[Evaluation of our psycho-educative program by participating caregivers]. / Evaluation de notre programme de psychoéducation par les accompagnants de patients déments.

Facing difficulties due to dementia syndromes, systemic care is necessary. Amongst therapies assessed specifically to caregivers, psychoeducative steps seem to be the strongest effective one on neuropsychiatrics symptoms. Psychoeducations tend to teach the caregivers to modify their interactions with patients via a better understanding of illnesses and patients. Our training "Pour mieux vivre avec la maladie d'Alzheimer", applied in groups of eight to twelve persons, consists in twelve sessions of two hours each. To assure the biggest possible availability, we recently incorporated the concomitant coverage of patients into artistic workshops. These sessions of art-therapy realized in parallel to our psychoeducative program will thus be estimated according to the same rigorous methodology. The critical evaluations realized by participants at the end of our program reflect the outcome of our main objective (to teach to modify interactions with the patients) while contributing to the improvement of social contacts and to the learning of calling to existing helps. These preliminary results strongly argue for the pursuit and even extension of this kind of caregiver's management.

[New promising caregiver's psychoeducation training program: a Belgian experience in dementing disorders]. / La psychoéducation des accompagnants de patients déments comme nouvelle approche thérapeutique à l'efficacité démontrée.

Facing difficulties due to dementia syndromes, systemic care is necessary. But nevertheless, caregivers are generally lacking in medical welfare. Therapies assessed specifically to caregivers are missing. Amongst these, psychoeducative steps seem to be the strongest effective's one on neuropsychiatrics symptoms. Psychoeducations tend to learn to caregivers to modify their interactions with patients via a better understanding of illnesses and patients. Our training "Pour mieux vivre avec la maladie d'Alzheimer ", done in groups of eight to twelve persons, is constituted of twelve sessions of two hours each. Complete formation includes behavioural and cognitive aspects of the disease and proposes some multidimensional approach which content at least pedagogical, psychological and cognitivo behavioural aspects. We illustrate here with the use of two peculiar cases that our program can reach its objectives. These preliminary results strongly argue for the pursuit and even extension of this kind of caregiver's management.

[Esthesioneuroblastoma: a case report and literature review]. / Esthésioneuroblastome: à propos d'un cas et revue de la littérature.

Esthesioneuroblastoma (ENB) or olfactive neuroblastoma is a rare cancer arising from the neuroepithelium of the olfactory epithelium of the nasal cavity. Sinusal, orbital and intracranial expansions are common. The anatomopathological diagnosis will frequently require immuno-histochemical tests and sometimes electron-microscopy as well as genetic testing. Medical imaging with CT scan and MRI is essential for the stadification. Treatment will generally associate debulking or curative surgery (with combined rhino-neurosurgical accesses) and conformal stereo-tactic radiotherapy. Chemotherapy was generally reserved for palliative cases; it can be now proposed as neoadjuvant treatment. Most patients will relapse; thus the follow-up will remain ad vitam.

NF-kappaB inhibition impairs the radioresponse of hypoxic EMT-6 tumour cells through downregulation of inducible nitric oxide synthase.

Hypoxic EMT-6 tumour cells displayed a high level of inducible nitric oxide synthase (iNOS) and an increased radiosensitivity after a 16 h exposure to lipopolysaccharide, a known activator of nuclear factor-kappaB (NF-kappaB). Both iNOS activation and radioresponse were impaired by the NF-kappaB inhibitors phenylarsine oxide and lactacystin. Contrasting to other studies, our data show that inhibition of NF-kappaB may impair the radioresponse of tumour cells through downregulation of iNOS.

Imaging in radiotherapy.

