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Objective: To localize aquaporin (AQP)2, vasopressin type 2 receptor (V2-R), and transient receptor potential channel vanilloid subfamily 1, 4 (TRPV1, TRPV4) in the human endolymphatic sac (ES)., Methods: Three samples of human ES were sampled during the removal of vestibular schwannoma by way of the translabyrinthine approach. The samples were immediately fixed in 4% paraformaldehyde and embedded in OCT compound; immunohistochemistry was performed with AQP2, V2-R, TRPV1, and TRPV4 polyclonal antibodies., Results: AQP2, V2-R, TRPV1, and TRPV4 proteins were detected in the epithelial layer of the ES but were not observed in connective tissue around the ES. TRPV1 was also expressed in blood vascular endothelial cells of the connective tissue of ES., Conclusions: AQP2, V2-R, and TRPV4 were expressed in the luminal epithelium of human ES. The same characteristic distribution of water and ion channels is seen in the kidney, where a significant amount of fluid is filtrated and resorbed. ES probably plays an active role in the homeostasis of the endolymph.

Objective: To establish primary vestibular schwannoma (VS) cultures that selectively favor the growth of schwannoma cells., Background: The lack of a suitable in vitro model of human VS cells has directly limited the progress of research on tumorigenesis and therapy. The problems of establishing pure VS culture include control of fibroblast proliferation. Current efforts to extend VS cell life span using viral oncogenes, by conferring the ability to proliferate in vitro, will yield cells intrinsically different from in vivo VS tumors. Much more desirable is the ability to culture VS cells without cellular transformation., Methods: Tumor specimens from 17 patients were processed for cell culture and grown at 37 degrees C with 5% CO2 and 100% humidity. Key modifications limiting fibroblast proliferation included using selective medium without L-valine, supplemented by Nu-Serum for at least a week; the use of cytosine arabinoside to kill contaminating fibroblasts; and using the Dulbecco modified medium, supplemented with brain-derived neurotrophic factor and 10% fetal calf serum after the initial serum-free period., Results: Twelve of 17 VS were successfully cultured. The presence of schwannoma cells and the absence of fibroblasts were confirmed immunohistochemically using S100 and CD90 markers, respectively. Scanning and transmission electron microscopy demonstrated typical spindle-shaped cells and the presence of "fibrous long-spacing collagen.", Conclusion: We describe a method for obtaining short-term, essentially fibroblast-free, primary VS cultures. Such pure VS cultures, retaining in vivo characteristics, are extremely useful as an in vitro model to study the pathobiology of schwannoma cells.

Objectives: The G1 regulators of the cell cycle, cyclin D(1) and D(3), have been implicated in the regulation of Schwann cell proliferation and differentiation. The purpose of this study is to evaluate cyclin D(1) and D(3) protein expression and the corresponding clinical characteristics of vestibular schwannomas., Study Design and Methods: Tissue sections of 15 sporadic vestibular schwannomas were prepared. Immunohistochemical analysis of the vestibular schwannomas was performed with anticyclin D(1) and anticyclin D(3) antibodies. The immunoreactivity was evaluated in comparison with adjacent vestibular nerves. Tissue sections of breast carcinoma and prostate carcinoma were used as positive controls for cyclin D(1) and D(3) staining, respectively. Patient demographics, tumor characteristics, and cyclin D expression were reviewed, and statistical analysis was performed., Results: While the breast carcinoma control expressed abundant cyclin D(1) protein, none of the 15 vestibular schwannomas showed detectable cyclin D(1) staining. In contrast, seven of 15 vestibular schwannomas stained positive for the cyclin D(3) protein. Cyclin D(3) staining was taken up in the nucleus of schwannoma tumor cells in greater proportion than Schwann cells of adjacent vestibular nerve. Although sample size was small, no significant difference in the average age of presentation, tumor size, and male to female ratios for the cyclin D(3)(+) or cyclin D(3)(-) groups was found., Conclusion: The Cyclin D(1) protein does not appear to play a prominent role in promoting cell cycle progression in vestibular schwannomas. In contrast, cyclin D(3) expression was seen in nearly half of the tumors examined, suggesting that it may have a growth-promoting role in some schwannomas. Further studies are needed to define its cellular mechanism.

