First clinical experience with fractionated intracavitary radioimmunotherapy using [177Lu]Lu-6A10-Fab fragments in patients with glioblastoma: a pilot study.

BACKGROUND: Following resection and standard adjuvant radio- and chemotherapy, approved maintenance therapies for glioblastoma are lacking. Intracavitary radioimmunotherapy (iRIT) with 177Lu-labeled 6A10-Fab fragments targeting tumor-associated carbonic anhydrase XII and injected into the resection cavity offers a novel and promising strategy for improved tumor control. METHODS: Three glioblastoma patients underwent tumor resection followed by standard radio- and chemotherapy. These patients with stable disease following completion of standard therapy underwent iRIT on compassionate grounds. After surgical implantation of a subcutaneous injection reservoir with a catheter into the resection cavity, a leakage test with [99mTc]Tc-DTPA was performed to rule out leakage into other cerebral compartments. IRIT comprised three consecutive applications over three months for each patient, with 25%, 50%, 25% of the total activity injected. A dosimetry protocol was included with blood sampling and SPECT/CT of the abdomen to calculate doses for the bone marrow and kidneys as potential organs at risk. RESULTS: All three patients presented without relevant leakage after application of [99mTc]Tc-DTPA. Two patients underwent three full cycles of iRIT (592 MBq and 1228 MBq total activity). One patient showed histologically proven tumor progression after the second cycle (526 MBq total activity). No relevant therapy-associated toxicities or adverse events were observed. Dosimetry did not reveal absorbed doses above upper dose limits for organs at risk. CONCLUSIONS: In first individual cases, iRIT with [177Lu]Lu-6A10-Fab appears to be feasible and safe, without therapy-related side effects. A confirmatory multicenter phase-I-trial was recently opened and is currently recruiting.

Intracavitary radioimmunotherapy of high-grade gliomas: present status and future developments.

There is a distinct need for new and second-line therapies to delay or prevent local tumor regrowth after current standard of care therapy. Intracavitary radioimmunotherapy, in combination with radiotherapy, is discussed in the present review as a therapeutic strategy of high potential. We performed a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The available body of literature on intracavitary radioimmunotherapy (iRIT) in glioblastoma and anaplastic astrocytomas is presented. Several past and current phase I and II clinical trials, using mostly an anti-tenascin monoclonal antibody labeled with I-131, have shown median overall survival of 19-25 months in glioblastoma, while adverse events remain low. Tenascin, followed by EGFR and variants, or smaller peptides have been used as targets, and most clinical studies were performed with I-131 or Y-90 as radionuclides while only recently Re-188, I-125, and Bi-213 were applied. The pharmacokinetics of iRIT, as well as the challenges encountered with this therapy, is comprehensively discussed. This promising approach deserves further exploration in future studies by incorporating several innovative modifications.

The beginnings of Acta Neurochirurgica and the work of Fritz Loew, chief editor from 1958 - 1997. An historical vignette.

Acta Neurochirurgica was founded in 1950, in the difficult time after World War II, by Mario Milletti (Bologna) and Wolfram Sorgo (Innsbruck), and published by Springer press, Vienna. From the beginning the new journal was conceived as an international journal with an impressive list of outstanding neurosurgeons in the editorial board. Only a few years later the issues appeared at irregular intervals due to individual problems of both editors. Wilhelm Tönnis took the initiative to keep the journal alive, when he asked-in consent with Springer press-his staff member Fritz Loew to continue the editorial work and to assemble a new prestigious editorial board. Loew succeeded with both tasks and remained editor-in-chief for nearly 38 years. Initially, all papers were published in the native languages of the authors: English, French, German, Italian and Spanish. With ongoing time the journal accepted manuscripts in English only. The slow progress of this process exemplifies the slow integration of the European countries. In 1971, at the founding meeting of the European Association of Neurosurgical Societies (EANS) in Prague, Acta Neurochirurgica became the official organ of the EANS. Right from the beginning of Acta Neurochirurgica, Supplement volumes were added. Also, the book series Advances and Technical Standards in Neurosurgery is an offspring of Acta Neurochirurgica. Acta Neurochirurgica has become one of the most important neurosurgical journals worldwide. This historical sketch is based on an interview with Fritz Loew, now 91 years old, to which data from the available literature and the Archives of German Neurosurgery, as well as personal information by several colleagues were added.

Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial.

BACKGROUND: 5-Aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas-a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. METHODS: 322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670. FINDINGS: Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. INTERPRETATION: Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.

Distribution of labelled anti-tenascin antibodies and fragments after injection into intact or partly resected C6-gliomas in rats.

INTRODUCTION: For treatment of malignant glioma, radioimmunotherapy has become a valuable alternative for more than 2 decades. Surprisingly, very little is known about the distribution of intralesionally administered labelled antibodies or fragments. We investigated the migration of labelled antibodies and antibody fragments injected into intact and partly resected C6-glioma in rats at different times after injection. MATERIALS AND METHODS: Nine days after induction of a C6-glioma, 5 microl of 125I-labelled murine anti-tenascin antibodies (n = 31) or 125I-labelled fragments of anti-tenascin antibodies (n = 32) was injected slowly into the tumour (group I). In group II the tumour was subtotally resected 9 days after induction of the C6-glioma, and 24 h later the labelled antibodies (n = 30) or fragments (n = 12) were injected into the resection cavity. At 6, 24 or 48 h after the injection, animals were sacrificed, and brains removed. Distribution of labelled antibodies and fragments was determined by superimposing autoradiographs onto frozen sections and HE-stained neighbouring sections using a digital image analysing system. RESULTS: After injection into intact C6-glioma, labelled antibodies covered a maximum distance of 3.2 +/- 1.0, 4.1 +/- 1.9 and 4.8 +/- 0.9 mm after 6, 24 and 48 h, respectively; while labelled fragments were found at a distance of 6.7 mm (+/-1.1) after 24 h and 5.8 mm (+/-0.9) after 48 h (significant in univariate analysis). Following partial tumour resection, the respective distances at 24 h were 3 +/- 0.4 mm for anti-tenascin antibodies and 3.4 +/- 0.3 mm for Fab fragments. CONCLUSION: After injection into C6-glioma, labelled fragments are able to cover a greater distance than labelled antibodies. Injection of antibodies and fragments 1 day after tumour resection results in reduced velocity of both antibodies and fragments.

Photoirradiation therapy of experimental malignant glioma with 5-aminolevulinic acid.

OBJECT: Accumulation of protoporphyrin IX (PPIX) in malignant gliomas is induced by 5-aminolevulinic acid (5-ALA). Because PPIX is a potent photosensitizer, the authors sought to discover whether its accumulation might be exploited for use in photoirradiation therapy of experimental brain tumors, without injuring normal or edematous brain. METHODS: Thirty rats underwent craniotomy and were randomized to the following groups: 1) photoirradiation of cortex (200 J/cm2, 635-nm argon-dye laser); 2) photoirradiation of cortex (200 J/cm2) 6 hours after intravenous administration of 5-ALA (100 mg/kg body weight); 3) cortical cold injury for edema induction; 4) cortical cold injury with simultaneous administration of 5-ALA (100 mg/kg body weight) and photoirradiation of cortex (200 J/cm2) 6 hours later; or 5) irradiation of cortex (200 J/cm2) 6 hours after intravenous administration of Photofrin II (5 mg/kg body weight). Tumors were induced by cortical inoculation of C6 cells and 9 days later, magnetic resonance (MR) images were obtained. On Day 10, animals were given 5-ALA (100 mg/kg body weight) and their brains were irradiated (100 J/cm2) 3 or 6 hours later. Seventy-two hours after irradiation, the brains were removed for histological examination. Irradiation of brains after administration of 5-ALA resulted in superficial cortical damage, the effects of which were not different from those of the irradiation alone. Induction of cold injury in combination with 5-ALA and irradiation slightly increased the depth of damage. In the group that received irradiation after intravenous administration of Photofrin II the depth of damage inflicted was significantly greater. The extent of damage in response to 5-ALA and irradiation in brains harboring C6 tumors corresponded to the extent of tumor determined from pretreatment MR images. CONCLUSIONS: Photoirradiation therapy in combination with 5-ALA appears to damage experimental brain tumors selectively, with negligible damage to normal or perifocal edematous tissue.