Radiotherapy, more then any other treatment modality, relies heavily and often exclusively on medical imaging to determine the extent of disease and the spatial relation between target region and neighbouring healthy tissues. Radically new approaches to radiation delivery are inspired on CT scanning and treat patients in a slice-by-slice fashion using intensity modulated megavoltage fan beams. For quality assurance of complex 3-D dose distributions, MR based 3-D verificative dosimetry on irradiated phantoms has been described. As treatment delivery becomes increasingly refined, the need for accurate target definition increases as well and sophisticated imaging tools like image fusion and 3-D reconstruction are routinely used for treatment planning. While in the past patients were positioned on the treatment machines based exclusively on surface topography and the well-known skin marks, such approach is no longer sufficient for high-accuracy radiotherapy and special imaging tools like on-line portal imaging are used to verify and correct target positioning. Much of these applications rely on digital image processing, transmission and storage, and the development of standards, like DICOM and PACS have greatly contributed to these applications. Digital imaging plays an increasing role in many areas in radiotherapy and has been fundamental in new developments that have demonstrated impact on patient care.

Using appropriate comparisons in economic evaluations. An exercise in Belgium.

This paper considers standard effective treatments for non-Hodgkin's lymphoma and early breast cancer in premenopausal women. The literature assesses the treatments' effectiveness, and expected charges for different treatments in the context of the Belgian Health Insurance System are compared. Ovariectomy in breast cancer (770 ECU) and conventional chemotherapy in non-Hodgkin (2,745 lymphoma ECU) prove equally effective and are less costly in comparison with chemotherapy (1,904 ECU) in breast cancer or chemotherapy and autologous bone marrow transplantation (19,262 ECU) in non-Hodgkin's lymphoma. Further unbiased insights in competitive treatments' costs and outcome could save money and enhance developments in cancer care.

Radiosensitization of hypoxic tumour cells by S-nitroso-N-acetylpenicillamine implicates a bioreductive mechanism of nitric oxide generation.

The radiosensitizing activity of S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide (NO) donor, was assessed in a model of non-metabolic hypoxia achieved in an atmosphere of 95% nitrogen-5% carbon dioxide. A 10 min preincubation of hypoxic EMT-6 cells (10 x 10(6) ml(-1)) with 0.1 and 1 mM SNAP before radiation resulted in an enhancement ratio of 1.6 and 1.7 respectively. The level of spontaneous NO release, measured by a NO specific microsensor, correlated directly with the concentration of SNAP and was enhanced 50 times in the presence of cells. Dilution of the cell suspension from 10 to 0.1 x 10(6) ml(-1) resulted in a 16-fold decline in NO release, but only a twofold decrease in radiosensitization was observed. Preincubation of hypoxic cells with SNAP for 3 min up to 30 min caused an increasing radiosensitizing effect. Extended preincubation of 100 min led to the loss of radiosensitization although the half-life of SNAP is known to be 4-5 h. Taken together, these observations suggest that SNAP generates NO predominantly by a bioreductive mechanism and that its biological half-life is unlikely to exceed 30 min. The lack of correlation between free NO radical and radiosensitizing activity may reflect a role of intracellular NO adducts which could contribute to radiosensitization as well.

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.

Activation of inducible nitric oxide synthase results in nitric oxide-mediated radiosensitization of hypoxic EMT-6 tumor cells.

EMT-6 cells treated for 16 h with 1-10 units/ml IFN-gamma showed a gradual activation of inducible nitric oxide synthase (iNOS) in Western and Northern blots, a simultaneous raise in NO output, and an increase in hypoxic cell radiosensitivity almost to the level of aerobic cells. Both the NO signal and radiosensitization were counteracted by the NO scavenger oxyhemoglobin, by the specific iNOS inhibitor aminoguanidine, and by the L-arginine analogue N(G)-monomethyl-L-arginine. Collectively, these data demonstrate that IFN-gamma can radiosensitize EMT-6 cells through iNOS induction and that NO is the effector molecule responsible for radiosensitization. Compared with the spontaneous NO releaser (2)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino)diazen-1-ium -1,2-diolate], the iNOS-generated NO signal appeared to be 10 times lower yet resulting in the same enhancement ratio of 2.4. Direct stimulation of NO synthesis in tumor cells through the L-arginine/iNOS pathway represents a novel approach to exploit the radiosensitizing properties of NO.

Microprocessor controlled limitation system for a stand-alone freely movable treatment couch.

