An efficient method for small field treatment dose calculation for stereotactic radiosurgery using a LINAC

The normal procedure for a physician-physicist team designing a treatment plan for multiarc stereotactic radiosurgery is the trial-and-error approach of changing the collimator size and the location of the isocenter of radiation and viewing the isodose curves on two-dimensional computed tomography (CT) or magnetic resonance imaging (MRI) image planes. Automatic optimization procedures have also been used to optimize beam weight or beam size. However, either process is very time consuming. To improve the speed of the dose calculation, a random sampling method has been proposed. Unfortunately, the sampled values of an objective function are different from one sample to another. Such a sampling method cannot be used in automatic optimization because the next move in an optimization process is based on the current and past objective function values. To this end, an adaptive method based on the size of the collimators is proposed and used to determine a small volume in the shape of a hollow sphere for which the dose is calculated. With an appropriate choice of an adaptive hollow sphere, the objective function calculated based on such a hollow sphere is the same as that calculated with the traditional three-dimensional (3-D) cube matrix. However, with the new adaptive method, the speed of calculating a dose can be improved by a factor of 4 to a factor of 100. Because of the improvement in the speed of calculating a treatment dose, the new adaptive hollow sphere method for calculating a treatment dose can be used routinely in designing a treatment plan.     

Three-dimensional optimization of treatment planning for gamma unit treatment system

During a treatment using the Leksell gamma unit, the physician and physicist need to determine a treatment plan by changing the parameters such as collimator sizes, the position of isocenters and isocenters' weights. This is a complex problem because the set of parameters is large, especially when targets are geometrically close to a critical structure. For this reason, we present here an optimization algorithm, namely the multiplier penalty method, to mathematically determine those parameters. Two cases are presented in this article: the first one is really planned by a physicist in a clinical treatment, and is redone in our optimization algorithm to show the effectiveness of this method; the second one is theoretical where a critical structure is placed close to the target volume. The results show that this method achieves an excellent conformation to the specified isodose curve with the contour of the target volume, allowing minimal damage to surrounding healthy tissue.     

Profile of ambulatory radiosurgery with the gamma knife system. 1: Method and multicenter irradiation concept]

Radiosurgery represents a minimally invasive radiologic method for the treatment of intracranial tumours and arteriovenous malformations. In 1994 the radiosurgical device 'Leksell Gamma Knife' (LGK) was installed in a dedicated logistic environment for outpatient treatments. High quality requirements have to be met for radiosurgery. The target point accuracy taking into account the whole system was shown to be reliably below 0.5 mm whereas the spatial therapeutic resolution was 0.035 cm3. Quality parameters of the dose plan were evaluated for the first 500 consecutive treatments. These values and examples of dose plans were used to emphasize the advantages of the treatment principle with multiple isocenters. An analysis of data in the literature revealed that there is no uniform standard of treatment available in radiosurgery. A highly significant correlation between a risk prediction model for the stereotactic linear accelerator on the one hand and a different model for the LGK on the other could be shown. This result could be helpful in order to proceed towards a more uniform treatment standard in radiosurgery and to improve overall treatment results.     

Comparison of parental and health care professional preferences for the acellular or whole cell pertussis vaccine

PURPOSE: To evaluate the efficacy and toxicity of gamma knife radiosurgery in the treatment of melanoma metastases to the brain. PATIENTS AND METHODS: We retrospectively reviewed 55 patients with single or multiple intracranial melanoma metastases treated at the University of California, San Francisco, with gamma knife radiosurgery from 1991 through 1995. Sixteen patients were treated with gamma knife radiosurgery for recurrence following previous radiation therapy, 11 received radiosurgery as a boost to whole-brain radiation therapy, and 28 had radiosurgery alone for initial management of brain metastases. The median minimum radiosurgery tumor dose for 140 treated lesions was 19 Gy (range, 10-22 Gy) prescribed at the 35% to 90% isodose contour (median, 50%). The median total target volume per patient was 6.1 cc (range, 0.25-28.3 cc). RESULTS: With a median follow-up of 75 weeks in living patients, the median survival times were 35 weeks overall: 35 weeks for patients with solitary metastases versus 33 weeks for those with multiple metastases. A factor that was significant in univariate analysis of survival was total target volume treated. This parameter remained significant on multivariate analysis. The actuarial median freedom from progression analyzed by lesion for 113 lesions in 46 patients with imaging follow-up was 89 weeks with 6-month and 1-year actuarial freedom from progression rates of 89% (95% confidence interval, 80%-95%) and 77% (95% confidence interval, 62%-87%). In univariate analysis, improved freedom from progression was associated with smaller target volume treated, smaller maximum diameter, or higher prescribed dose. Four patients (7%) developed acute Radiation Therapy Oncology Group grade > or = 2 morbidity, and five patients (9%) developed late grade > or = 2 morbidity. DISCUSSION: Median survival and freedom from progression in patients treated with radiosurgery for melanoma metastatic to the brain are comparable to results in published radiosurgery series of grouped histologies. For melanoma patients, total intracranial tumor volume appears to be of greater prognostic significance than the absolute number of metastases treated. We conclude that gamma knife radiosurgery is effective and should be considered among various management strategies.     

