High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study.

BACKGROUND: To improve survival of elderly patients with primary central nervous system lymphoma (PCNSL), we conducted a phase II study with high-dose methotrexate (MTX) combined with procarbazine and CCNU. To reduce neurotoxicity, whole-brain irradiation was reserved for patients not responding to chemotherapy. PATIENTS AND METHODS: High-dose MTX was applied on days 1, 15, and 30, procarbazine on days 1-10, and CCNU on day 1. Study treatment comprised up to three 45-day cycles. There was no lower limit of Karnofsky performance status (KPS). RESULTS: Thirty patients with PCNSL (n = 29) or primary ocular lymphoma (n = 1) were included (median age 70 years, range 57-79 years). The median initial KPS was 60% (range 30%-90%). Best documented response in 27 assessable patients were 12 of 27 (44.4%) complete remissions, 7 of 27 (25.9%) partial remissions, and 8 of 27 (29.6%) disease progressions. Two patients died of probable treatment-related causes. With a median follow-up of 78 months (range 34-105), the 5-year overall survival is 33%. Eight of 30 patients (26.7%) are currently alive and well, six without signs of leukoencephalopathy. CONCLUSION: The combination of high-dose MTX with procarbazine and CCNU is feasible and effective and results in a low rate of leukoencephalopathy. Comorbidity and toxicity remain of concern when treating PCNSL in elderly patients.

Molecular genetic analysis as a tool for evaluating stereotactic biopsies of glioma specimens.

Over the last years, distinct genetic lesions have been associated with individual tumor entities. Stereotactic biopsy has become an essential diagnostic tool in surgical neuro-oncology. In order to evaluate the potential of molecular analyses in stereotactic biopsies, we examined a series of 156 human brain tumors from patients undergoing stereotactic biopsy for molecular alterations typically seen in astrocytic gliomas and compared those results with a control group of 268 astrocytic tumors obtained at open surgery. Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades II and III showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade II from open surgery (p = 0.011). Stereotactic biopsies of astrocytomas with borderline histopathological features between the WHO grades III and IV showed a higher rate of allelic losses on chromosome 10 than those of the WHO grade III from open surgery (p = 0.013). This indicates that stereotactic biopsies with features intermediate between grades are likely to correspond to the higher malignancy grade. Our data demonstrate that molecular genetic approaches can be successfully applied to stereotactic glioma biopsies. The difference in the distribution of malignancy associated genetic alterations between a stereotactic and openly resected group of gliomas indicates that histopathology may underestimate the malignant potential in some stereotactic specimens. We propose to further evaluate the molecular analysis of stereotactic glioma biopsies as a useful adjunct to standard histopathological procedures.

The risk of interstitial radiotherapy of low-grade gliomas.

BACKGROUND AND PURPOSE: The risk of side effects of low activity (i.e. <20 mCi) Iodine-125I (125I) interstitial radiotherapy was analyzed in patients with low-grade gliomas. MATERIALS AND METHODS: Permanent (247 patients) or temporary 125I-implants (268 patients) were used with a median reference dose of 60 Gy and 100 Gy, respectively, which was calculated to the outer rim of the tumour. The mean dose rate for temporary implants was low (median, 10 cGy/h). Risk factors were obtained from the multivariate proportional-hazards model. RESULTS: Radiogenic complications occurred in 39/515 patients (28 patients with transient symptoms and 11 patients with progressive symptoms). The most important risk factor was the volume of the intratumoural 200 Gy isodose. Available experimental data have associated a high dose zone in this range with the size of the treatment induced radionecrosis. Rapid tumour shrinkage (decrease of the tumour volume > or =50%) within the first 6 months with subsequent centripetal movement of non-pathologic tissue into the high dose zone and a reimplantation were additional risk factors. Radiation injury after rapid tumour shrinkage could be better avoided with temporary implants. A 200 Gy isodose volume <4.5 ml corresponded to an estimated risk of radiogenic complications <3%. There was a steep increase of the risk beyond this limit. Translation of the 200 Gy isodose volume in terms of the treatment volume and the reference dose allows rational treatment planning. The estimated risk of a temporary implant with an applied reference dose of 60 Gy and a treatment volume <23 ml was <3%. CONCLUSIONS: The intratumoural necrotizing effect of a low activity 125I implant limits its application to small treatment volumes. Radiation injury outside the treatment volume can be better avoided with temporary implants in the case of rapid tumour shrinkage.

