Hyperfractionated and accelerated-hyperfractionated radiotherapy for glioblastoma multiforme.

Because of promising radiobiological advantages allowing dose escalation and/or reduction of treatment time, hyperfractionated and accelerated-hyperfractionated radiotherapy (hf-rt, ahf-rt) were introduced as part of treatment of glioblastoma multiforme (gbm). In December 1988 we started a prospective study of hf-rt (total dose 78 Gy, two daily fractions of 1.3 Gy, interval between daily fractions 6 hr, treatment time 6 weeks, n = 34 patients). The results were compared with our previous regimen of conventionally fractionated radiotherapy (cf-rt: total dose 60 Gy, single dose 2 Gy, treatment time 6 weeks, n = 32 patients). In June 1990, the protocol was modified in order to reduce treatment time (ahf-rt: total dose 60 Gy, two daily fractions of 1.5 Gy, interval 6 hr, treatment time 4 weeks, n = 92 patients until December 1996). No chemotherapy was given. Entry criteria were: age > or = 17 years, pathological diagnosis of supratentorial gbm, and no previous treatment other than surgery. The ahf-rt group included significantly more patients with previous surgical resection instead of biopsy only. Compared with the cf-rt group, both the hf-rt and the ahf-rt group included significantly more patients with frontal tumor location. We found no significant survival difference between the groups (median survival 7-10 months, 1-year survival rate 19%-29%). Progression-free survival, clinical course, and toxicity were also not significantly different. Karnofsky performance status, age, and corticosteroid dose during radiotherapy were the most important prognostic factors. The results of this trial are in large agreement with most previous publications. It demonstrated no improved survival. However, it showed that treatment time can be reduced by ahf-rt without loss of survival benefit or intolerable toxicity. A short radiotherapy course might be appropriate for many patients with gbm who are not suitable for rather aggressive investigational therapies.

[Classification and grading of gliomas and meningiomas]. / Klassifikation und Grading von Gliomen und Meningeomen.

GLIOMAS: As we demonstrated for supratentorial, diffuse gliomas in adults, a stratification into just two grades of malignancy, 'low' and 'high grade,' proved reliable and prognostically relevant. The discriminating histomorphological criterion for high-grade astrocytoma (WHO glioblastoma) as well as anaplastic oligodendroglioma and anaplastic oligoastrocytoma is endothelial hyperplasia/proliferation, which is usually associated with uptake of contrast medium in computed tomography and magnetic resonance imaging. As neoangiogenesis indicates glioma progression, it is worthwhile considering these radiographic features to judge the representativeness of the tumor samples critically. MENINGIOMAS: The revised edition of the WHO classification of brain tumors now includes the 'atypical' meningioma (WHO 'grade' II): Based on both its histomorphological features and prognosis, it should be placed between the common type and anaplastic meningioma. Nuclear area related Ki-67 proliferation indices, as determined by morphometry, were the prerequisite for outlining its histomorphological spectrum better. Cytogenetically, the most consistent progression-associated feature was loss of the distal part of the short arm of one chromosome 1 (1p-). Thus, a screening method using the tissue non-specific form of alkaline phosphatase (ALPL) as the respective marker enzyme was established. Diagnosing a meningioma of the intermediate type implies careful clinical and radiological patient follow-ups to detect tumor recurrences early.

[Grading of astrocytomas and oligodendrogliomas]. / Grading von Astrozytomen und Oligodendrogliomen.

The histologic determination of the degree of tissue anaplasia and grade of malignancy of gliomas is based upon qualitative histological features (nuclear pleomorphism, mitoses, endothelial proliferation, tumor necrosis). This grading approach is influenced by the subjective interpretation of the pathologist, especially concerning the weighting of criteria (scant, moderate, pronounced). An observer-independent approach seems to be feasible by abandoning the concept of parameter weighting in favor of an binary approach noting only the presence or absence of these structure parameters. This grading procedure is recognized in the revised WHO classification of brain tumors for common type astrocytomas (Ste. Anne-Mayo System, SAMS). Our results indicate that a similar approach is also suitable for grading purposes of oligodendrogliomas and mixed gliomas. Our recent investigations on glioma grading showed, both for astrocytomas and oligodendrogliomas, that a two-tiered grading scheme distinguishing only "low-grade" and "high grade" cases was prognostically relevant. For all glioma entities the onset of tumor angiogenesis with endothelial proliferation and contrast enhancement in CT and MRI seems to be the key criterion indicating irreversible tumor progression to the "high" malignancy grade.