Radiation optic neuropathy after stereotactic radiosurgery

PURPOSE: The purpose of the study is to report the occurrence of optic neuropathy after stereotactic radiosurgery for perichiasmal tumors. METHODS: Records of four patients with visual deterioration after stereotactic radiosurgery were reviewed, including clinical findings, neuroimaging results, and treatment methods. RESULTS: Optic neuropathy developed 7 to 30 months after gamma knife radiosurgery. All patients experienced an abrupt change in visual function. Clinical findings indicated anterior visual pathway involvement. Patterns of field loss included nerve fiber bundle and homonymous hemianopic defects. Gadolinium-enhanced magnetic resonance imaging (MRI) showed swelling and enhancement of the affected portion of the visual apparatus in three patients. Systemic corticosteroids were administered in all patients and one partially recovered. One patient also received hyperbaric oxygen without improvement. CONCLUSIONS: Although rare, optic neuropathy may follow radiosurgery to lesions near the visual pathways. Careful dose planning guided by MRI with restriction of the maximal dose to the visual pathways to less than 8 Gy will likely reduce the incidence of this complication.     

Arnold-Chiari malformation in a captive African lion cub

PURPOSE: Surgery and systemic chemotherapy offer modest benefit to patients with recurrent glioblastoma multiforme. These tumors are associated with rapid growth and progressive neurological deterioration. Radiosurgery offers a rational alternative treatment, delivering intensive local therapy. A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous (i.v.) Taxol as a radiation sensitizer. METHODS AND MATERIALS: The treatment outcome was analyzed in 14 patients with recurrent glioblastoma treated with fractionated stereotactic radiosurgery and concurrent Taxol. Median tumor volume was 15.7 cc and patients received a mean radiation dose of 6.2 Gy at 90% isodose line, 4 times weekly. The median dose of Taxol was 120 mg/m2. RESULTS: The median survival was 14.2 months, 1-year survival was 50%. CONCLUSIONS: Survival for this small group of patients was similar to or better than historical controls or patients treated with single-fraction radiosurgery alone. This data should stimulate the investigation of both fractionated radiosurgery and the development of radiation sensitizers to further enhance treatment.     