Diagnostic value of CT in patients with Huntington's chorea and their offspring.

Striatal and cortical atrophy are significant features in the pathology of Huntington's chorea (HCh). A correlative study revealed that the CT findings of atrophy in HCh (8 patients) parallel the clinical and neurophysiological findings. In offspring (8 subjects) of HCh patients, however, the CT changes were insignificant although neurophysiological data were already suspicious in four of them. One patient with hereditary non-progressive chorea showed no CT changes at all. Perhaps with a more sensitive CT scanning technique minor morphological alterations may also be detected and used for a pre-clinical diagnosis.

Ventricular somatostatin-like immunoreactivity in patients with basal ganglia disease.

The concentrations of somatostatin-like immunoreactivity (SLI) in lateral ventricular fluid of patients with extrapyramidal motor disease were determined by specific radio-immunoassay. Mean SLI levels were significantly lower in patients with Parkinson's disease (mean +/- SEM); 42.9 +/- 2.9 fmol/ml) and in patients with dystonic syndromes (39.4 +/- 3.2) than in patients with benign essential tremor (65.3 +/- 9.7). The lowest levels were found in patients with athetosis (34.7 +/- 5.4). In parkinsonian patients somatostatin levels correlated with the degree of akinesia, rigidity and autonomic disturbances.

Regional cerebral blood flow in peritumoral brain edema during dexamethasone treatment: a xenon-enhanced computed tomographic study.

OBJECTIVE: Regional cerebral flood flow (rCBF) in peritumoral brain edema is assumed to be decreased because of increased interstitial pressure. Impaired blood flow might lead to local hypoxia, altered metabolism, and disturbed ion homeostasis, thus causing neurological sequelae. Steroid treatment is thought to positively influence the sequelae of brain edema. We aimed to determine the rCBF in peritumoral edema in humans receiving dexamethasone treatment and the relationship of rCBF to global CBF. METHODS: We measured rCBF in 11 patients with untreated anaplastic gliomas or glioblastomas that were World Health Organization Grade III or IV restricted to one hemisphere with significant peritumoral edema who were receiving a standard dose of dexamethasone. rCBF was determined using stable xenon-enhanced computed tomography in a stereotactic frame. Edema was defined both by means of actual histology (stereotactic biopsies) and by imaging criteria. RESULTS: rCBF in peritumoral edema was decreased by 32% as compared with contralateral normal white matter. In each patient, this reduction was linearly related to blood flow in nonaffected white matter and cortex. The flow ratio in the different compartments was 1 (edema):1.5 (contralateral white matter):2.7 (contralateral cortex). Absolute perfusion values in contralateral cortex (means +/- standard deviations) (29.9+/-7.1 ml/100 g/min) and contralateral white matter (16.1+/-3.7 ml/100 g/min) were significantly decreased as well. CONCLUSION: Our study demonstrated that rCBF in peritumoral brain edema during steroid treatment is still decreased and is in a range in which it may cause neurological sequelae. Also, global CBF was decreased in all patients.

Sequential morphological changes in the dog brain after interstitial iodine- 125 irradiation.

Iodine- 125 seeds (3.55 mCi) were stereotactically implanted into the subcortical white matter of the left coronal gyrus in six beagle dogs. Morphological changes were studied at intervals ranging from 25 to 368 days after implantation. In all of the animals, there was a calcifying necrosis 3 to 6 mm in diameter with an adjacent small zone of demyelination. There were no signs of delayed radiation damage outside the demyelinated perifocal zone. The central tissue necrosis was sharply delineated and did not increase in size after 70 days, i.e., an accumulated dose of 18,000 cGy. In addition, widespread vasogenic edema was present in the homolateral hemisphere. The morphological changes observed differed in many aspects from those found with other radioactive sources, such as gold-198, yttrium-90, or iridium-192. The low energy gamma radiation, the absence of beta radiation, and the half-life of 60.2 days makes iodine-125 a favorable radioactive source to produce a well-defined necrosis without delayed radiation damage in the surrounding brain.