Oligodendrogliomas. Part II: A new grading system based on morphological and imaging criteria.

This second part of our study of 'pure' oligodendrogliomas focuses on survival data analysis. In order to identify potentially useful prognostic factors and to assess the effectiveness of a new grading system, the 79 patients in the previously analyzed series for whom adequate follow-up could be obtained (52%) were entered in the present analysis. Statistical analysis demonstrated that contrast enhancement and endothelial hyperplasia had powerful and similar influence on survival. Median survival with and without contrast enhancement were: 3 versus 11 years, and with or without endothelial hyperplasia were: 3.5 versus 11 years. Conversely, the degree of nuclear atypia and presence or absence of mitosis or necrosis were not correlated with survival. These findings allowed us to devise a simple grading system which discriminates two malignancy grades as follows: absence of endothelial hyperplasia and of contrast enhancement = Grade A, presence of endothelial hyperplasia and/or of contrast enhancement = Grade B. Of the 79 oligodendrogliomas in this study, 59 tumors were categorized as grade A and 20 as grade B. Median survival were: 11 years in grade A and 3.5 years in grade B. Five-year and 8-year survival rates were: 89% and 60% in grade A and: 33% and 15% in grade B. Double blind grading between two independent observers was concordant in 96% of the cases. Application of this simple efficient and reproducible grading scheme should permit reliable comparison of retrospective or prospective therapeutic data emanating from various institutions.

Histologic and morphometric grading of gliomas. A comparative survival analysis.

OBJECTIVE: A grading system based upon morphometrically assessed quantitative parameters (HOM system) was correlated with the results of classical histologic grading (St. Anne/Mayo system [SAMS], 1988, and World Health Organization classification, 1993). Validation was done by comparison with survival data. STUDY DESIGN: This retrospective study consisted of representative paraffin-embedded tissue sections of 139 adults who had been surgically treated for supratentorial common gliomas between 1988 and 1994. Histologic grading diagnoses were adapted to the latest standard. Computer-assisted image analysis of Ki-67 (MIB1)/ Feulgen-stained sections provided nuclear parameters appropriate to define homogeneous grades of malignancy by multivariate statistical analyses: average segment length of the minimum spanning trees (ASLMST) for the quantitation of tumor growth pattern; nuclear area percentage (NAP), reflecting cellularity; and volume-weighted mean nuclear volumes (vV) for estimating nuclear size and pleomorphism. RESULTS: Analysis of survival data yielded no statistically significant differences between astrocytomas and oligoastroacytomas (Lee-Desu test, alpha = 5%). Furthermore, only two prognostically different grades could be established, "low grade" and "high grade" gliomas, with the first representing SAMS grades 2 and 3 and the latter SAMS grade 4 (alpha = .1%). The same applied to HOM grades (alpha = .1%). Cox regression analysis of survival data demonstrated that histologic grading diagnoses and NAP tallied best with patients' outcome.

[Meningioma. Classification and grading]. / Meningeome. Klassifikation und Grading.

Meningiomas account for the most frequent primary intracranial neoplasms in adults. In 1993, the so-called atypical meningioma has additionally been introduced in the revised edition of the WHO Classification of Tumors of the Central Nervous System and should characterize meningiomas with an increased propensity to recur. Since the given qualitative histological criteria apply both to the "atypical" and anaplastic meningioma, mere histological grading appears somewhat critical. Therefore, additional parameters were tested for their contribution to meningioma grading: First of all, we succeeded in defining 3 meningioma "grades" by calculating corresponding 95% confidence intervals for the morphometrically assessed Ki-67 indices of 160 meningiomas in total, the validity of which was proved by comparison with the "recurrence"-free intervals. Histologically, atypical meningiomas were distinguished by a "syncytial", poorly structured growth pattern and macronucleoli. Only occasionally, nuclear pleomorphism, necroses and mitotic figures were found. Cytogenetics revealed, in 50% of the "atypical" and anaplastic meningiomas, partial loss of the short arm of one chromosome 1 (1p-). Histochemically, we could demonstrate, that the tissue non-specific type of alkaline phosphatase (ALPL), which is coded on chromosome 1p, is a convenient recurrence- and progression-associated marker enzyme for meningiomas with 1p-loss (loss of enzyme activity in 30/39 of intermediate and 8/8 anaplastic meningiomas). We favor to address the WHO "atypical" meningioma as meningioma of the intermediate type, since the attribute "atypical" in the context of histological diagnoses is highly susceptible to misinterpretations.

Characterization of intermediate type (WHO "atypical") meningiomas.