Effects of gamma knife radiosurgery for brain tumors: clinical evaluation

BACKGROUND: Gamma knife radiosurgery is a safe and effective alternative to microsurgery in the management of selected intracranial lesions. In our initial three-year experience with gamma knife radiosurgery, 431 patients were treated using this method. This report presents the treatment results for three different types of brain tumors: benign meningiomas, malignant metastases and gliomas. METHODS: A retrospective study was performed to analyze a consecutive series of 71 meningiomas, 31 metastatic tumors and 21 gliomas treated by gamma knife radiosurgery between March 1993 and May 1996. The treatment results were investigated using regular magnetic resonance examinations and tumor volume measurement at six-month intervals to observe sequential changes of the tumors. Patients with meningiomas were further divided into three groups according to the peripheral radiation doses: high-dose (20-17 Gy, n = 18), medium-dose (16-15 Gy, n = 33) and low-dose (14-12 Gy, n = 20). The Generalized Estimation Equation was applied to compare treatment results in these three groups with different doses and tumor volumes. RESULTS: Volume measurements of the 71 meningiomas showed that 76% decreased in size, 16% stabilized and 8% increased in size. The volumes increased most frequently in the early stage (6-12 months) after treatment and subsequently regressed after the twelfth month. The tumor control rate for meningiomas in our three-year follow-up was over 90%. For meningiomas, the statistical analysis showed that both the radiation dose and tumor volume were significantly related to the development of adverse radiation effects (p < 0.05). In metastatic tumors, rapid tumor regression after radiosurgery was found in 87% of the patients. In gliomas, radiosurgery effectively inhibited tumor growth in selected patients with small, circumscribed, less infiltrative tumors. Ependymomas and low-grade astrocytomas had more favorable outcomes than other gliomas. CONCLUSIONS: Gamma knife radiosurgery is effective for controlling tumor growth in benign meningiomas for up to three years after surgery. In selected cases of malignant metastasis and gliomas, most patients appeared to benefit from the treatment with symptomatic improvement and prolonged survival. Treatment strategy and dose selection in radiosurgery should be adjusted to optimize tumor control and avoid adverse radiation effects.     

Risk analysis of linear accelerator radiosurgery

PURPOSE: To evaluate the toxicity of stereotactic single-dose irradiation and to compare the own results with already existing risk prediction models. METHODS AND MATERIALS: Computed tomography (CT) or magnetic-resonance (MR) images, and clinical data of 133 consecutive patients treated with linear accelerator radiosurgery were analyzed retrospectively. Using the Cox proportional hazards model the relevance of treatment parameters and dose-volume relationships on the occurrence of radiation-induced tissue changes (edema, localized blood-brain barrier breakdown) were assessed. RESULTS: Sixty-two intraparenchymal lesions (arteriovenous malformation (AVM): 56 patients, meningioma: 6 patients) and 73 skull base tumors were selected for analysis. The median follow-up was 28.1 months (range: 9.0-58.9 months). Radiation-induced tissue changes (32 out of 135, 23.7%) were documented on CT or MR images 3.6-58.7 months after radiosurgery (median time: 17.8 months). The actuarial risk at 2 years for the development of neuroradiological changes was 25.8% for all evaluated patients, 38.4% for intraparenchymal lesions, and 14.6% for skull base tumors. The coefficient: total volume recieving a minimum dose of 10 Gy (VTREAT10) reached statistical significance in a Cox proportional hazards model calculated for all patients, intraparenchymal lesions, and AVMs. In skull base tumors, the volume of normal brain tissue covered by the 10 Gy isodose line (VBRAIN10) was the only significant variable. CONCLUSIONS: These results demonstrate the particular vulnerability of normal brain tissue to single dose irradiation. Optimal conformation of the therapeutic isodose line to the 3D configuration of the target volume may help to reduce side effects.     

Frame slippage verification in stereotactic radiosurgery

PURPOSE: To develop a method for detecting frame slippage in stereotactic radiosurgery by interactively matching in three dimensions Digitally Reconstructed Radiographs (DRRs) to portal images. METHODS AND MATERIALS: DRRs are superimposed over orthogonal edge-detected portal image pairs obtained prior to treatment. By interactively manipulating the CT data in three dimensions (rotations and translations) new DRRs are generated and overlaid with the orthogonal portal images. This method of matching is able to account for ambiguities due to rotations and translations outside of the imaging plane. The matching procedure is performed with anatomical structures, and is used in tandem with a fiducial marker array attached to the stereotactic frame. The method is evaluated using portal images simulated from patient CT data and then tested using a radiographic head phantom. RESULTS: For simulation tests a mean radial alignment error of 0.82 mm was obtained with the 3D matching method compared to a mean error of 3.52 mm when using conventional matching techniques. For the head phantom tests the mean alignment displacement error for each of the stereotactic coordinates was found to be delta(x) = 0.95 mm, delta(y) = 1.06 mm, delta(z) = 0.99 mm, with a mean error radial of 1.94 mm (SD = 0.61 mm). CONCLUSION: Results indicate that the accuracy of the system is appropriate for stereotactic radiosurgery, and is therefore an effective tool for verification of frame slippage.     