To explore a possible influence of the immune system in the development of brain tumors, we evaluated the relationship between history of allergies and autoimmune diseases and risk of brain tumors within a large, hospital-based case-control study. Cases (n = 782) were patients recently diagnosed with glioma (n = 489), meningioma (n = 197) or acoustic neuroma (n = 96) at hospitals in Boston, Phoenix and Pittsburgh (USA). Controls (n =799) were patients hospitalized for a variety of nonmalignant conditions and frequency-matched to cases by hospital, age, sex, race/ethnicity and distance of residence from hospital. Research nurses collected data by personal interview of patients. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression. There was a significant inverse association between glioma and history of any allergies (OR = 0.67, 95% CI = 0.52-0.86) or autoimmune diseases (OR = 0.49, 95% CI = 0.35-0.69). No significant associations were evident for meningioma or acoustic neuroma with history of any allergies. An inverse association was observed between meningioma and history of autoimmune diseases (OR = 0.59, 95% CI = 0.38-0.92). There was a suggestion of interaction between allergies and autoimmune diseases on risk of glioma (p = 0.06), with subjects having both conditions being at lowest risk (OR = 0.24, 95% CI = 0.14-0.42). Among the specific conditions, asthma and diabetes showed the most consistent associations (OR = 0.63, 95% CI = 0.43-0.92 and OR = 0.44, 95% CI = 0.27-0.70, respectively). Our results add to evidence that persons with allergies or autoimmune diseases are at reduced risk of glioma. The basis of the associations is not clear, but they might imply a role of immunologic factors in the development of brain tumors. Published 2002 Wiley-Liss, Inc.

Calcification in vestibular schwannoma is extremely rare. A 36-year-old man presented with a history of decreased hearing on the left since childhood. Computed tomography showed a left cerebellopontine angle lesion protruding into the porus acousticus and enlarging the internal auditory meatus, with significant deposits of calcification. Histological and immunohistochemical examination, including staining for CD-34, a myeloid progenitor cell antigen, found highly degenerated schwannoma with collagen-rich tissue, calcification, formation of bone, abnormal vessels of various sizes, and old haemorrhage with marked haemosiderin-laden macrophages. Most of the surgical specimen was sclerotic collagenous tissue containing sparse spindle-shaped cells which formed approximately 90% of the total specimen. However, the spindle-shaped cells were partly concentrated into islands forming the cellular part (approximately 10% of the total). The spindle-shaped cells in both parts showed almost typical immunohistochemical characteristics of schwannoma. However, many spindle-shaped cells in only the sclerotic part were positive for CD-34, which is widely used for the diagnosis of solitary fibrous tumours. Cerebellopontine angle tumour showing fibromatous tissue, including calcification, may contain foci of typical schwannoma. Careful histological examination with detailed immunohistochemical staining is required for the correct diagnosis. In particular, spindle-shaped cells occasionally show positive immunoreactivity for CD-34 antigen in the areas of degenerated and calcified schwannoma characteristic of our case.

Histopathological examination of seven temporal bones from patients who underwent a removal of vestibular nerve schwannomas by the translabyrithine or middle fossa approaches has demonstrated small tumor remnants that failed to grow as long as 25 years after surgery. In spite of the high incidence of residual tumors, the clinical recurrence rate of tumors operated at our institution by the translabyrinthine or middle fossa approaches is low (0.3%). Immunohistochemical labeling of dividing cells demonstrated that segments of tumor adjacent to the vestibular nerve and ganglion contained more dividing cells than were present in areas of the tumor at a distance from them., (Copyright 2002 S. Karger AG, Basel)