Stereotactic management of lesions of the pineal region.

OBJECTIVE: The relevance of the computed tomography-guided stereotactic approach for the management of lesions of the pineal region is analyzed. METHODS: In a retrospective analysis conducted between 1985 and 1993, the risk profile, the diagnostic accuracy, and the therapeutic relevance of the stereotactic approach in 106 patients was studied. Survival analysis was used to assess the reliability of the stereotactically obtained diagnosis in terms of follow-up observation. RESULTS: A histological diagnosis was obtained in 103 of the 106 patients. In three patients, a conclusive diagnosis could not be established because of intraoperative complications. One lesion was misdiagnosed as a pineocytoma instead of a pineoblastoma. Two of the 106 patients died; 9 patients experienced perioperative morbidity. In 38 patients, the stereotactic approach was also useful for therapy. Cyst aspiration and/or internal drainage was performed in 18 patients with symptomatic cystic lesions, and radiosurgical treatment with use of interstitial 125iodine was performed in 16 patients with low-grade tumors and in 4 patients with solitary metastases. In 12 patients, the obtained tissue diagnosis was the basis for deferring additional therapy. In 43 patients with germ-cell tumors, pineoblastomas, or malignant gliomas, a stereotactic biopsy was the starting point for additional radiotherapy/chemotherapy. Open tumor resection played a minor role (five patients). CONCLUSION: The stereotactic approach to the pineal region is a relatively safe procedure in experienced hands. The diagnosis obtained by computed tomography-guided stereotactic biopsy is a valid basis for treatment decisions. Long-term follow-up observation of the benign lesions is necessary for a definite confirmation of diagnostic accuracy.

L-buthionine-sulfoximine-mediated radiosensitization in experimental interstitial radiotherapy of intracerebral D-54 MG glioma xenografts in athymic mice.

An intracranial (i.c.) interstitial radiotherapy model in athymic nude mice bearing i.c. D-54 MG human glioma xenografts was developed, allowing evaluation of the therapeutic benefits seen after L-buthionine-S,R-sulfoximine (L-BSO)-mediated depletion of tumor glutathione levels. Administration of L-BSO [2.5 mmol/kg intraperitoneal injections x 4 doses plus concomitant availability in acidified (pH 3.0) drinking water at a concentration of 20 mM] resulted in depletion of tumor glutathione levels to 0.15 mumol/g wet weight (7.9% of control). The therapeutic activity of i.c. interstitial radiotherapy with an 125I seed was enhanced after L-BSO-mediated glutathione depletion, with increases in median survival of 13.4 to 30.5% over that seen with 125I seeds alone. These studies demonstrate a potential role for BSO in enhancing the therapeutic activity of interstitial radiotherapy.

The effect of 125I interstitial radiotherapy on blood-brain barrier function in normal canine brain.

Blood-brain barrier (BBB) function was studied in 14 normal dogs at time periods from 7 to 717 days after permanent insertion of 5- to 7-mCi seeds of iodine-125 (125I) for interstitial radiation. The BBB function was measured with carbon-14-labeled alpha aminoisobutyric acid (AIB) and quantitative autoradiography, and expressed as a unidirectional blood-to-brain transfer constant, K. The 125I radiation lesions consisted of three concentric histologically and functionally distinct zones: 1) a central zone of calcified necrosis; 2) a spongy fluid-filled zone; and 3) a narrow rim (2.6 +/- 0.6 mm wide) of viable brain tissue with increased permeability. Within this rim, the mean value of the K of AIB was 5.8 times that of normal cortex. Over the 7- to 392-day time period the value of K remained rather constant, and by 716 days K values had returned to normal. There was moderate regional variation in the value of K; it was highest in the white matter and lowest in the gray matter surrounding the radiation lesion. The radiation lesion progressively increased in size from 7 to 80 days, after which there was little change. This study illustrates that the geographically circumscribed radiation from 125I seeds is accompanied by similarly well-defined changes in BBB function, which may persist for over 1 year following insertion of the 125I seed. This altered BBB function is probably responsible for the cerebral edema associated with 125I interstitial radiotherapy.

