Evaluation of 177Lu[Lu]-CHX-A″-DTPA-6A10 Fab as a radioimmunotherapy agent targeting carbonic anhydrase XII.

INTRODUCTION: Due to their infiltrative growth behavior, gliomas have, even after surgical resection, a high recurrence tendency. The approach of intracavitary radioimmunotherapy (RIT) is aimed at inhibiting tumor re-growth by directly administering drugs into the resection cavity (RC). Direct application of the radioconjugate into the RC has the advantage of bypassing the blood-brain barrier, which allows the administration of higher radiation doses than systemic application. Carbonic anhydrase XII (CA XII) is highly expressed on glioma cells while being absent from normal brain and thus an attractive target molecule for RIT. We evaluated a CA XII-specific 6A10 Fab (fragment antigen binding) labelled with 177Lu as an agent for RIT. METHODS: 6A10 Fab fragment was modified and radiolabelled with 177Lu and characterized by MALDI-TOF, flow cytometry and radio-TLC. In vitro stability was determined under physiological conditions. Biodistribution studies, autoradiography tumor examinations and planar scintigraphy imaging were performed on SCID-mice bearing human glioma xenografts. RESULTS: The in vitro CA XII binding capacity of the modified Fab was confirmed. Radiochemical purity was determined to be >90% after 72 h of incubation under physiological conditions. Autoradiography experiments proved the specific binding of the Fab to CA XII on tumor cells. Biodistribution studies revealed a tumor uptake of 3.0%ID/g after 6 h and no detectable brain uptake. The tumor-to-contralateral ratio of 10/1 was confirmed by quantitative planar scintigraphy. CONCLUSION: The radiochemical stability in combination with a successful in vivo tumor uptake shows the potential suitability for future RIT applications with the 6A10 Fab.

Anatomic features of glioblastoma and their potential impact on survival.

BACKGROUND: Many reports on glioblastoma multiforme discuss the prognostic impact of anatomical features such as cysts, necrotic changes, extent of edema or subependymal spread of tumor cells. In the present study, we examined different growth patterns and their possible relations to patient survival. METHODS: To analyze whether anatomical characteristics are related to prognosis, we reviewed the prospectively collected pre- and postoperative MRIs of 83 patients in the 5-ALA study, provided by the 5-ALA Glioma Study Group. Following a standardized analytic work flow, the tumor volume and site, presence of necrosis or cysts, and perifocal edema were assessed preoperatively. In the same way, postoperative MRI and the MRI at first recurrence were analyzed. In addition, survival time of the patients was documented. RESULTS: Median survival time of all 83 patients was 15.1 months (range 1.5 to 70.1, mean 18). The site or volume of glioblastoma, as well as the presence of intratumoral necrosis or cysts, did not exert a significant effect on survival time; 96.4 % of recurrences occurred within the former resection margin. Tumors with initial contact with the subependymal zone had multifocal or ventricular recurrences significantly more often. In patients with residual tumor on early postoperative MRI, the follow-up images displayed enlargement of the remnants in 91.9 % of these cases. CONCLUSIONS: A merely anatomical analysis of the glioblastoma growth pattern cannot reliably provide prognostic information. The occurrence of most recurrences next to the resection margin and the high percentage of growing residual tumors underline the importance of complete resections.

Training charter in epilepsy surgery added competence.

The present Training Charter in Epilepsy Surgery Added Competence constitutes the third stage of a program initiated by the European Society for Stereotactic and Functional Neurosurgery (ESSFN) and substantiated in close collaboration with the Union Européennedes Médecins Spécialists (UEMS) and the European Association of Neurosurgical Societies (EANS). This program aims to raise the standards of clinical practice by guiding education and quality control concepts. The particular sections of this Charter include: definitions and standards of added competence training, relations of the Epilepsy Unit with the Neurosurgical Department, duration of epilepsy surgery fellowship, institution and training program director requirements, operative totals for epilepsy surgery, educational program, individual requirements, and evaluation and qualification of the trainees. The specification of all these requirements is expected to improve harmonisation and quality of epilepsy surgery practice across Europe, and enhance the clinical activity and the scientific productivity of existing neurosurgical centres.