The intermediate type meningioma (formerly "meningioma variant with signs of increased proliferation activity"; WHO "atypical" meningioma) represents a meningioma group the mean Ki-67 index and the recurrence rate of which lie between those of the ordinary and the anaplastic type [Kolles et al. 1995]. In the study cited (n = 160) the percentage of recurrences was 9% in the common, 29% in the intermediate, and 50% in the anaplastic type. The present study focuses on 49 subsequently diagnosed meningiomas of the intermediate type. Apart from certain histopathological features, the most important independent factors associated with recurrence were Ki-67 indices covering the 95% confidence interval between 3.7% and 4.9%. At the light-microscopic level, however, meningiomas in general, and especially those supposed to belong to the intermediate type, are highly variable in tissue architecture and do, in contrast to the anaplastic type, not display frank histological features of anaplasia. Morphologically, the growth pattern of solid ("syncytial") sheets, micronecroses, and large distinct nucleoli are suspicious. Cytogenetically, independent of the loss of one chromosome 22, it has been shown that terminal loss of the short arm of one chromosome 1 (1p-) or complete loss of this chromosome were useful additional indicators of meningioma progression.

[Dysembryoplastic neuroepithelial tumor (DNT). Pattern of neuroradiologic findings]. / Dysembryoplastischer neuroepithelialer Tumor (DNT). Neuroradiologische Befundmuster.

Dysembryoplastic neuroepithelial tumors (DNT) were first described as a new tumor entity by Daumas-Duport et al. in 1988 and were introduced into the revised WHO classification of brain tumors in 1993. The purpose of this study was to work out neuroradiological CT and MRT patterns of DNT. Five patients, aged 11-61 years (three female, two male) underwent complete presurgical neuroradiological exploration (5 CT, 4 MRT investigations, 2 angiography) because of brain tumor. Four cases complained of seizures and one of occipital-located headache. Total microsurgical excision was achieved in two cases. Two further lesions were resected subtotally after stereotactic biopsy diagnosis. In one case, stereotactic biopsy alone was carried out. All DNTs were localized cortically: two frontobasal medial in the gyrus rectus, two temporobasal in the gyrus occipitotemporalis lateralis and one infratentorial in the lobus caudalis cerebelli. They were sharply demarcated from the surrounding brain tissue. Cortical localization was better visualized by MRT, especially on coronal and sagittal images. CT scans showed a hypodense lesion, MRT a high-signal intensity in T2, low signal in T1 and in proton-weighted images a hyperintense rim with a slightly hyperintense small cyst. The multinodular tumor architecture was best seen in MRT. Two DNTs presented partial contrast enhancement, while three DNTs did not take up contrast. In two lesions there were focal calcifications. The infratentorial DNT was associated with a bony defect of the tabula interna into which the tumor expanded. Two angiographies showed no pathological tumor neovascularization. A hypodense sharply demarcated lesion with a multinodular pattern in MRT with cortical location and without space-occupying signs is, in combination with the clinical symptom of epileptic seizures, highly suggestive of DNT. As our results demonstrate, DNT can also occur in the infratentorial space.

Data-driven approaches to decision making in automated tumor grading. An example of astrocytoma grading.

OBJECTIVE: To compare four data-driven approaches to automated tumor grading based on morphometric data. Apart from the statistical procedure of linear discriminant analysis, three other approaches from the field of neural computing were evaluated. STUDY DESIGN: The numerical basis of this study was computed tomography-guided, stereotactically obtained astrocytoma biopsies from 86 patients colored with a combination of Feulgen and immunhistochemical Ki-67 (MIB1) staining. In these biopsies the cell nuclei in four consecutive fields of vision were evaluated morphometrically and the following parameters determined: relative nuclei area, secant lengths of the minimal spanning trees and relative volume-weighted mean nuclear volumes of the proliferating nuclei. RESULTS: Based on the analysis of these morphometric features, the multivariate-generated HOM grading system provides the highest correct grading rates (> 90%), whereas the two widely employed qualitative histologic grading systems for astrocytomas yield correct grading rates of about 60%. For automated tumor grading all approaches yield similar grading results; however, back-propagation networks provide reliable results only following an extensive training phase, which requires the use of a supercomputer. All other neurocomputing models can be run on simple UNIX workstations (AT&T, U.S.A). CONCLUSION: In contrast to discriminant analysis, backpropagation and Kohonen networks, the newly developed neural network architecture model of self-editing nearest neighbor nets (SEN3) provides incremental learning; i.e., the training phase does not need to be restarted each time when there is further information to learn. Trained SEN3 networks can be considered ready-to-use knowledge bases and are appropriate to integrating further morphometric data in a dynamic process that enhances the diagnostic power of such a network.