Surgical resection and radiation therapy versus biopsy and radiation therapy in the treatment of glioblastoma multiforme.

There has been considerable controversy over the concept of treating glioblastoma multiforme with cytoreductive surgery. Therefore, a retrospective study of cases treated between 1986 and 1991 was conducted to analyze and compare the results of stereotactic biopsy followed by radiation therapy performed in 58 patients with those of surgical resection plus radiation therapy in 57 patients. In both groups, conventionally fractionated radiation (1.7 to 2.0 Gy/day) was delivered, with a total dose of 50 to 60 Gy. Biopsy was performed only in patients with tumors judged to be inoperable. These patients carried a higher surgical risk and were in worse neurological condition than the patients in the resection group. The median survival time for the resection group was 39.5 weeks, as compared with 32 weeks for the biopsy group. This difference was not significant. The most important prognostic factor was the patient's age. The treatment variable biopsy versus resection did not reach prognostic relevance. In patients with midline shift who underwent biopsy, the Karnofsky Performance Scale score decreased in more patients during radiation therapy. The clinical status 6 weeks after surgery, however, showed no significant differences between the two groups. The comparable survival times for the two groups place doubt on the concept of treating glioblastoma multiforme with cytoreductive surgery. Presently, radiation therapy is the most effective treatment for patients with glioblastoma. There is no question that decompressive surgery followed by radiation therapy should be performed whenever necessary for sever space-occupying lesions and when it will not cause new neurological deficits.

Interstitial radiosurgery of low-grade gliomas.

The treatment of patients with low-grade gliomas remains a subject of controversy, especially with respect to new treatment modalities such as interstitial radiosurgery (brachytherapy), radiosurgery, and stereotactic radiotherapy. In a retrospective analysis conducted between 1979 and 1991, the authors studied the results of interstitial radiosurgery in 455 patients with low-grade gliomas (World Health Organization (WHO) Grade I+WHO Grade II) with regard to survival time, quality of life, the risk of malignant transformation, and the risk profile of the treatment concept. Interstitial radiosurgery with iodine-125 was performed using permanent (1979-1985) or temporary implants (after 1985) with low-dose rates (< or = 10 cGy/hr) and a reference dose of 60 to 100 Gy calculated to the outer rim of the tumor. The 5- and 10-year survival rates in patients with pilocytic astrocytomas (97 patients) were 84.9% and 83%, and in patients with WHO Grade II astrocytomas (250 patients) 61% and 51%, respectively. Five-year survival rates for patients with oligoastrocytomas (60 patients), oligodendrogliomas (27 patients), and gemistocytic astrocytomas (21 patients) were 49%, 50%, and 32%, respectively. In the group with WHO Grade II gliomas, young age and a good performance status were associated with a better prognosis. Unfavorable factors were midline shift, enhancement on computerized tomography (CT) scan, and tumor recurrence after previous radiotherapy or surgery. Tumor location had no influence on the prognosis (247 patients in this series had deep-seated tumors). Malignant transformation was the major cause of death. Important risk factors for malignancy were the patient's age, tumor enhancement in CT scan, and tumor recurrence after previous surgery or radiotherapy. Perioperative mortality was 0.9% and perioperative morbidity was 1.7%. Radiogenic complications were observed in 2.7% of all patients, most often in larger tumors and after using permanent implants. The authors conclude that interstitial radiosurgery represents a specific treatment modality for selected patients with unifocal circumscribed low-grade gliomas with a diameter of less than 4 cm in any location. The efficacy of this treatment lies in the same range as the best results after surgery and radiotherapy.

