Assessment of organ doses, peak skin doses and effective doses in patients undergoing anterior cervical discectomy and fusion utilising VirtualDose-IR software.

In this study, the effect of patient- and procedure-related parameters on organ doses (ODs), peak skin dose (PSD) and effective dose (E) during anterior cervical discectomy and fusion (ACDF) was evaluated. Patient- and procedure-related parameters, as well as fluoroscopy time, kerma-area product (KAP), cumulative air-kerma (Kair) and incident Kair, were analysed for 50 ACDF procedures performed with a mobile C-arm. These parameters were inserted in VirtualDose-IR software implementing sex-specific and body mass index (BMI)-adjustable anthropomorphic phantoms to calculate OD, PSD and E. The BMI, gender and type of implants did not significantly affect KAP, incident Kair, PSD and E. However, the type of fusion significantly affected the E. The single fusions in C5/C6 resulted in significantly higher KAP, incident Kair and E than C4/C5 levels, while those performed in C6/C7 resulted in significantly higher E and PSD than C4/C5 levels. The thyroid, oesophagus and salivary glands received the largest doses in all groups studied. The BMI did not significantly affect ODs. The salivary glands absorbed significantly higher doses in males than females, while the extrathoracic region's dose significantly increased for multi- than single-level fusions. The fusions in C6/C7 resulted in significantly higher oesophagus and thyroid doses than C3/C4 and C4/C5 levels, as well as fusions performed in C5/C6 compared with C4/C5 levels. The data presented here could be used by the neurosurgeons as a comparator for future studies in optimising radiation protection during ACDF procedures in the operating theatre by keeping the ODs, PSD and E as low as reasonably practicable.

Polycystin-2 Associates With Malignancy in Meningiomas.

The involvement of polycystin-2 (PC2) in cell survival pathways raises questions about its role in carcinogenesis. Aberrant expression of PC2 has been associated with malignancy in various tumors. No evidence exists referring to PC2 expression in meningiomas. The aim of this study was to investigate the expression levels of PC2 in meningiomas and compare them with normal brain samples including leptomeninges. PC2 immunohistochemical expression was quantitatively analyzed in archival tissue from 60 patients with benign (WHO grade 1) and 22 patients with high-grade (21: WHO grade 2 and 1: grade 3) meningiomas. Specifically, the labeling index [the percentage of positive (labeled) cells out of the total number of tumor cells counted] was determined. PC2 mRNA levels were evaluated by quantitative real-time polymerase chain reaction. PC2 immunostaining was not detected in the leptomeninges. Gene expression analysis revealed increased levels of PC2 in WHO grade 1 ( P = 0.008) and WHO grade 2 ( P = 0.0007) meningiomas compared with that of normal brains. PC2 expression was significantly associated with an ascending grade of malignancy by both immunohistochemistry and quantitative real-time polymerase chain reaction ( P < 0.05). Recurrent meningiomas displayed higher levels of PC2 compared with primary meningiomas ( P = 0.008). Although no significant association of PC2 with the overall survival of the patients was found ( P > 0.05), it was noticed that the patients with WHO grade 2 meningiomas with low expression of PC2 survived longer compared with the patients with WHO grade 1 meningioma with high expression of PC2 (mean survival 49.5 and 28 months, respectively). The above results indicate a possible association of PC2 with malignancy in meningiomas. However, the mechanisms underlying PC2 implication in meningioma pathogenesis should be further elucidated.

Lumbar discectomy and fusion: Organs' dose and effective dose estimation using Monte Carlo simulation.