Early proliferation enhancement by monosomy 10 and intratumor heterogeneity in malignant human gliomas as revealed by smear preparations from biopsies.

We performed simultaneous fluorescence in situ hybridization (FISH) with centromere-specific DNA probes for chromosomes 7 and 10 and Ki-67 proliferation labelling on smear preparations of 17 differentiated and anaplastic human astrocytomas and glioblastomas. In 15 of the 17 cases studied, Ki-67-positive clones differed from Ki-67-negative clones mainly by the loss of one copy of chromosome 10, either combined with or independent of trisomy 7. The findings suggest that monosomy 10 is an earlier event than generally supposed in the development of human gliomas and that it is directly related to cellular hyper-proliferation.

[Computer-assisted speech recognition in diagnostic pathology. Development of the DragonDictate-30 K system for documentation]. / Computergestützte Spracherkennung in der diagnostischen Pathologie. Etablierung des DragonDictate-30 K-Systems zur Befundschreibung.

The speech recognition system DragonDictate-30 K is the first commercially available product for personal computers (PC) that includes a thesaurus of 30,000 words which can replace the computer keyboard completely for report writing. The system is speaker-adaptative, i.e., it can learn the phonetic pattern of the pathologist's voice. We have developed a thesaurus with special terms from the field of diagnostic pathology to shorten the time-consuming training phase. DragonDictate is compatible with all text-oriented DOS computer software tools. The recommended minimal hardware configuration is a personal computer with a 80,486 processor with 16 MB on board and a 200 MB hard disk.

Polysyndactyly and asymptomatic hypothalamic hamartoma in mother and son: a variant of Pallister-Hall syndrome.

We report on a 53-year-old woman and her 20-year-old son who both presented with polysndactyly, without other external malformations or mental retardation. MRI imaging revealed, as an incidental finding, asymptomatic hypothalamic hamartomas in both patients. The siblings of both mother and son are unaffected. This family may represent an autosomal dominant variant of Pallister-Hall syndrome.

Automated grading of astrocytomas based on histomorphometric analysis of Ki-67 and Feulgen stained paraffin sections. Classification results of neuronal networks and discriminant analysis.

In stereotactically obtained astrocytoma biopsies, four morphometric nuclear parameters were determined with the use of an image analysis system. A special Ki-67 (MIB1)/Feulgen stain made it possible to quantify the essential characteristics of gliomas of the astrocytoma/glioblastoma group: growth pattern, cellularity, proliferation tendency and nucleus pleomorphism. A grading scale based on a cluster analysis resembling the WHO-scheme, which is suitable for automated astrocytoma grading, was developed. Large back propagation neural networks were used and their results compared with those of a classical multivariate discriminant classification analysis. It is possible to show that the neural network technology is superior to the statistical approach for automated astrocytoma grading. Based on the results of our study we believe neural network technology to be useful for tumour grading problems. The presented approach can be generalized for the automated grading of other tumour entities.

Triple approach for diagnosis and grading of meningiomas: histology, morphometry of Ki-67/Feulgen stainings, and cytogenetics.

With regard to meningioma grading and the recently introduced "atypical" meningioma, we evaluated 160 cases retrospectively by conventional histology and image analysis. For that, the cell nuclei were stained with a Ki-67 (MIB1)/Feulgen-method on paraffin sections, thus enabling the assessment of both the Ki-67 proliferation index and nuclear morphometric features, such as tumour cell arrangement, nuclear pleomorphism, and cellularity. It could be demonstrated that the Ki-67 proliferation index is the most important criterion for distinguishing anaplastic meningiomas (WHO "grade" III) (mean Ki-67 index: 11%) from those of common type (WHO "grade" I) (mean Ki-67 index: 0.7%). The parameter for the "relative volume weighted mean nuclear volume" is another valuable morphometric feature. The "atypical" meningioma (WHO "grade" II) which should represent an intermediate category between common type and anaplastic meningiomas is characterized by a mean Ki-67 proliferation index of 2.1%. Common type meningiomas which comprise almost 50% of the cases of this series have a relapse rate of 9%. "Atypical" and anaplastic meningiomas recurred in 29% and 50%, respectively. Since the term "atypical" meningioma is confusing in the context of tumour grading, the term "intermediate type meningioma" is proposed. Furthermore, the results of cytogenetic analyses of 142 cases of this series were evaluated and compared with the meningioma grades. Thereby, 25 cases disclosed, independent of the typical loss of one chromosome 22, cytogenetic features assumed to be progression-associated, e.g., the gain or loss of different chromosomes and the deletion of the short arm of one chromosome 1 (hyperdiploidy, increased hypodiploidy, 1p-), when correlated to the histological and morphometric findings or the high relapse rate. For meningioma diagnosis and grading, a practical guideline is proposed based upon histology, morphometry (Ki-67), and cytogenetics.