An autoimmune hypothesis for the etiology of Meniere's disease has been proposed. In this study, we focused on gangliosides as potential antigens for autoantibodies in Meniere's disease patients. In an attempt to investigate ganglioside antigens which respond to the serum of patients with Meniere's disease, we analyzed gangliosides of human acoustic neurinomas, and used them as antigens to broadly explore gangliosides that react to serum. All the acoustic neurinoma samples used in the present study showed a similar ganglioside profile on TLC (thin-layer chromatography). For the microscale ganglioside analysis, a newly developed TLC blotting/secondary ion mass spectrometry (SIMS) system together with TLC immunostaining method was employed. Most of the ganglioside bands could be analyzed, and they were identified as GM3, GM2, SPG, GM1a, GD3, S-i (sialyl-i ganglioside) and GD1a. GD1a was the predominant ganglioside and many neolactoseries gangliosides were recognized by immunological analysis. Next, the immune reactivity of serum samples, from patients with Meniere's disease, with the acoustic neurinoma gangliosides was studied by TLC immunostaining. The result showed that five of 11 patients with Meniere's disease and one of eight normal subjects reacted with a specific band, which was identified as S-i by the TLC blotting/SIMS system. The findings of the present study indicate that S-i ganglioside is an autoantigen and possibly involved in the pathogenesis of Meniere's disease.

Changes of serum immunoglobulin (Ig) concentrations may occur in both brain tumours and lumbar disc diseases (LDD). The purpose of this study was to investigate the changes of pre- and post-operative serum Ig levels in brain tumours and LDDs. Serum IgG, IgA and IgM levels were measured in 127 patients with brain tumour, 100 patients with LDD and 20 healthy subjects without neurological disease. Increases in one or more of the pre-operative serum Ig levels were observed in the patients with both brain tumours and LDDs compared with controls. However pre-operative serum IgG level was highly increased in all brain tumour types and LDDs (p<0.001). Serum IgA levels and IgM levels in the post-operative stage were significantly decreased in patients with acoustic neurinoma (p<0.01, p<0.001, respectively). Post-operative serum IgG, IgA and IgM levels were significantly decreased (p<0.001) in patients with meningioma. Post-operative serum IgG and IgM levels were significantly decreased (p<0.001) in patients with glioma. Patients with LDD showed a significantly decline in post-operative serum IgA and IgM levels (p<0.001). We think that decline in post-operative serum Ig levels may be of prognostic value in the patients with brain tumours and LDDs.

Objective: This study aimed to evaluate the role of positron emission tomography (PET) as an in vivo determinant of tumor aggressiveness and growth., Study Design: The study design was a prospective pilot study., Setting: Positron emission tomography was performed at the Clarke Institute of Psychiatry. All patients were treated at the Sunnybrook Health Science Centre. Both institutions are affiliated with the University of Toronto, Toronto, Canada., Patients: The study consisted of five consecutive patients with vestibular schwannomas with tumor size of 1 cm or larger within the cerebellopontine angle. One was a recurrent tumor and four were primary tumors., Interventions: Preoperative PET studies were conducted using 18-fluorodeoxyglucose (FDG) as a radionuclide tracer to measure glucose metabolism within tumors. Tumors were processed and immunostained against Ki-67 nuclear antigen; their proliferative potentials were quantified based on immunoreactivity of tumor cells., Main Outcome Measures: Tumor metabolic activity on PET was compared with that of contralateral cerebellum to arrive at an FDG index. This number was compared with clinical parameters and Ki-67 reactivity., Results: On PET, all tumors showed less metabolic activity than the cerebellum. The FDG uptake varied greatly between tumors independent of clinical parameters. All the tumors had a low proliferative index (<5%) with immunohistochemistry; there were quite a bit of intralesional variations in proliferative activities., Conclusion: Large tumor size and recurrent disease did not correlate well with increased FDG uptake on PET. Similarly, they did not show increased cellular activities as expressed by Ki-67 immunostaining.

Analyzing the immunological responsiveness of patients with acoustic neurinomas on the antitumor immunomodulator leacadin has revealed some significant features. In leacadin-treated patients, postimmunotherapy promotes the formation of high sanogenetic responses: an increase in the rigidity of the brain-immune system; elevations of the levels of antitumor factors of the immune system: T helper cells and locally synthesized antibodies; a decrease in neuro-sensitization after tumor removal, which prevents tumor stimulation and recurrence; an indirect reduction in the activity of T suppressors that inhibit immunological responses in growing neoplasm. Immunotherapy with the antitumor immunomodulator leacadin in patients with acoustic neurinomas contributes to the development and optimization of the tumor carrier's immunological adaptative responses, creates conditions for the optimal postoperative course and prevents recurrence.

