rate brachytherapy in a selected group of bladder cancer patients. Both patient outcome and side-effects are comparable to the best results obtained with low dose rate schedules. Additional follow-up is still needed to enforce the comparison.

Long-term survival in an adult metastatic renal peripheral primitive neuroectodermal tumor (PPNET) with multimodality treatment including high-dose chemotherapy.

We describe a 42-year-old male patient with a primitive peripheral neuroectodermal tumor (PPNET) arising from the kidney. The patient was treated sequentially with surgery, radiotherapy, experimental cytokine treatment (rhIL-6), combination chemotherapy and consolidated in complete remission with high-dose chemotherapy, supported by autologous stem cells (AST) and hematopoietic growth factors. The patient remains in complete remission at 34+ months after AST and is surviving disease-free for five years after initial presentation. The case presented here is unusual because of the renal origin and the long remission duration and survival when compared with the usual outcome of adult metastatic PPNET. High-dose chemotherapy may have favorably influenced the outcome in this patient. The case is discussed in the context of the general treatment of metastatic PPNET.

Short-term and long-term neuropsychological consequences of cardiac surgery with extracorporeal circulation.

OBJECTIVE: Cognitive dysfunction after extracorporeal circulation is a major continuing problem in modern cardiac surgery. We designed this prospective study to update the incidence of postoperative neuropsychological changes after routine cardiopulmonary bypass (CPB) and to identify perioperative variables associated with these complications. METHODS: We assessed the patients with a comprehensive neuropsychological test battery 1 day before, 7 days after (n = 109) and 6 months after (n = 91) cardiopulmonary bypass. We used patients undergoing major vascular or thoracic surgery as a surgical control group (n = 20). RESULTS: Repeated measures multivariate analysis of variance (using surgical group as a between-subjects factor) on the group data revealed significant changes early after surgery compared with the preoperative performance (P = 0.001). The early changes are characterized by a significant decrease of visual attention and verbal memory performance (univariate F-tests, always P < 0.05). Cardiac patients showing cognitive impairment after cardiac surgery had lower preoperative ejection fractions (P = 0.014) and a more complicated medical history (P = 0.046). At 6-month follow-up, the patients performed significantly better than before surgery (P < 0.001). CPB patients showing persistent cognitive impairment at follow-up were significantly older at the time of surgery (P = 0.005). Individual comparisons revealed that 45% of the patients undergoing CPB showed evidence of cognitive impairment soon after surgery. In 12% of the patients, the cognitive sequelae persisted at follow-up. Both group data and individual incidence rates revealed neither significant pre-post differences between the surgical groups nor a time-by-group interaction effect. Variables directly associated with CPB were not significantly associated with the occurrence of cognitive impairment after surgery. CONCLUSIONS: We conclude that an important proportion of the cognitive impairment after cardiac surgery is likely to be due to nonspecific effects of surgery.

Intrinsic radiosensitivity of human pancreatic tumour cells and the radiosensitising potency of the nitric oxide donor sodium nitroprusside.

A panel of eight human pancreatic tumour cell lines displayed high intrinsic radioresistance, with mean inactivation doses between 2.4 and 6.5 Gy, similar to those reported for melanoma and glioblastoma. The radiosensitising potency of sodium nitroprusside, a bioreductive nitric oxide donor, was assessed in a model of metabolism-induced hypoxia in a cell micropellet. Sodium nitroprusside at 0.1 mM revealed a radiosensitising effect with an overall enhancement ratio of 1.9 compared with 2.5 for oxygen. Radiosensitising activity correlated with the enhancement of single-strand DNA breakage caused by radiation. In suspensions with cell densities of between 3% and 30% (v/v), the half-life of sodium nitroprusside decreased from 31 to 3.2 min, suggesting a value of around 1 min for micropellets. Despite this variation, the radiosensitising activity was similar in micropellets and in diluted cell suspensions. S-nitroso-L-glutathione was found to possess radiosensitising activity, consistent with a possible role of natural thiols in the storing of radiobiologically active nitric oxide adducts derived from sodium nitroprusside. As measured by a nitric oxide-specific microsensor, activation of sodium nitroprusside occurred by bioreduction, whereas S-nitroso-L-glutathione showed substantial spontaneous decomposition. Both agents appear to exert radiosensitising action through nitric oxide as its scavenging by carboxy phenyltetramethylimidazolineoxyl N-oxide (carboxy-PTI0) and oxyhaemoglobin resulted in attenuated radiosensitisation. Sodium nitroprusside was at least 10-fold more potent than etanidazole, a 2-nitroimidazole used as a reference. Our data suggest that sodium nitroprusside, a drug currently used for the treatment of hypertension, is a potential tumour radioresponse modifier.

Prospective evaluation of verbal memory performance after cardiopulmonary bypass surgery.

One hundred and four patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and a surgical control group undergoing major vascular or thoracic surgery (n = 18) were tested with the Auditory Verbal Learning Test (AVLT) at the following intervals: 1 day before, 1 week after, and 6 months after surgery. Early after surgery a significant decline in AVLT-performance was found, characterized by a smaller carry-over of learned words on subsequent acquisition trials. Six-month follow-up data revealed significant improvement in the delayed retention of words as compared to the preoperative assessment. No surgical group differences or time by group interaction effects were found. In the CPB group, deeper levels of hypothermia, reflecting longer and more extensive cardiac surgery, were associated with reduced improvement on retest.

Subjective complaints versus neuropsychological test performance after cardiopulmonary bypass.

The study by Newman et al. (Journal of Psychosomatic Research, 1989) compared subjective reports of cognition with assessed cognitive performance in patients one year after coronary artery bypass surgery. The current study reinvestigated this relation in a larger and more heterogeneous group--90 cardiac patients six months after cardiopulmonary bypass--using a more extensive checklist of subjective complaints and different neuropsychological tests. In agreement with previous research, the patients who reported complaints in specific cognitive areas were not found to have impaired cognitive functions as assessed with appropriate neuropsychological tests. The patients who reported deterioration in cognition after surgery were found to have higher levels of depression and state anxiety. These differences were significant for almost all evaluated cognitive functions. An alternative explanation of the relationship between mood and cognitive complaints based on personality traits, i.e., neuroticism, is offered.

Perceptual scaling of synthesized musical timbres: common dimensions, specificities, and latent subject classes.

To study the perceptual structure of musical timbre and the effects of musical training, timbral dissimilarities of synthesized instrument sounds were rated by professional musicians, amateur musicians, and nonmusicians. The data were analyzed with an extended version of the multidimensional scaling algorithm CLASCAL (Winsberg & De Soete, 1993), which estimates the number of latent classes of subjects, the coordinates of each timbre on common Euclidean dimensions, a specificity value of unique attributes for each timbre, and a separate weight for each latent class on each of the common dimensions and the set of specificities. Five latent classes were found for a three-dimensional spatial model with specificities. Common dimensions were quantified psychophysically in terms of log-rise time, spectral centroid, and degree of spectral variation. The results further suggest that musical timbres possess specific attributes not accounted for by these shared perceptual dimensions. Weight patterns indicate that perceptual salience of dimensions and specificities varied across classes. A comparison of class structure with biographical factors associated with degree of musical training and activity was not clearly related to the class structure, though musicians gave more precise and coherent judgments than did non-musicians or amateurs. The model with latent classes and specificities gave a better fit to the data and made the acoustic correlates of the common dimensions more interpretable.