In this study, the effect of patient- and procedure-related parameters on organs' dose (OD), peak skin dose (PSD) and effective dose (ED) during lumbar discectomy and fusion (LDF) was assessed. Intra-operative parameters obtained from 102 LDFs were inserted into VirtualDose-IR software implementing sex-specific and BMI-adjustable anthropomorphic phantoms for dosimetric calculations. Fluoroscopy time (FT), kerma-area product (KAP), cumulative and incident air-kerma (Kair) were also recorded from the dosimetric report of the mobile C-arm. An increase in KAP, Kair, PSD and ED was found for male or higher BMI patients, multi-level or fusion or L5/S1 procedures. However, a significant difference was found only for PSD and incident Kair between normal and obese patients and for FT between discectomy and discectomy and fusion procedures. The spleen, kidneys and colon received the highest doses. The BMI have a significant impact only for kidneys, pancreas, and spleen doses when comparing obese to overweight and for urinary bladder when comparing overweight to normal patients. Multi-level and fusion procedures resulted in significantly higher doses for lungs, heart, stomach, adrenals, gallbladder and kidneys, while pancreas and spleen doses significantly increased only for multi-level procedures. Additionally, a significant increase was found only for urinary bladder, adrenals, kidneys, and spleen ODs when comparing L5/S1 and L3/L4 levels. The mean ODs were lower compared to the literature. These data may aid neurosurgeons in optimising exposure techniques during LDF to keep patients' dose as low as is practicably possible.

Heat shock factor 1 in brain tumors: a link with transient receptor potential channels TRPV1 and TRPA1.

Novel data report a "cross-talk" between Heat-Shock Factor 1 (HSF1) and the transient receptor potential vanilloid 1 cation channel (TRPV1) located in the cell membrane, introducing these channels as possible drug targets for the regulation of HSF1 activation. This study aims to investigate the co-expression of TRPV1 and HSF1 in human brain tumors. Additionally, the expression of the transient receptor potential ankyrin 1 channel (TRPA1), which is co-operated with TRPV1 in a plethora of cells, was studied. Immunohistochemical staining for HSF1, TRPV1 and TRPA1 expression was quantitatively analyzed in paraffin-embedded semi-serial tissue sections from 74 gliomas and 71 meningiomas. mRNA levels of HSF1, TRPV1 and TRPA1 were evaluated using real-time PCR. Although HSF1 was significantly increased compared with TRPV1/TRPA1 (p ≤ 0.001) in both gliomas and meningiomas, high co-expression levels for HSF1, TRPV1 and TRPA1 were found in 62.50% of diffuse fibrillary astrocytomas (WHO, grade II), 37.50% of anaplastic astrocytomas (WHO, grade III), 16.32% of glioblastomas multiforme (WHO, grade IV), and 42.25% of meningiomas (WHO, grade I and II). Correlation analysis revealed a relationship of HSF1 with TRPV1/TRPA1 in diffuse fibrillary astrocytomas (WHO, grade II) and benign meningiomas (WHO, grade I) contrary to glioblastomas multiforme (WHO, grade IV) and high grade meningiomas (WHO, grade II). Importantly, TRPA1 and TRPV1 expression levels were significantly increased in meningiomas compared with astrocytic tumors (p < 0.05). In conclusion, HSF1 and TRPV1/TRPA1 co-expression may be implicated in the pathogenesis of human brain tumors and should be considered for the therapeutic approaches for these tumors.

Evaluation of AQP4/TRPV4 Channel Co-expression, Microvessel Density, and its Association with Peritumoral Brain Edema in Intracranial Meningiomas.

Apart from VEGF-A pathway activation, the existence of peritumoral edema (PTBE) in meningiomas has been correlated with the expression levels of water transporter aquaporin 4 (AQP4). A novel cooperation of AQP4 with the transient receptor potential isoform 4 (TRPV4), a polymodal swelling-sensitive cation channel, has been proposed for regulating cell volume in glial cells. We investigated AQP4/TRPV4 channel co-expression in meningiomas along with the neovascularization of tumors and associate with PTBE. Immunohistochemical staining for AQP4 and TRPV4 expression was quantitatively analyzed in semi-serial sections of archival tissue from 174 patients. Microvessel density was expressed as microvessel count (MVC). PTBE was measured and edema index (EI) was assessed in 23 patients, based on magnetic resonance images (MRI) whereas mRNA levels of AQP4 and TRPV4 were evaluated in these patients using quantitative real-time PCR. High AQP4 was associated with lower-tumor grade (p < 0.05). AQP4 and TRPV4 were correlated in benign (WHO, grade I) (p < 0.0001) but not in high-grade (WHO, grades II and III) meningiomas (p > 0.05). AQP4/TRPV4 levels were independent of EI and MVC (p > 0.05). In contrast, EI was correlated to MVC (p = 0.02). AQP4/TRPV4 co-expression was detected in both edematous and non-edematous meningiomas. However, most of tumors with larger edema (EI ≥ 2) demonstrated increased levels of AQP4 and TRPV4. Importantly, peri-meningioma tissue of edematous meningiomas demonstrated significantly increased expression for AQP4 (p = 0.007) but not for TRPV4 (p > 0.05) compared with the main tumor. AQP4 and TRPV4 expression is rather associated with a response to vasogenic edema of meningiomas than with edema formation.