A report on neurosurgical workforce in the countries of the EU and associated states. Task Force "Workforce Planning", UEMS Section of Neurosurgery.

AIM: Aim of this report was to present recently collected data on neurosurgical workforce in the countries of the EU and associated states. METHODS: Data were obtained from 27 countries by means of a questionnaire developed by members of a working group of the UEMS Section of Neurosurgery (UEMS = Union Europénne des Médecins Spécialistes; European Union of Medical Specialists). Most data originate from 2005/2006. Results were discussed, amended, and approved by the countries' delegates of the UEMS Section of Neurosurgery. RESULTS: The number of Neurosurgeons (NS) per population varies considerably among these countries. The mean is one neurosurgeon per 99,152 population. The number of neurosurgical operations per population per year varies similarly with a mean of 1,642 operations per million population/year. Countries with fewer neurosurgeons per population tend to have less neurosurgical operations per population and vice versa. The average number of operations performed by one neurosurgeon per year (annual caseload) is between 56 and 300 with a mean of 154. A numerus clausus for neurosurgical training is reported in 13 countries, another 13 countries have no numerus clausus. The annual intake of new trainees is between 2.4 and 10.3% of the number of accredited neurosurgeons with a mean of approx. 5.2%. The average yearly loss rate due to retirement, sickness, other activities, etc. can only be estimated and lies in the range between 2.3 and 3.36% of the number of accredited NS. According to the figures provided by the countries, the total number of accredited NS in 2005/2006 was approx. 6,280 for a population of about 504.7 millions. These countries had an annual intake of approx. 332 new trainees.

The revised European neurosurgical electronic logbook of operations.

The revised electronic neurosurgical logbook is a standalone windows application supporting multiple languages that allows the neurosurgeon in training to enter all operations he is involved in. This data can be summarised and printed as required by the UEMS at the end of the training period.

Oedema formation in experimental photo-irradiation therapy of brain tumours using 5-ALA.

BACKGROUND: Five-aminolevulinic acid (5-ALA) induces the specific accumulation of photosensitising porphyrins in malignant gliomas and has been explored for photo-irradiation therapy of these tumours. However, information is unavailable on whether and to what extent this treatment modality may induce the formation of brain oedema, and how potential oedema might be treated. METHODS: Rats were implanted with C6 gliomas. Eight days later magnetic resonance images (MRI) were obtained. On day 9 rats received 100 mg 5-ALA/kg b.w. and were craniotomized for photo-irradiation of tumours 6 hours later (100 J/cm2, 635 nm argon-dye laser). Part of the animals was treated with daily dexamethasone injections (0.3 mg/kg), beginning 6 hours before phototherapy. 72 hours later, brains were removed and dissected according to tumour dimensions on pre-therapy MRI into "tumour", "brain around tumour" (BAT), residual cortex and basal ganglia, for measurements of water contents. Measurements were also performed in untreated animals with tumours, with or without steroid treatment and in control animals. An additional group of animals lacking tumours, with or without steroid treatment, underwent 5-ALA-phototherapy to determine effects on normal brain. RESULTS: C6 gliomas induced brain oedema, which responded to steroid treatment. 5-ALA-phototherapy resulted in additional oedema, which responded partly to steroids. 5-ALA-phototherapy of normal brain increased water content moderately in irradiated cortex. This oedema was also partly counteracted by steroids. CONCLUSIONS: Photo-irradiation therapy with 5-ALA induces oedema which is partly counteracted by steroid therapy. The possibility of steroid resistant oedema formation should be considered when planning human trials with this treatment modality.

Image guided interstitial laser thermotherapy: a canine model evaluated by magnetic resonance imaging and quantitative autoradiography.