Prognostic impact of TP53 mutations and P53 protein overexpression in supratentorial WHO grade II astrocytomas and oligoastrocytomas.

PURPOSE: The purpose of this study was to analyze retrospectively timing, frequency, and prognostic impact of TP53 mutations and P53 protein accumulation in supratentorial WHO grade II astrocytomas and oligoastrocytomas of adult patients. EXPERIMENTAL DESIGN: We included 159 consecutively treated patients (1991-1998), and each tumor was screened for TP53 mutations and P53 protein overexpression. Prognostic evaluation was performed with the multivariate proportional hazards model. RESULTS: TP53 mutations (P53 protein overexpression) were detected in 49% (47%) of all tumors with a preference for the gemistocytic subtype (P < 0.05). The TP53 status of the primary tumor was predictive for the status of the recurrent tumor, and tumor recurrence/progression was associated with an increase of P53 immunopositive cells in 68% of the investigated tumors. Univariately, gemistocytic subtype and presence of TP53 mutation (but not P53 accumulation) were unfavorable predictors for progression-free survival (P < 0.05); multivariately, only the gemistocytic subtype remained unfavorable influence (P = 0.04). No overall prognostic impact of the TP53 status on survival and time to malignancy was observed (P < 0.05). Five nongemistocytic tumors with a codon 175 TP53 mutation exhibited a significantly worse prognosis as compared with those with any other mutational sites (5-year progression-free survival: 0%; 5-year malignant transformation: 100%; P < 0.001). CONCLUSIONS: TP53 mutations are frequent and early events in the pathogenesis of WHO grade II astrocytomas/oligoastrocytomas, and most of the univariately detected overall prognostic impact of the TP53 status must be related to the influence of the gemistocytic subtype. In nongemistocytic astrocytomas, a hot spot codon 175 TP53 mutation indicates a worse prognosis in terms of time to progression and malignancy.

Surgical resection of grade II astrocytomas in the superior frontal gyrus.

OBJECTIVE: Surgery in the superior frontal gyrus partially involving the supplementary motor area (SMA) may be followed by contralateral transient weakness and aphasia initially indistinguishable from damage to the primary motor cortex. However, recovery is different, and SMA deficits may resolve completely within days to weeks. No study has assessed the distinct postoperative deficits after tumor resection in the SMA on a homogeneous patient group. METHODS: Twenty-four patients with World Health Organization Grade II astrocytomas in the superior frontal gyrus consecutively treated by surgery were studied. Degree and duration of postoperative deficits were evaluated according to tumor location and boundaries via magnetic resonance imaging scans, intraoperative neuromonitoring results, and extent of tumor resection. RESULTS: Postoperatively, motor deficits were evident in 21 of 24 and speech deficits in 9 of 12 patients. Motor function quickly recovered in 11 and speech function in 3 patients. None of the 12 patients in whom the posterior tumor resection line was at a distance of more than 0.5 cm from the precentral sulcus experienced persistent motor deficits. Eight of these patients developed typical SMA syndrome with transient initiation difficulties. Seven of 12 patients in whom the tumor extended to the precentral sulcus still had motor deficits at the 12-month follow-up assessment. CONCLUSION: Surgery for Grade II gliomas in the superior frontal gyrus is more likely to result in permanent morbidity when the resection is performed at a distance of less than 0.5 cm from the precentral gyrus or positive stimulation points. Therefore, cortical mapping of motor and speech function, in critical cases under local anesthesia with the patient as his or her own monitor, is recommended; resection should be tailored to obtain good functional outcome and maintain quality of life.