PATIENT SIZE INDICES AND DOSE IN FLUOROSCOPICALLY GUIDED LUMBAR DISCECTOMY AND FUSION: A PRELIMINARY STUDY.

Patient dose values varied significantly during interventional procedures, mainly due to the patient size, operators' choices and clinical complexity. In this study, the effect of applying a previously described and validated size-correction method to normalise kerma-area product (KAP) and average KAP rate values of the whole procedure (KAP rate) and isolate variations in dose due to the patient size and complexity, during lumbar discectomy and fusion (LDF) procedures, was investigated. Fluoroscopy time (FT), KAP, KAP rate and patient size data (weight, height and equivalent diameter) were recorded, for 96 patients who underwent single or multilevel LDF procedures by three senior neurosurgeons, defining three different patient groups (surgeon 1, surgeon 2, surgeon 3). Simple linear regression and coefficients of determination were used to investigate the relationship between uncorrected and corrected KAP and KAP rate values and patient size indices in these groups. The results showed that the size correction decreased the influence of patient size and could contribute to the isolation of the variations in patient dose due to the patient size. From this point of view, dose surveys during lumbar spine interventions may include dosimetric data from all patients independently of their body size and not only for standard-sized patients, providing the advantage of accessible data collection for the establishment of local dose reference levels and optimisation purposes, within the framework of the radiation protection program in the Neurosurgery Department.

Transient receptor potential vanilloid (TRPV) channel expression in meningiomas: prognostic and predictive significance.

The TRPV1-4 members of TRPV cation channel subfamily are mainly regarded as polymodal receptors that may be activated by diverse changes in cellular microenvironment and endogenous and exogenous agents. Abnormal expression of these channels has been reported in various tumors but not in meningiomas. Meningioma cells are thought to originate from arachnoid cap cells due to cytological and functional similarities between the two types of cells. To investigate the expression profile of TRPV1-4 channels in meningiomas and compare with TRPV1-4 channel expression in leptomeninges, we used immunohistochemistry in formalin-fixed, paraffin-embedded semi-serial tissue sections from 175 meningiomas with different grades and histological subtypes, and normal brain or meningioma specimens that contained leptomeninges. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. Leptomeninges were TRPV1-4 immunonegative. A significant percentage of tumors exhibited TRPV1-4 channel expression which was independent of the proliferation index of the tumors but was significantly associated with histopathological subtypes. The TRPV1 and TRPV3 immunoexpression was decreased whereas TRPV4 immunoexpression was significantly greater in high-grade (WHO, grade II and III) as compared with low-grade (WHO, grade I) meningiomas. Additionally, TRPV4 emerged as an independent predictor for the degree of malignancy using the binary logistic regression model [dependent variable: grade I versus higher grades (II and III)]. Kaplan-Meier analysis for 102 patients showed no significant association of TRPV1-4 expression with overall survival. The above data support that TRPV1-4 channels are implicated in meningioma pathogenesis, and TRPV4 has predictive significance in the disease.

DO THE BMI AND SURGEON INFLUENCE THE PATIENT DOSE IN FLUOROSCOPICALLY GUIDED LUMBAR DISCECTOMY AND FUSION?☆.