Two immunohistologic demonstrations of markers of proliferating cells, Ki-67 and proliferating cell nuclear antigen, were applied to tissues from 10 vestibular schwannomas. Each method demonstrated three distinct rates of positively stained cells (p < .01 and p < .015, respectively, for each method). There was a one-to-one correspondence between the two immunohistologic methods in the assignment of cases to each growth rate category except for two cases (Spearman rank correlation r = 0.76, p < .05). These data support the concept of distinct growth rates in vestibular schwannoma. Tissues were also sampled from different areas of the same tumor within nine samples. The results suggest that tumor growth is not homogeneous within a tumor, but that proliferation may be more active near the surface.

BACKGROUND Understanding the tumor growth rate is very important when considering strategies for the treatment of an acoustic neuroma, although the natural course of acoustic neuromas has not been reviewed in detail. METHODS The clinicopathologic features and the postoperative growth of tumors were evaluated in 32 patients with acoustic neuromas. This study was undertaken to assess the variability of the growth potential of cells within an acoustic tumor and to determine the relationships between the growth rate and the clinicopathologic characteristics of the patients with acoustic neuromas, including age at surgery, gender, tumor location and preoperative size, the duration of the symptoms, the presence of cystic regions, the presence of Antoni type A and B cells, the tumor cell density, tumor vascularity, mitotic rate, the presence of hyaline degeneration and hemosiderin deposition, nucleolar organizer regions (NORs), and the level of proliferating cell nuclear antigen (PCNA). RESULTS The growth patterns of the tumors were divided into three groups according to their growth rate: a regression group, a "no-growth" group (growth rates from 0-0.11 cm/year) and a progression group (growth rates from 0.19-1.72 cm/year). An additional operation was required in all patients whose growth rate was more than 0.38 cm/year. A statistical study on the factors associated with an increased growth rate showed that the three histopathologic factors most significantly associated with a postoperative growth rate were hyaline degeneration (p < 0.05), cell density (p < 0.005), and PCNA labeling index (p < 0.005). CONCLUSIONS These results strongly suggest that acoustic tumors can be subdivided into several groups, based upon different biologic activities and tumor growth rates.

The levels of circulating immune complexes (CIC) were assayed in the sera of 109 patients with intracranial space occupying lesions. The CIC levels were significantly increased in all the brain tumours. After treatment, the CIC levels were still significantly increased when compared to the controls but showed no change when compared to their respective pre-operative values. Further, no change was observed in the CIC levels between the malignant and benign tumour case. Moreover, in brain tumours, 90% of the CIC precipitate consisted of IgG. However, the CIC levels fail to prognosticate the process of the disease in these patients.

The paper reports the data obtained on the efficacy of a new anti-cancer immunomodulator leacadin in neurinoma of the acoustic nerve. Leacadin participates in formation of a close regulatory relation between the brain and immune system, promotes centralization of immunity regulation in conditions of surgical trauma. The drug can also increase the level of natural killers and helpers, reduce neurosensitization and the amount of suppressors.

The paper specifies the role of leacadin immunotherapy in combined treatment of acoustic nerve neurinomas. The antitumor immunomodulator leacadin contributes to establishment and consolidation of the tumor carrier's immunological adaptation which results in uneventful postoperative developments and recurrent-free survival.

The growth rate of acoustic tumors varies widely. An immunohistochemical study with Ki-67 monoclonal antibody was performed on a random sample of 21 acoustic neuromas. The tumors belonged to 2 well-defined groups: 1 with a short duration of preoperative symptoms (< 1 year) and 1 with a long duration of preoperative symptoms (> 5 years). The tumors were of small to medium size (7 to 27 mm), and no large, cystic, or Recklinghausen tumors were included. The tumor proliferative fraction expressed by monoclonal antibody Ki-67 was determined. The results revealed a significant relation between the tumor proliferative fraction and symptom duration. Tumors with a high proliferative status had a short preoperative symptom duration, while tumors with a low proliferative status had a long symptom duration. The clinical implications of these results are discussed.