Viability of an isocentric cobalt-60 teletherapy unit for stereotactic radiosurgery

The potential for radiosurgery with an isocentric teletherapy cobalt unit was evaluated in three areas: (1) the physical properties of radiosurgical beams, (2) the quality of radiosurgical dose distributions obtained with four to ten noncoplanar converging arcs, and (3) the accuracy with which the radiosurgical dose can be delivered. In each of these areas the cobalt unit provides a viable alternative to an isocentric linear accelerator (linac) as a radiation source for radiosurgery. A 10 MV x-ray beam from a linac used for radiosurgery served as a standard for comparison. The difference between the 80%-20% penumbras of stationary radiosurgical fields in the nominal diameter range from 10 to 40 mm of the cobalt-60 and 10 MV photon beams is remarkably small, with the cobalt-60 beam penumbras, on average, only about 0.7 mm larger than those of the linac beam. Differences between the cobalt-60 and 10 MV radiosurgical treatment plans in terms of dose homogeneity within the target volume, conformity of the prescribed isodose volume to the target volume, and dose falloffs outside the target volume are also minimal, and therefore of essentially no clinical significance. Moreover, measured isodose distributions for a radiosurgical procedure on our Theratron T-780 cobalt unit agreed with calculated distributions to within the +/- 1 mm spatial and +/- 5% numerical dose tolerances, which are generally specified for radiosurgery. The viability of isocentric cobalt units for radiosurgery will be of particular interest to centers in developing countries where cobalt units, because of their relatively low costs, provide the only megavoltage source of radiation for radiotherapy, and could easily and inexpensively be modified for radiosurgery. Of course, the quality assurance protocols and mechanical condition of a particular teletherapy cobalt unit must meet stringent requirements before the use of the unit for radiosurgery can be advocated.     

Preventive effects of an antiallergic drug, pemirolast potassium, on restenosis after percutaneous transluminal coronary angioplasty

PURPOSE: Radiosurgery is an effective treatment for cerebral arteriovenous malformations. We conducted the present study to investigate the feasibility and efficacy of gamma knife radiosurgery for dural arteriovenous fistulas (DAVFs) of the cavernous sinus. METHODS: Eighteen patients (12 women and six men; 29-75 years old [mean age, 55 years]) with DAVFs of the cavernous sinus (Barrow's type B:1, C:7, and D:10) treated by gamma knife radiosurgery were enrolled in the study. DAVFs were bilateral in six patients and unilateral in 12. Stereotactic X-ray angiography and MR imaging were performed for targeting the radiosurgery. Areas of arteriovenous communication targeted for irradiation were first outlined on the X-ray angiograms. The target regions were then transferred to and displayed on the MR images. Dose planning was based on findings on the integrated images. Prescribed maximum target doses were 22 to 38 Gy (mean, 28 Gy). The targets were covered by 50% to 90% isodose levels. Radiation doses to the surrounding optic apparatus were kept to less than 8 Gy. The patients were followed up with color Doppler sonography and MR imaging. When noninvasive imaging suggested obliteration, X-ray angiography was performed to verify the results. RESULTS: The DAVFs were totally obliterated in 12 (80%) of the 15 patients. In the other three, one was almost completely obliterated at 14 months and two were partially obliterated at 19 and 27 months, respectively, after radiosurgery. No complications or symptom worsening occurred during the follow-up period. CONCLUSION: Gamma knife radiosurgery is a feasible, effective, and safe treatment for DAVFs of the cavernous sinus. Integration of stereotactic X-ray angiography and MR imaging not only aids treatment efficacy but also protects the relevant vital structures, especially the optic apparatus, from the hazards of radiation.     

Pathological changes in surgically resected angiographically occult vascular malformations after radiation