A survey was conducted to evaluate the role of the surgeon and the patients' body size, on patient radiation dose in fluoroscopically guided lumbar discectomy and fusion (LDF) procedures. Fluoroscopy time (FT), kerma area product (KAP), cumulative dose (CD), as well as anatomical and technical data were recorded for 100 patients, who underwent single or multi-level posterior LDF, which was carried out by three senior neurosurgeons utilising a C-arm fluoroscopy system. The patients were divided into three groups based on the body mass index (BMI) values (normal, overweight, obese) and the neurosurgeon that performed each procedure (surgeon 1, surgeon 2, surgeon 3). Entrance surface dose (ESD) was estimated based on KAP values and exposure data, while the effective dose (ED) was estimated utilising the KAP values and appropriate conversion coefficients. The mean FT, KAP, CD, ESD and ED values were 11.7 s, 0.65 Gy cm2, 2.96 mGy, 11.7 mGy and 0.08 mSv for normal patients, 22.1 s, 0.94 Gy cm2, 4.27 mGy, 21.4 mGy and 0.11 mSv for overweight patients and 67.7 s, 3.59 Gy cm2, 17.79 mGy, 107.2 mGy and 0.44 mSv for obese patients. The corresponding values were 21.5 s, 0.77 Gy cm2, 3.51 mGy, 17.5 mGy, 0.09 mSv for the first, 23.0 s, 1.44 Gy cm2, 6.52 mGy, 30.2 mGy, 0.18 mSv for the second and 14.2 s, 0.64 Gy cm2, 2.91 mGy, 17.0 mGy, 0.08 mSv for the third surgeon. Overweight patients received 83% and 38% higher ESD and ED, while obese patients 816% and 450%, compared to normal patients, respectively. The CD values should be implemented with caution, as a skin dose indicator, for all patient sizes. The weight-FT product could be useful in estimating KAP during LDF procedures. The third surgeon achieved the lowest dose values. Although the first surgeon had the same FT with the second surgeon, the corresponding dose values were decreased by 50%. The differences in FT, KAP, CD and ED values among the groups of patients studied were not statistically significant (Kruskal-Wallis test, p > 0.05), although the p-values were close to the threshold of statistical significance. The pairwise comparisons showed statistically significant differences for KAP, CD and ED values between obese and normal patients and between surgeon 1 and surgeon 3 (Mann-Whitney test, p < 0.05). The ESD values showed statistically significant differences among the BMI-based groups and among the surgeon-based groups studied (Kruskal-Wallis test, p < 0.05). This fact can be attributed to the better implementation of the fluoroscopy system technical parameters concerning the patients' size, clinical conditions and complexity of the procedures. Training and awareness of neurosurgeons on radiation protection issues are of critical importance; however, further studies should be performed towards optimisation procedures regarding patient dose.

OPTIMISATION OF PATIENT DOSE AND IMAGE QUALITY IN FLUOROSCOPICALLY GUIDED CERVICAL SPINE SURGERY: A PHANTOM-BASED STUDY.

The purpose of the current study was to provide useful data, which may help neurosurgeons to manage the patient dose and image quality in spinal surgery procedures, utilising a phantom and a test object. The kerma area product, cumulative dose (CD) and entrance surface dose (ESD) rate on the phantom and image intensifier were measured, for selectable fields of view (FOVs), fluoroscopy modes, two geometric magnifications and various phantom thicknesses. The images were subjectively evaluated regarding low-contrast detectability and high-contrast resolution. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), high-contrast spatial resolution (HCSR) and figure of merit (FOM) values were also estimated. The ESD rates increased with increasing phantom thickness, when using electronic or geometric magnification, continuous or high-definition fluoroscopy (HDF). The observers' evaluation showed relatively slight changes in image quality when pulsed fluoroscopy was used. SNR, CNR and HCSR values decreased with increasing phantom thicknesses, while remained almost constant when using pulsed fluoroscopy. SNR and HCSR improved in HDF, while the CNR remained almost constant only for the FOVs 23 and 17 cm. By applying electronic magnification, this resulted in improved HCSR. FOM values decreased in HDF, with increasing phantom thickness and using electronic magnification. For the 'thinnest' patients, CD may overestimate skin dose by 25% than the actual values. Geometric magnification resulted in improved FOM, especially for low-dose fluoroscopy and FOV 23 cm. The knowledge of the increments in dose values, image quality and FOM indices concerning phantom thickness may help neurosurgeons to optimise spinal surgery procedures by selecting the appropriate operational parameters, which could contribute toward the establishment of a radiation protection culture.