Adenosine deaminase (ADA) activity in serum was estimated in 86 patients with intracranial tumours and 40 healthy volunteers. Although high ADA concentrations in biological fluids and tumour tissues were observed in several neoplastic conditions, there was no significant difference in the ADA in sera of brain tumour patients when compared to the control values. Therefore, cell-mediated immunity probably does not play a significant role in brain tumours.

Immunoglobulin level in the sera of 62 patients with intracranial space occupying lesions was assayed using the radial immunodiffusion method. Serum IgM levels showed a highly significant increase in all types of brain tumour when compared to controls. Serum IgG levels were also increased in benign as well as malignant cases. Serum IgA levels were high only in benign cases. Hence, increased serum Ig levels may be of prognostic value in these cases.

Sera from 27 malignant glioma patients were tested for antibodies to surface antigens of cultured human glioma cells using enzyme-linked immunosorbent assay. Average antibody titer for glioma cell lines was 0.558 +/- 0.123, which was significantly higher than in the normal control group (0.165 +/- 0.082). Surprisingly, average antibody titer for autologous glioma cells was low (0.207 +/- 0.154) in these patients. The results suggest that various surface antigens in glioma cells include specific autologous antigens, antigens associated with gliomas, and common antigens present on cultured normal and malignant cells. These analyses are important in the evaluation of monoclonal antibodies and explanation of escape mechanisms.

Brain tumor growth results from the relative proportion of cells contained in three populations: a) cycling/proliferative; b) quiescent (GO)/static, and c) terminally differentiated/dying. The cycling compartment can be detected by the mouse monoclonal Ki-67 antibody, an available, rapid, safe, sensitive, and specific method for immunostaining of proliferative cells. We report the Ki-67 labeling index (LI) in 48 brain tumors. Malignant brain tumors have elevated LIs, ranging from 6.0% to 56.9%: anaplastic astrocytoma, 8.0 +/- 7.3; glioblastoma multiforme, 10.1 +/- 4.2; germinoma, 11.7; medulloblastoma, 13.1 +/- 6.6; metastases, 40.3 +/- 13.1. By contrast, slow-growing tumors showed lower values (P less than .001), approaching 1%: acoustic schwannoma, 0.4 +/- 0.6; pituitary adenoma, 1.3 +/- 1.9; meningioma, 1.2 +/- 1.2; low-grade astrocytoma, less than 1; pilocytic astrocytoma, 5.6. Human brain tumors can therefore be ranked according to the percentage of cycling cells with the acoustic schwannoma among the least proliferative and the metastatic carcinoma among the most proliferative. Within a given histotype, the Ki-67 LI may have prognostic and therapeutic implications for the individual patient. Already important for neuro-oncology research, the Ki-67 labeling index should be added to the armamentarium of the clinical neuropathologist to complement the standard histopathologic diagnosis with a cytokinetic analysis of cellular proliferation.

Frozen sections from 37 schwannomas of the VIII nerve were reacted with a panel of monoclonal antibodies to macrophage, lymphocyte, HLA-Dr invariant chain and nuclear proliferation antigens. A moderate number of macrophages was demonstrated in 96% of tumours. CD8- and CD4-lymphocytes were detected in slightly smaller numbers in up to 87% and 23% of tumours respectively. B-lymphocytes were present in only 2/32 cases and NK-cells were absent from all 16 cases tested. HLA-Dr antigen was expressed by macrophages in most cases and by tumour cells in 13/24 tumours. These findings may represent evidence for a degree of cellular immune response. Occasional cells featuring nuclear proliferation were detected in 15/27 cases.