Because of the capability of free movement in the treatment room, we recently introduced a Hercules treatment couch on one of our linear accelerators. One of the advantages of this couch is that it allows for a more flexible way of patient setup and that it can be moved entirely out of the way to enable treatment with a hospital bed. A disadvantage, however, is that the couch can hit a wall or a cover of the accelerator accidentally. A limitation system has been developed to protect both the table and the accelerator against such collisions.

3D conformal intensity-modulated radiotherapy planning: interactive optimization by constrained matrix inversion.

BACKGROUND AND PURPOSE: This paper presents a method for interactive optimization of 3D conformal intensity-modulated radiotherapy plans employing a quadratic objective that also contains dose limitations in the organs at risk. This objective function is minimized by constrained matrix inversion (CMI) that follows the same approach as the gradient technique using matrix notation. MATERIALS AND METHODS: Sherouse's GRATIS radiotherapy design system is used to determine the outlines of the target volume and the organs at risk and to input beam segments which are given by the beam segmentation technique. This technique defines the beam incidences and the beam segmentation. The weights of the segments are then calculated using a quadratic objective function and CMI. The objective function to be minimized consists of two components based on the planning target volume (PTV) and the organ at risk (OAR) with an importance factor w associated with the OAR. RESULTS: Optimization is tested for concave targets in the head and neck region wrapping around the spinal cord. For a predefined w-value, segment weights are optimized within a few seconds on a DEC Alpha 3000. In practice, 5-10 w-values have to be tested, making optimization a less than 5 min procedure. This optimization procedure predicts the possibility of target dose escalation for a tumour in the lower neck to 120-150 Gy without exceeding the spinal cord tolerance, whereas human planners could not increase the dose above 65-80 Gy. CONCLUSIONS: Treatment plans optimized using a quadratic objective function and the CMI algorithm are superior to those which are generated by human planners. The optimization algorithm is very fast and allows interactive use. Quadratic optimization by CMI is routinely used by clinicians at the Division of Radiotherapy, U.Z.-Gent.

Initial experience with intensity-modulated conformal radiation therapy for treatment of the head and neck region.

PURPOSE: The efficacy of a conventional, noninvasive fixation technique in combination with a commercially available system for conformal radiotherapy by intensity modulation of the treatment beam has been studied. METHODS AND MATERIALS: A slice-by-slice arc-rotation approach was used to deliver a conformal dose to the target and patient fixation was performed by means of thermoplastic casts. Eleven patients have been treated, of which 9 were for tumors of the head and neck region and 2 were for intracranial lesions. A procedure for target localization and verification of patient positioning suitable for this particular treatment technique has been developed based on the superposition of digitized portals with plots generated from the treatment-planning system. A dosimetric verification of the treatment procedure was performed with an anthropomorphic phantom: both absolute dose measurements (alanine and thermoluminescent detectors) and relative dose distribution measurements (film dosimetry) have been applied. The dose delivered outside the target has also been investigated. RESULTS: The dose verification with the anthropomorphic phantom yielded a ratio between measured and predicted dose values of 1.0 for different treatment schedules and the calculated dose distribution agreed with the measured dose distribution. Day-to-day variations in patient setup of 0.3 cm (translations) and 2.0 degrees (rotations) were considered acceptable for this particular patient population, whereas the verification protocol allowed detection of 0.1 cm translational errors and 1.0 rotational errors. CONCLUSIONS: The noninvasive fixation technique in combination with an adapted verification protocol proved to be acceptable for conformal treatment of the head and neck region. Dose measurements, in turn, confirmed the predicted dose values to the target and organs at risk within uncertainty. Daily monitoring becomes mandatory if an accuracy superior to 0.1 cm and 1.0 degree is required for patient setup.

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.

Low-level doxorubicin resistance in P-glycoprotein-negative human pancreatic tumour PSN1/ADR cells implicates a brefeldin A-sensitive mechanism of drug extrusion.