Institutional (local) diagnostic reference levels in fluoroscopically guided spine surgery.

In this study, institutional (local) diagnostic reference levels (LDRLs) and action levels (ALs) for spine interventional procedures are reported. Fluoroscopy time (FT), kerma area product (KAP), cumulative dose (CD), as well as anatomical, clinical and technical factors affecting procedure complexity were recorded for 156 patients who underwent cervical and thoraco-lumbar interventions. Patient entrance surface dose (ESD), effective dose (ED), thyroid absorbed dose and gonadal dose were also estimated, based on KAP measurements. The LDRLs and ALs were calculated as the 75th and 10th percentile of FT, KAP and CD values for the total group of patients, as well as utilizing the weight banding method and the size correction method. For the total distribution of patients, the LDRLs for cervical and thoraco-lumbar interventions are 0.15min and 0.29min for FT values, 0.10Gycm2 and 0.71Gycm2 for KAP values, as well as 0.47mGy and 3.24mGy for CD values, respectively. The corresponding ALs are 0.03min and 0.03min, 0.01Gycm2 and 0.07Gycm2, as well as 0.05mGy and 0.33mGy for FT, KAP and CD values, respectively. The age and treated levels had a significant influence on the reference dose values only for cervical interventions, whereas none of the other included factors showed statistically significant association for both cervical and thoraco-lumbar interventions. The weight banding method resulted to reference values comparable to those obtained for the whole group of patients, while the size correction method resulted to lower values. The mean ESD values were 1.58mGy (range 0.02-13.58mGy) for cervical and 23mGy (range 0.004-390.3mGy) for thoraco-lumbar interventions. The corresponding mean ED values were 0.012mSv (range 0.001-0.097mSv) and 0.124mSv (range 0.00002-2.11mSv), respectively. The mean thyroid and gonadal doses were 0.14mGy (range 0.002-1.12mGy) and 0.044mGy (range 0.000003-1.56mGy), respectively. The LDRLs and ALs reported could contribute in the effort for establishing national DRLs and for increasing neurosurgeons awareness regarding patient dose and radiation protection issues during spine interventional procedures.

Patient Dose in Fluoroscopically Guided Cervical Discectomy and Fusion.

Cervical discectomy and fusion (CDF) is a minimally invasive procedure, where the accurate placement of the implants is accomplished using fluoroscopic guidance. Therefore, the evaluation of the radiation dose becomes mandatory. The purpose of the current study was to assess patient dose during fluoroscopically guided anterior and/or posterior CDF procedures. Thirty-three patients undergoing single or multiple-level CDF were studied using a mobile C-arm system. Data regarding fluoroscopy time (FT), air kerma area product (KAP) and cumulative dose (CD) were recorded. Patient entrance surface dose (ESD), thyroid absorbed dose and effective dose (ED) were calculated from KAP measurements, utilizing the CALDoseX software. The average FT was 0.12 min (range 0.02-0.48 min), resulting to a KAP value of 0.21 Gy cm2 (range 0.01-1.46 Gy cm2) and a CD value of 0.96 mGy (range 0.04-6.58 mGy). The ESD ranged between 0.08 and 13.58 mGy (average 1.95 mGy), the ED between 0.001 and 0.097 mSv (average 0.015 mSv), while the dose absorbed by the thyroid ranged between 0.01 and 1.12 mGy (average 0.194 mGy). The dose associated with the CDF procedure is very low, comparable to that delivered by a lateral X-ray radiograph of the cervical spine. However, higher doses can be revealed, due to the non-optimum use of the X-ray system and extended FTs, mainly affected by complex clinical conditions, as well as the experience of the neurosurgeon. Additional studies need to be conducted for further investigation of the patient dose from the CDF procedure.

Occipital lobe gumma: a case report and review of the literature.

Syphilis has plagued humanity for thousands of years. Despite the measures of precaution against its transmission and the advancement of modern pharmacology, late-stage phenomena like intracerebral gumma are not uncommon even today. We present a complex case, which has misled the physicians twice. Additionally, we performed a review of the contemporary literature about the common location, clinical findings and up-to-date treatment of intracerebral gummas.