OBJECTIVE: To determine the applicability and safety of a new canine model suitable for correlative magnetic resonance imaging (MRI) studies and morphological/pathophysiological examination over time after interstitial laser thermotherapy (ILTT) in brain tissue. MATERIAL AND METHODS: A laser fibre (Diode Laser 830 nm) with an integrated temperature feedback system was inserted into the right frontal white matter in 18 dogs using frameless navigation technique. MRI thermometry (phase mapping i.e. chemical shift of the proton resonance frequency) during interstitial heating was compared to simultaneously recorded interstitial fiberoptic temperature readings on the border of the lesion. To study brain capillary function in response to ILTT over time quantitative autoradiography was performed investigating the unidirectional blood-to-tissue transport of carbon-14-labelled alpha amino-isobutyric acid (transfer constant K of AIB) 12, 36 hours, 7, 14 days, 4 weeks and 3 months after ILTT. RESULTS: All laser procedures were well tolerated, laser and temperature fibres could be adequately placed in the right frontal lobe in all animals. In 5 animals MRI-based temperature quantification correlated strongly to invasive temperature measurements. In the remaining animals the temperature fibre was located in the area of susceptibility artifacts, therefore, no temperature correlation was possible. The laser lesions consisted of a central area of calcified necrosis which was surrounded by an area of reactive brain tissue with increased permeability. Quantitative autoradiography indicated a thin and spherical blood brain barrier lesion. The magnitude of K of AIB increased from 12 hours to 14 days after ILTT and decreased thereafter. The mean value of K of AIB was 19 times (2 times) that of normal white matter (cortex), respectively. CONCLUSION: ILTT causes transient, highly localised areas of increased capillary permeability surrounding the laser lesion. Phase contrast imaging for MRI thermomonitoring can currently not be used for reliable temperature readings in vivo. The suggested new canine model proved to be safe, accurate, easy to use, and provides clinical, radiographic, pathological and physiological correlations.

Internal regulations and general guidelines of a neurosurgical department and training programme.

It is strongly recommended that general guidelines and internal regulations be laid down in written form by the department. The guidelines regulate the general workflow and related trainee duties and responsibilities, education and research, special procedures for particular diseases and conditions (standards of care). Regarding general workflow of the department, the following items should be laid down once in written form: time table of department, working hours, admission procedures, medical records directives, responsibilities on wards and in the emergency unit, patient information, discharge procedures, outpatient consultations, call schedule and on-call duty plan, as well as week-end and holiday regulations for rounds on wards and ICU. Regarding education and research, the following items should be written down: conferences and teaching rounds, policies on presentations and publications, policies regarding meetings and courses, research leave and vacation plan. The written definition of standards of care is still considered optional in neurosurgery at the present time.

Prospective documentation and analysis of the pre- and early clinical management in severe head injury in southern Bavaria at a population based level.

Treatment of patients suffering from severe head injury is so far restricted to general procedures, whereas specific pharmacological agents of neuroprotection including hypothermia have not been found to improve the outcome in clinical trials. Albeit effective, symptomatic measures of the preclinical rescue of patients (i.e. stabilization or reestablishment of the circulatory and respiratory system) or of the early clinical care (e.g. prompt diagnosis and treatment of an intracranial space occupying mass, maintenance of a competent circulatory and respiratory system, and others) by and large constitute the current treatment based on considerable organizational and logistical efforts. These and other components of the head injury treatment are certainly worthwhile of a systematic analysis as to their efficacy or remaining deficiencies, respectively. Deficits could be associated with delays of providing preclinical rescue procedures (e.g. until intubation of the patient or administration of fluid). Delays could also be associated in the hospital with the diagnostic establishment of intracranial lesions requiring prompt neurosurgical intervention. By support of the Federal Ministry of Education and Research and under the auspices of the Forschungsverbund Neurotraumatology, University of Munich, a prospective system analysis was carried out on major aspects of the pre- and early clinical management at a population based level in patients with traumatic brain injury. Documentation of pertinent data was made from August 1998 to July 1999 covering a catchment area of Southern Bavaria (5.6 mio inhabitants). Altogether 528 cases identified to suffer from severe head injury (GCS < or = 8 or deteriorating to that level within 48 hrs) were enrolled following admission to the hospital and establishment of the diagnosis. Further, patients dying on the scene or during transport to the hospital were also documented, particularly as to the frequency of severe head injury as underlying cause of mortality. The analysis included also cases with additional peripheral trauma (polytrauma). The efficacy of the logistics and organization of the management was studied by documentation of prognosis-relevant time intervals, as for example until arrival of the rescue squad at the scene of an accident, until intubation and administration of fluid, or upon hospital admission until establishment of the CT-diagnosis and commencement of surgery or transfer to the intensive care unit, respectively. The severity of cases studied in the present analysis is evident from a mortality of far above 40% of cases admitted to the hospital, which was increased by about 20% when including prehospital mortality. The outcome data notwithstanding, the emerging results demonstrate a high efficacy of the pre- and early clinical management, as indicated by a prompt arrival of the rescue squad at the scene, a competent prehospital and early clinical management and care, indicative of a low rate of avoidable complications. It is tentatively concluded on the basis of these findings that the patient prognosis is increasingly determined by the manifestations of primary brain damage vs. the development of secondary complications.