The human pancreatic tumour cell line PSN1/ADR, stepwise selected in 17-510 nM doxorubicin, displayed a multidrug resistance not conferred by P-glycoprotein (P-gp). Resistance to 17-51 nM doxorubicin was accompanied by overexpression of the vesicular marker lung resistance-related protein (LRP). Further selection in 170 nM doxorubicin led to the activation of multidrug resistance-associated protein (MRP) and to the development of drug accumulation/retention defects sensitive to verapamil. In addition, these defects were reversible by the vesicular traffic inhibitors brefeldin A, fluoroaluminate and nocodazole. In contrast, in human ovarian H134AD cells that are resistant to 1700 nM doxorubicin and used as P-gp-positive controls, the drug efflux was inhibited only by verapamil. The tyrosine kinase inhibitor genistein was a potent blocker of doxorubicin efflux in the PSN1/ADR cells but showed no activity in the H134 AD cells. The doxorubicin cytotoxicity in the PSN1/ADR cells was enhanced both by verapamil and brefeldin A, whereas in the parental PSN1 cells they demonstrated the opposite effects, being respectively sensitising and protecting. The P-gp-negative PSN1/ADR cells adapted to 510 nM doxorubicin retained brefeldin A-sensitive doxorubicin accumulation defects while MRP declined. The persistence of brefeldin A-responsive phenotype on the background of variable MRP expression suggests this agent as a useful functional probe for non-P-gp-mediated resistance to plasma-achievable doxorubicin concentrations.

Computers create new perspectives in radiotherapy.

In diagnostic radiology a revolution has taken place over the last decade with the development of computer-based imaging (CT, MR). Such technologies are now available routinely even in medium-sized radiology departments. In radiotherapy departments, however, computer applications have often been limited to calculation of dose distributions on CT images and administrative tasks. The last few years applications are emerging and utilize the full power of modern computer technology and promise to revolutionize treatment planning and execution in everyday radiotherapy. The authors present their view on some of these applications and the way they may push ahead frontiers in clinical radiotherapy.

Calculation of the effective index for nonguiding regions: comment.

In computer simulations the effective-index method is often used to reduce three-dimensional waveguide structures to two dimensions by definition of an effective index. For nonguiding regions, however, an effective index cannot be calculated. Jaeger and Lai [Appl. Opt. 31, 7183-7190 (1992)] present a method in which the choice of an effective index for nonguiding regions is based on a linear extrapolation formula. We show, however, that this linear relationship does not hold in the vicinity of cutoff and therefore yields an arbitrary effective index for the waveguide under cutoff. Furthermore it is shown that errors in simulations based on the effective-index method can actually be increased by the Jaeger and Lai method because of a further overestimation of the lateral contrast.

Evidence for abrogation of oncogene-induced radioresistance of mammary cancer cells by hexadecylphosphocholine in vitro.

Hexadecylphosphocholine (HePC), an experimental and clinical antitumour agent of the alkyllysophospholipid group, was tested for its radiosensitising effect on a panel of nine human mammary cancer cell lines in vitro. Growth inhibition by ionising radiation and recovery from it were not influenced by pretreatment with HePC in most cases, except for two cell lines expressing an activated ras oncogene. In the latter we found an enhanced radioresistance that was abolished by pretreatment with HePC. Our results suggest that HePC may act as a radiosensitiser for cells carrying an activated ras oncogene.

5'-Nor-anhydrovinblastine (Navelbine) has an anti-invasive effect on MO4 mouse fibrosarcoma cells in vitro and in vivo.

5'-nor-anhydrovinblastine (Navelbine) is a hemisynthetic Vinca alkaloid for which a selectivity for mitotic microtubules has been demonstrated. In previous studies, we have demonstrated an anti-invasive effect of other Vinca alkaloids. Here the results of in vitro and in vivo assays concerning the effect of 5'-nor-anhydrovinblastine on growth and invasion of MO4 cells are presented. It is demonstrated that at cytostatic concentrations, 5'-nor-anhydrovinblastine also has an anti-invasive effect.

Radiotherapy in squamous cell esophageal cancer.

As the classical surgical treatment of squamous cell esophageal carcinoma is associated with poor 5-year survival rates and high operative mortality, radiotherapy and chemotherapy are being used as adjuvant or alternative primary treatments. The authors present their view on several therapeutic approaches and describe their irradiation technique.