OBJECTIVE: The goal of this study was to evaluate the pathological changes associated with radiation treatment (stereotactic radiosurgery or conventional irradiation) of angiographically occult vascular malformations (AOVMs). METHODS: Eleven patients underwent surgical resection of an AOVM in the mesial temporal lobe, brain stem, thalamus, or basal ganglia after previous radiation treatment. The indications for surgery were recurrent symptomatic bleeding from the lesion in 10 patients and recurrent intractable seizures in 1 patient. Radiation was used as the initial therapy because the risk of surgical resection was deemed too high. Three patients received conventional radiation therapy of 3000 to 5400 rads at an outside institution. One patient received radiosurgery with the gamma knife at another institution using a dose of 15 Gy to the margin. The remaining 7 patients received stereotactic radiosurgery with a helium-ion particle beam. The dose range was from 18 to 26 Gy equivalents. The interval from radiation to surgical resection ranged from 1 to 10 years, with a mean of 3.5 years. These lesions were compared with 10 nonirradiated cavernous malformations. RESULTS: One irradiated lesion was identified pathologically as a true arteriovenous malformation despite being angiographically occult. This lesion did not demonstrate significant changes in the vasculature but did have radiation necrosis of the surrounding brain 5 years after 25 Gy equivalents of helium-ion radiosurgery. Two other specimens were too small to identify the type of vascular malformation adequately. Of the remaining eight malformations identified as cavernous malformations, six showed a combination of marked fibrosis of the vascular channels, fibrinoid necrosis, and ferrugination. However, the fibrinoid necrosis was the only finding unique to the irradiated lesions compared with nonirradiated controls. All the irradiated lesions still had patent vascular channels; none were completely thrombosed. CONCLUSION: Radiosurgery or conventional radiation therapy did not cause histologic vascular obliteration in intracranial AOVMs evaluated 1 to 10 years (mean 3.5 yr) after radiation delivery. It should be recognized that these patients are irradiation failures who may not be representative of all irradiated patients. However, recurrent bleeding from AOVMs may relate to poor radiation response in some patients.     

Anaesthetic considerations for children undergoing stereotactic radiosurgery

An anaesthetic case report of children undergoing stereotactic radiosurgery is presented, with a review of the inherent unique anaesthetic challenges. Twelve stereotactic radiosurgery procedures performed at The Prince of Wales Hospital, Sydney, were retrospectively reviewed. Despite differences in approach by individual anaesthetists to managing these children, an overall safe sequence may be evolved. The use of stereotactic radiosurgery for paediatric neuropathology is reviewed. The potential anaesthetic problems related to the paediatric patient and the peculiarities of the procedure are discussed and related to our series.     

Stereotactic radiosurgery with linear accelerator

Stereotactic radiosurgery is a method that applies a radiation dose to a limited and well-defined volume while the irradiation of adjacent healthy tissues is minimized. It is most commonly used in the treatment of intracranial lesions because the skull hardness assures the stable location of its contents. Treatment of the rest of the body has recently been proposed and carried out, using original immobilization systems. Stereotactic radiosurgery was first described in 1951 by the Swedish neurosurgeon Lars Leksell who originally used X-rays and then high-energy protons as a source of radiation. In the '80s photons from linear accelerators were used as radiation source, with various stereotactic systems and computerized treatment planning. The method used with all radiosurgical systems, regardless of the source of irradiation, is similar. The lesion is detected with common diagnostic imaging and adequate location frames. At present, to prevent errors in location, MRI and CT data are matched using an Image Fusion computer program. The objective of stereotactic radiosurgery is to destroy tumor cells or to induce changes in tissues that, as in brain arteriovenous malformations lead to the occlusion of their abnormal vessels. Stereotactic radiosurgery is increasingly used today in the treatment of a variety of intracranial lesions to the patients' benefit.     

Interim report on the radiosurgical treatment of cerebral arteriovenous malformations. The influence of size, dose, time, and technical factors on obliteration rate