To clarify the involvement of cochlear nerves in small acoustic tumors, we used immunoperoxidase techniques to determine the presence and distribution of vimentin and S-100 antigens in two acoustic tumor specimens and a transected vestibular nerve. Schwann cells and acoustic tumor cells failed to react positively with monoclonal antibody to vimentin. Reaction was observed in mesenchymal-appearing cells within both the normal nerve and the acoustic tumors, predominantly in association with blood vessels. Normal schwann cells and acoustic tumor cells reacted with polyclonal antibody to S-100 antigen with a similar, uniform distribution. Mesenchymal-appearing cells did not react with antibody to S-100. Immunostaining of a vestibular nerve from a Meniere's disease patient, used as a control, did not differ significantly from nerves adjacent to acoustic tumors. Because tumor cells and normal schwann cells stained similarly with antibody to S-100, it was not possible to establish with certainty if tumor cells invaded adjacent nerves.

Intraosseous endolymphatic sacs obtained from patients with acoustic neuromas who had undergone total labyrinthectomy during tumor removal were examined for the presence of T helper/inducer and T suppressor/cytotoxic lymphocytes, B lymphocytes, plasma cells, and macrophages. Immunoperoxidase staining of cryostat sections revealed the presence of T helper/inducer lymphocytes, T suppressor/cytotoxic lymphocytes, and macrophages. The number of B lymphocytes and plasma cells was much smaller than the number of T lymphocytes. The number of T suppressor/cytotoxic lymphocytes was higher than the number of T helper/inducer lymphocytes. This study supports the notion of local immune responsiveness in the human inner ear. This is the first immunohistochemical study to analyze lymphocyte subpopulations; specifically, to provide insight into T-cell function in the endolymphatic sac.

The ultrastructure of ten normal human endolymphatic sacs (ES), fixed immediately after death and obtained at autopsy, was observed by transmission electron microscopy. The roles of the epithelium, subepithelial space, vasculature, and ES leukocytes were morphologically studied to evaluate possible immunologic functions of the human ES. In addition, five intraosseous ES biopsies from patients undergoing translabyrinthine acoustic neuroma resection were studied using the immunoperoxidase technique to identify specific leukocyte subpopulations. Evidence of phagocytic activity included the presence of phagocytic epithelial cells, monocytes, macrophages, and polymorphonuclear leukocytes. Immune surveillance was suggested by intraepithelial and subepithelial T-lymphocytes, numerous fenestrated blood vessels, and the presence of a homogeneously staining substance within the lumina of ES epithelial tubules. No B-lymphocytes were found. The findings support the existence of a local immune system of the normal human inner ear.

Lymphocytes from 8 patients with acoustic neuromas and 8 healthy control persons were exposed to acoustic neuroma extract. Indirect leukocyte migration agarose technique was applied for detection of leukocyte migration inhibition (LMI). The standard technique was additionally modified using a specific assay for release of human leukocyte migration inhibitory factor (LIF). Both the standard technique and the LIF-specific assay revealed a significant LMI exerted by lymphocytes from patients, as compared with control persons. The LIF-specific assay demonstrates that the LMI is an expression of cell-mediated immunity due to release of LIF. The immune reaction is raised against an unknown antigen in acoustic neuroma extract. Further studies must determine whether the immune reaction is specific for acoustic neuroma patients vis-a-vis patients with other tumours, especially other neuromas.

11 acoustic neuroma patients, exhibiting cell-mediated immunity in vitro against acoustic neuroma extract, were tested for cell-mediated immunity in vitro against perilymph samples from other acoustic neuroma patients. 14 of 21 perilymph samples were antigenic. None of three healthy persons reacted against antigenic perilymph samples. The perilymph antigenicity was reproducible and negatively correlated to the perilymph sample volume. Differences in sample volume could not be ascribed to admixture of endolymph, cerebrospinal fluid, plasma or blood. The perilymph protein concentration varied from 31 to 54 g/l. Gel electrophoresis of perilymph proteins revealed less staining in the alpha-region compared to plasma proteins and a distinct band in the pre-gamma region absent in plasma. Tau-transferrin was not detected in any of 13 samples. The findings support that the cell-mediated immune response against acoustic neuroma extract may be mediated through release of antigen(s) to the perilymph.