Iodine-125 interstitial irradiation of virally induced dog brain tumours.

Brain tumours were induced by intracerebral inoculation of beagle puppies with Avian sarcoma virus (ASV) suspension. The inoculation produced solitary or multiple sarcomas in three dogs and intraventricular anaplastic gliomas in four dogs. At the time of the first tumour positive CT-control Iodine-125 seeds (activity 8.5-10.5 mCi) were placed into the lesion. The radioactive Iodine-125 implants produced sharply delineated calcifying necroses with vital unaffected tumour outside the necrosis. The necrotizing and calcifying effect was apparent after 18 days and complete after 97 days when a transitional zone was no longer detectable. The response of neoplastic tissue to low dose rate interstitial irradiation was distinctly different in terms of the volume of necrosis when compared with Iodine-125 radionecroses in healthy brain tissue.

The effects of continuous and single-dose radiation on choline uptake in organotypic tissue slice cultures of rabbit hippocampus.

The objective of the present study was to determine the time-dependent course of choline uptake in mature organotypic slice cultures of rabbit hippocampal formation and to assess the effects of continuous and single high-dose irradiation on choline uptake in cultivated slices in vitro. Transverse slices of hippocampus were dynamically incubated in a cerebrospinal fluid-like culture medium for 72 h. To study the changes in choline uptake longitudinally, the slice cultures were processed with 0.1 microM [3H]-choline, and tritium accumulation was counted. Two different gamma irradiation sources (125I seeds and a clinical 60Co source) were used as representative models of interstitial radiosurgery and other radiosurgical techniques. A total dose of approximately 6000 cGy was delivered to the brain slices in one session or in a continuous, relatively low-dose rate fashion, and their effects on high-affinity choline uptake were examined. In another set of experiments with 125I, 5 microM hemicholinium-3 was used in choline uptake procedures as a competitive high-affinity choline uptake inhibitor. The results can be summarized as follows: (1) in the control group of the hippocampal tissue culture, there was a significant increase in tritium accumulation values from 0 to 48 h and a decrease thereafter; (2) continuous 125I irradiation caused a highly significant depression of the accumulation of tritium compared to that observed in the control group throughout its application for 72 h; (3) there was no significant change in the accumulation of tritium in the slices after single high-dose rate irradiation with a 60Co source; and (4) 5 microM hemicholinium significantly depressed the accumulation of tritium in both the control and the 125I-irradiated groups, and there was no longer a difference between 125I-irradiated and control groups when both groups were treated with hemicholinium. These results demonstrate that the delivery of continuous but relatively low-dose rate gamma irradiation is more efficacious than single high-dose external irradiation on high-affinity choline uptake in hippocampal nervous tissue. The results also indicate that continuous irradiation specifically affected the high-affinity energy-dependent choline uptake mechanism, whereas nonspecific choline uptake did not seem to be disturbed.

Stereotactic interstitial radiotherapy for brain tumors.

The narrow margin between tumor sensitivity and healthy brain sensitivity to radiation considerably limits conventional radiation therapy (teletherapy). Interstitial radiotherapy (brachytherapy) with iodine-125 permanent implants is effective for local tumor control. So far, interstitial radiotherapy using low activity permanent or temporary implants has been carried out in 179 patients with differentiated gliomas (132 cases) and other tumors-anaplastic gliomas and glioblastomas (16 cases), ependymomas and papillomas (4 cases) and a variety of other mostly extracerebral tumors (27 cases)-in functionally critical cortical or deep-seated location. Brachytherapy with I-125 implants is recommended for slowly proliferating, differentiated non-resectable tumors in functionally critical areas. It enables the surgeon to achieve a radiosurgical tumor removal while carefully avoiding radiation and operative damage to healthy brain. Experimental and clinical data make an individualized treatment for each patient desirable.