During the authors' initial 4-year experience with radiosurgery using the Leksell cobalt-60 gamma unit, they treated 121 patients with cerebral arteriovenous malformations (AVMs). The radiosurgical dose to the margin of the nidus was 20 Gy for lesions less than 2.0 cm in diameter (volume < or = 4.2 cm3); 18 Gy for malformations 2.1 to 3.0 cm in diameter (volume 4.2-14.1 cm3); and 16 Gy for malformations greater than 3.0 cm (volume > 14.1 cm3). Fifty-one patients underwent follow-up angiography between 1 and 3 years after treatment, and complete obliteration of the nidus was confirmed in 38 (74.5%) of these patients. Thirty-two (74.4%) of 43 AVMs with volumes of 10 cm3 or less and six (75%) of eight larger AVMs (volume 11-30 cm3) showed complete obliteration. Analysis of the time course of AVM nidus shrinkage and obliteration showed that most of the radiosurgically induced effect had occurred by 36 months after treatment. Retrospective analysis of the dose plans for 10 AVMs that were not obliterated by 36 months after gamma knife radiosurgery at the authors' institution (eight cases) or elsewhere (two cases) revealed that six AVMs had not been covered completely by the prescribed isodose. Six (5%) of the 121 patients developed neurological deficits as a direct result of radiosurgical treatment. The authors infer from these data that malformations up to 30 cm3 in volume (approximately 4.0 cm in average diameter) can be treated effectively with an acceptably low complication rate using a radiosurgical dose of 16 Gy to the margin of the nidus. The obliteration rate for the larger malformations that were treated with a dose of 16 to 18 Gy appears to be similar to that for smaller ones treated with 18 to 20 Gy. As more experience accrues using radiosurgery to treat AVMs, patient selection criteria and the variables associated with successful obliteration of the nidus should become more clearly defined.     

Specific activation of telomerase in pancreatic cancer tissue and preoperative diagnosis of pancreatic cancer by telomerase in pancreatic juice

OBJECTIVE AND IMPORTANCE: We describe the successful treatment of symptomatic giant arteriovenous malformations (AVMs) using staged volume radiosurgery followed by microsurgical resection. CLINICAL PRESENTATION: A 57-year-old man presented with Spetzler-Martin Grade 5 AVMs, with persistent headaches and seizures. He had previously undergone eight attempts at AVM embolization and a craniotomy for attempted AVM resection; he had suffered four episodes of brain hemorrhaging but had made a good neurological recovery. INTERVENTION: Because of the persistent symptoms of the patient and his history of hemorrhaging, a treatment plan based on staged radiosurgical treatments of different portions of the AVMs (three sessions, spaced 6 mo apart), followed by delayed microsurgical removal of the much-reduced residual AVMs (3 years later), was undertaken. The patient did not suffer any additional hemorrhaging episodes, his AVMs were completely removed, and he has made a good recovery. CONCLUSION: Staged volume radiosurgery followed by microsurgical resection of the residual AVMs represents a novel treatment strategy for the management of Grade 5 AVMs that might be untreatable by any single treatment method used alone.     

Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme

The purpose of this study was to compare the efficacy of stereotactic radiosurgery (SRS) and brachytherapy in the treatment of recurrent glioblastoma multiforme (GBM). The patients had either progressive GBM or pathologically proven GBM at recurrence after previous treatment for a lower grade astrocytoma. Thirty-two patients were treated with interstitial brachytherapy, and 86 received treatment with stereotactic radiosurgery (SRS). The patient characteristics were similar in the two groups. Those patients treated with SRS had a median tumor volume of 10.1 cm3 and received a median peripheral tumor dose of 13 Gy. Patients treated with brachytherapy had a median tumor volume of 29 cm3. Median dose to the periphery of the tumor volume was 50 Gy delivered at a median dose rate of 43 cGy/hour. Twenty-one patients (24%) treated with SRS were alive, with a median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with SRS was 10.2 months, with survivals of 12 and 24 months being 45 and 19%, respectively. A younger age and a smaller tumor volume were predictive of better outcome. The tumor dose, the interval from initial diagnosis, and the need for reoperation were not predictive of outcome after SRS. Five patients (16%) treated with brachytherapy were alive, with a median follow-up of 43.3 months. The median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals of 12 and 24 months were 44 and 17%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of saiboku-to and compornent herbs on the production of peptide leukotrienes (LTs) and LTB4]

We report our early experience using stereotactic radiotherapy (radiosurgery) in the treatment of cranial neuroma, by the linear accelerator method. We report the first 13 neuromas treated in 12 patients (follow-up 6-60 months). Radiologically, seven of 10 patients demonstrated signs of central tumour necrosis on follow-up scanning and four of these also demonstrated shrinkage. Of seven assessable acoustic neuroma patients treated, hearing was stabilized in three and improved in two. An abducent neuroma patient treated by this method is reported and demonstrated good response. Our preliminary studies endorse the opinion that stereotactic radiosurgery is a suitable and safe alternative to microsurgical procedures in the management of many cranial neuromas. Indications for stereotactic radiosurgery are discussed.