Leucocyte migration inhibition in response to ubiquitous antigens was studied in 104 patients as an in vitro indicator of cell-mediated immunity. Patients with cerebral glioma, benign intracranial tumours, and subarachnoid haemorrhage demonstrated impaired inhibition of leucocyte migration compared with control subjects. The greatest impairment occurred in patients with subarachnoid haemorrhage, while the least impairment was seen in patients with glioma. Significant rises in inhibition of leucocyte migration in response to antigen preparations from glioma and normal brain were seen in the early post-operative period in patients with glioma and subarachnoid haemorrhage. Impaired cellular immunity, together with sensitivity of lymphocytes to brain-derived antigens, are features of cerebral disease in general and not specific for glioma.

Nerve-growth factor (N.G.F.) from serum was assayed in 9 affected individuals from three kindreds with the trait "central neurofibromatosis". The hallmark of this disease is bilateral acoustic neuromas. Antigenic activity, as measured by radioimmunoassay, was significantly elevated. However, functional activity for N.G.F.; as measured by radioreceptor assay, was normal or low. This indicates that the central form of neurofibromatosis is characterised by high circulating N.G.F. levels which show low to normal function. These changes in N.G.F. differ from those in peripheral neurofibromatosis and suggest that the two hereditary conditions involve different alterations in N.G.F. synthesis and/or regulation.

Based on in vitro detection of cell-mediated immunity against human acoustic neuroma extract, a malignant potential of acoustic neuromas could be surmised, as malignant DNA patterns have been demonstrated in benign pituitary tumours. Flow-cytofluorometric characterization of the DNA content in 10 human acoustic neuromas, however, only revealed diploid cell lines and normal distributions of cells in different cell cycle phases. All acoustic neuromas were histopathology benign. The percentage of cells in S-phase (range: 1.8-8.3%, median: 3.6%) reflected a slow growth rate correlated neither to age, size of tumour, nor length of case history at time of surgery. These findings may in part be due to the analytical variation in the determinations of the S-phases. The investigation has not offered any explanation for the observed cell-mediated immunity against acoustic neuromas, and confirms that acoustic neuromas are benign tuours.

An indirect leukocyte migration agarose technique to detect cell-mediated immunity was modified to obtain a specific assay for release of human leukocyte migration inhibitory factor. Acoustic neuroma patients exhibited a significant cellular immune response against acoustic neuroma extract (P less than .01) as well as perilymph from acoustic neuroma patients (P less than .01) when compared to healthy control persons. All 19 patients tested reacted to acoustic neuroma extract. Seven of 21 perilymph samples did not elicit migration inhibition. Crossover determination of antigenicity of two negative and four positive perilymph samples against three patients revealed highly reproducible results, uncorrelated to perilymph concentration of potassium and protein. Flow cytofluorometry did not reveal malignant DNA patterns in 10 acoustic neuromas examined. Immunofluorescence studies did not reveal autoantibodies against acoustic neuromas in sera from 11 patients. The responsible antigen(s), the mechanism of immunization, and the diagnostic implications remain to be determined.

In an attempto to provide preoperative histologic identification of internal auditory canal and cerebellopontine angle tumors, and to attempt to detect small tumors and recurrent tumors, immunologic aspects of acoustic neuroma patients and control subjects were studied. Reactions based upon the interaction of patients' fresh lymphocytes in contact with acoustic neuroma antigens were studied by a leukocyte migration inhibition (LMI) assay and a locally developed refinement, the plasma effect assay. These were performed either preoperatively, postoperative, or both, in 17 patients with surgically confirmed acoustic neuromas and in 24 controls subjects. Preoperative tumor patients had a higher likelihood of having elevated LMI and plasma effect assay values than normals. False positive results were rare and the combination of the LMI and plasma effect assay decreased false negative responses to 20%. Meaningful conclusions must await more extensive testing but it has been demonstrated that tumor associated antigens do exist on the membranes of schwannoma cells and that most patients with an acoustic neuroma mount a cell-mediated immune response against these antigens.