A dermatologic decision support system that processes lexical knowledge from standard textbooks.

We present a decision support system that processes lexical fuzzy knowledge from standard pathology textbooks. The user can choose among four methods: full text and hypertext approaches (classic lexical retrieval methods) and two possibilistic, knowledge-based approaches (the fuzzy logic computation and an adapted evidence combination scheme based upon the theory of belief functions). All these methods, including their algorithms, are presented in this paper. The effectiveness of these approaches is demonstrated by examples from dermatopathology. At the top of the lists of differential diagnoses generated by the system the degree of conformity between the approaches is high.

Application of minimal spanning trees in glioma grading--a CLIPPER program for the calculation and construction of minimal spanning trees.

We present a CLIPPER program for the calculation and graphical representation of minimal spanning trees (MST) which is available on request on diskette from the authors. The MST are a useful parameter for structural cluster detection. They can be applied to grading problems in tumour biology. We present and discuss the applicability of MST by an example from the field of astrocytoma grading.

[Computer assisted grading of gliomas of the astrocytoma/glioblastoma groups]. / Computergestützte Graduierung von Gliomen der Astrocytom/Glioblastom-Gruppe.

For automated astrocytoma grading morphometric parameters are determined by means of an image analysis system and a special Ki-67(MIB1)/Feulgen-staining method allowing the quantification of the essential characteristics of malignant gliomas: growth pattern, cellularity, proliferation index and nucleus pleomorphism. Based upon a cluster analytical approach a grading scale resembling the WHO-scheme is established which is suitable for automatic glioma grading purposes (HOM-scale). For automatic glioma grading backpropagation neural networks are employed. The results are compared with those of a classical multivariate discriminant classificatory analysis. The presented approach can also be employed for automatic grading of other tumour entities.

An electronic tutorial of neurosurgical pathology--application of multi-media in clinical pathology.

We present an electronic tutorial of neurosurgical pathology developed for standard MS-DOS-computers. No additional software requirements are necessary. Digital pictures are displayed on the computer screen in Super-VGA quality. The user interface allows a dialogue between the pathologist and the engine. The dialogue component consists of scroll bar menus with lists of possible suggestions and answers. For each case the user is supplied with the basic clinical information and a set of representative pictures of the histological specimens. In some cases radiographs and CT-images are available. During the consultation session both routine and special staining methods are available on request. If the user proposes a wrong diagnosis the system offers a commentary. The presented cases are part of a teaching series developed for residents in neuropathology.

Combined Ki-67 and Feulgen stain for morphometric determination of the Ki-67 labelling index.

In this note we present a combined Ki-67 and Feulgen stain for morphometric determination of the Ki-67 labelling index. The immunohistochemical part of this double staining technique is based on the alkaline-phosphatase-anti-alkaline-phosphatase (APAAP) method, visualizing the enzyme activity by the nitro-blue-tetrazolium chloride (NBT)/bromo-chloro-3-indolyl-phosphate (BCIP) technique. The NBT/BCIP complex resists the hydrolytic activity of the Feulgen stain. The staining method presented allows semi-automatic determination of both the total nucleus-area as well as the Ki-67 positive nucleus-area using a morphometric computer system. The Ki-67 labelling index thus achieved is based on the relative nuclear area of Ki-67 positive nuclei and is clearly more precise and efficient than the counting method using an ocular grid.

[Cerebral multisystem atrophy in a patient with depressive hallucinatory syndrome. A case report]. / Zerebrale Multisystematrophie bei einer Patientin mit depressiv-halluzinatorischem Syndrom. Ein Fallbericht.

In a female patient, aged 47 years at the beginning, the successive appearance of extrapyramidal signs preceded by depression, paranoid-hallucinatory psychosis, autonomic and cerebellar dysfunction was followed up over a period of 8 years. Autopsy revealed--in accordance with the clinical symptomatology--both olivo-ponto-cerebellar atrophy and a striatonigral degeneration. As a rule these changes are accompanied by dementia. The reported case is unusual in having first presented with severe depression and paranoid-hallucinatory symptoms.