Surgical resection of gliomas WHO grade II and III located in the opercular region.

BACKGROUND: Surgery in the opercular region especially in the dominant hemisphere impose a major challenge for the neurosurgeon due to the close vicinity to functional important motor and speech areas. The purpose of the present study is to analyse on a homogenous patient group pre- and postoperative functional deficits with regard to different speech qualities (e.g. aphasia, apraxia), and to correlate these data with MR and intraoperative monitoring results. METHOD: Fourteen patients with suspected low grade astrocytomas in the opercular region consecutively treated by surgery were eligible for this study (histology revealed 3 WHO grade III tumours). Degree and duration of postoperative deficits were retrospectively evaluated according to tumour location and boundaries on MR, intraoperative neuromonitoring results and extent of tumour resection. FINDINGS: Postoperatively, 8 patients showed speech or language disturbances, in 4 patients combined with motor deficits mainly of the contralateral upper extremity. Fifty percent of the neuropsychologically tested patients exhibited speech apraxia while the other 50% had a true aphasic syndrome. Recovery of the latter deficits was in general faster and more complete. The severity and duration of postoperative deficits was in good correlation with the distance of the resection margin to the next positive stimulation point(s), and a distance of more than 0.5 cm proved to avoid major impairments. The distribution of functional important stimulation points in relation to the tumour extension was not predictable, and -- unexpectedly -- up to 50% of these sites were found overlaying the tumour. INTERPRETATION: Surgery for WHO grade II and III gliomas in the opercular region can result in speech apraxia or an aphasic syndrome with or without concomitant motor deficits. Intraoperative cortical electrical stimulation is essential in resecting tumours in the opercular region to avoid permanent morbidity.

Fluorescence-guided resections of malignant gliomas--an overview.

Radical resections of contrast-enhancing tumour in patients with malignant gliomas may be pertinent for survival but are often difficult to achieve due to uncertainties in distinguishing tumour margins intra-operatively. In this respect a number of novel methods are being examined which aim at enhancing resections. Among these methods, resections that exploit the accumulation of fluorescent porphyrins within malignant glioma tissue in response to exogenous administration of a metabolic percursor, 5-aminolevulinic acid, may offer particular advantages. This article summarises the clinical background and current status of 5-ALA drug development for fluorescence-guided resections of malignant gliomas and analyses the available literature with regard to possible mechanisms that govern the highly specific accumulation of fluorescent porphyrins in malignant glioma tissue in response to 5-ALA administration.

Intralesional radioimmunotherapy in the treatment of malignant glioma: clinical and experimental findings.

In the last two decades radioimmunotherapy has been used as an additional treatment option for malignant glioma in several centers. More than 400 patients have been reported, who were treated in the framework of different studies. Most of them received labelled antibodies to tenascin, an extracellular matrix-glycoprotein, which is expressed in high amounts in malignant gliomas. We report side effects and survival time of 46 patients, treated after surgical resection and conventional radiotherapy with intralesionally injected labelled (131-Iodine) antibodies to tenascin. Despite the fact, that many treatments have been performed, little is known about the distribution properties of labelled antibodies after injection in the tumour cavity. For an optimal effect labelled antibodies should be able to reach tumour cells, which have migrated into the surrounding tissue. We investigated the propagation velocity and area of distribution of labelled antibodies and their considerably smaller fragments after the injection in C6-gliomas of Wistar rats. Propagation increased with time and was significantly greater after injection of labelled fragments than after injection of labelled antibodies. According to our results labelled fragments might be better able to reach distant tumour cells in the peritumoural tissue of malignant gliomas than labelled antibodies.