[Comparative emission tomographic and transmission tomographic studies of cranial and intracranial diseases (author's transl)]. / Vergleichende emissionstomographische und transmissionstomographische Untersuchungen kranieller und intrakranieller Erkrankungen.

A comparative study was performed in 58 patients with brain lesions using emission computed tomography (ECAT -- single photon, Cleon 710) and transmission computed tomography (TCAT). ECAT better demonstrates vascular functional i.e. physiologic disturbances. A disadvantage of ECAT is that there is no way to produce survey scans of the head. Relatively long scanning times and moderate spatial resolution when compared with TCAT furthermore reduces the value of ECAT. It is expected that the technical development of ECAT will soon alter the situation.

Radiation effects of iridium-192 implants in the cat brain.

The radiation effects of 192Ir permanent implants into the cat brain were studied with respect to morphological changes, blood flow, brain water and electrolytes. 192Ir wires (10 animals) and non-radioactive silver wires (5 control animals) were placed stereotactically into the left internal capsule. Activity of 192Ir was 0.31 mCi, and accumulated dose at 5 mm distance was 3060 rad after 21 days and 4680 rad after 35 days, respectively. None of the animals presented a neurological deficit, and the EEG recording was without significant changes. Histological damage which could be attributed to the radiation was not observed. Serum proteins, however, were detected immunohistochemically in reactive astrocytes (3x), in macrophages (2x) and as diffuse perivascular accumulation. Brain water in the white matter near the implantation site increased from 68.6 to 73.2%, corresponding to a volume increase of about 17%. There was no change in the grey matter or the opposite hemisphere. Cerebral blood flow decreased slightly but there was no relationship with the development of edema. The findings suggest that low dose rate topical irradiation of the brain produces primarily membrane dependent changes, resulting in local brain edema.

Stereotactic biopsy of brain tumors.

Stereotactic biopsies from deep-seated brain tumors were carried out in 302 patients. There were more men (58 percent) than women. Peak of prevalence was in the second to fourth decade; the youngest patient was 18 months old. The tumors were deep-seated hemispheric in 36 percent, in the basal ganglia in 30 percent, in the diencephalic region, i.e., hypothalamus and suprachiasmatic region, in 21 percent, and in the midbrain and pineal region in 13 percent. The majority of lesions were gliomas (71 percent), the remaining being epithelial and various nonglial tumors. Operative mortality was 2.3 percent; transient deterioration was observed in 3 percent. Diagnosis was made instantly by cytological examination (smear preparations) and confirmed by conventional histological examination. In only 5 percent of the gliomas was a discrepancy found between the diagnosis from the smear preparation and the subsequent histological diagnosis. Integrating computerized tomography (CT) imaging techniques into the stereotactic technique makes it possible to take biopsies at exact and reproducible sites and with low risk. The findings suggest that exploratory craniotomies, risky free-hand punctures, and aspirations deep in the brain can no longer be advocated. No radiation treatment should be considered without histological confirmation.

Experimental aneurysms in the rabbit: occlusion by intrasaccular injection of fibrin sealant.

Experimental aneurysms of the carotid artery were produced using the microsurgical technique of grafting a venous sack onto the artery in the neck of rabbits after the removal of an elliptical piece of arterial wall. Twenty-five aneurysms were occluded with the fibrin sealant Tissucol. Microscopic examination showed complete resorption of the fibrin clot and the formation of dense granulation tissue within the aneurysm, which was covered with a layer of endothelial cells after 2 weeks. The results are only tentative and require further experimental studies.

Subspeciality training in neurosurgery.

Evolution for neurosurgeons is not at a standstill. The environment, competition from neighbouring fields, advances in biology and changes in the level of information available to our patients, the "market" will favour and demand subspecialisation. Subspecialists are characterized by recognized records of excellence. The best suited to impart knowledge to a clinical fellow is the senior subspecialist who is working within a group of other complementary subspecialists. To develop subspecialty expertise takes a minimum of one, preferably two years of training. Neurosurgery will retain and regain its strength as a discipline by diversification, not by clinging to monolithic uniformity.