Immunohistochemical profile of NF-κB/p50, NF-κB/p65, MMP-9, MMP-2, and u-PA in experimental cervical spondylotic myelopathy.

STUDY DESIGN: The immunohistochemical profile of nuclear factor-κ B (NF-κB)/p50, NF-κB/p65, matrix metalloproteinase (MMP)-9, MMP-2, and urokinase-type plasminogen activator (u-PA) proteins was examined in spinal cord tissues coming from rabbits, which underwent chronic cervical spinal cord compression. OBJECTIVE: To study the potential role of NF-κB and extracellular matrix proteins under the chronic mechanical compression of the cervical spinal cord. SUMMARY OF BACKGROUND DATA: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction among adults older than 55 years. Neuronal loss, myelin destruction, axonal degeneration, and glial scar formation are the principal neuropathological features of CSM. However, the biologic pathways that lead to these features remain unclear. METHODS: In this study, we used a new animal experimental model of CSM developed in our laboratory. Briefly, after posterior cervical laminectomy, gradual and progressive compression (during 20 weeks) was achieved by introducing a piece of aromatic polyether (0.07 mm thick) under the C6 lamina in 15 New Zealand rabbits. In control animals (n = 15), the aromatic polyether was implanted and then removed after 60 seconds (sham operation). The immunoreactivity of p50 and p65 subunits of NF-kB, as well as that of MMP-2, MMP-9, and u-PA, was evaluated in paraffin-embedded spinal cord sections coming from both groups. The evaluation was performed using immunohistochemistry technique and the results were analyzed using SPSS for Windows, release 12.0 (SPSS Inc., Chicago, IL). RESULTS: Increased immunoreactivity of both NF-κB subunits, p50 and p65, as well as MMP-2, MMP-9, and u-PA was demonstrated in animals with CSM in comparison with controls. Statistical analysis of the results revealed strong positive correlation between NF-κB subunits immunoreactivity and that of MMP-9, MMP-2, and u-PA. CONCLUSION: There is a strong correlation between the immunoexpression of NF-κB/p50, NF-κB/p65, MMP-2, MMP-9, u-PA, and CSM.

Loss of inhibitor of growth (ING-4) is implicated in the pathogenesis and progression of human astrocytomas.

Inhibitor of growth 4 (ING-4) is a tumor suppressor gene that interacts with nuclear factor-kappaB (NF-kappaB) and represses its transcriptional activity. Several lines of evidence suggest that the tumor suppressor gene ING-4, the transcription factor NF-kappaB and its target genes matrix metalloproteases MMP-2, MMP-9 and urokinase plasminogen activator (u-PA) are critically involved in tumor invasion. The aim of the present study was to investigate immunohistochemically the expression pattern of ING-4, NF-kappaB and the NF-kappaB downstream targets MMP-2, MMP-9 and u-PA in human astrocytomas from 101 patients. We found that ING-4 expression was significantly decreased in astrocytomas, and ING-4 loss was associated with tumor grade progression. Expression of p65, a NF-kappaB subunit, was significantly higher in grade IV than in grade III and grade I/II tumors, and a statistical significant negative correlation between expression of ING-4 and expression of nuclear p65 was noticed. MMP-9, MMP-2 and u-PA were overexpressed in human astrocytomas. Of note, astrocytomas of advanced histologic grades (grade III, IV) displayed significantly higher expression levels of these proteins compared to tumors of lower grades (grade I, II). Collectively, our data suggest an essential role for ING-4 in human astrocytoma development and progression possibly through regulation of the NF-kappaB-dependent expression of genes involved in tumor invasion.

A comparative biochemical analysis of glycosaminoglycans and proteoglycans in human orthotopic and heterotopic bone.

Glycosaminoglycans and proteoglycans are macromolecules of the bone and are involved in the assembly, maturation, mineralization, and maintenance of the extracellular matrix. Heterotopic ossification is the rapid development of calcified bone tissue at ectopic sites of the body, mainly in soft tissues that normally do not ossify. The aim of this study was to characterize the molecular profiles of glycosaminoglycans and proteoglycans in normal and heterotopic bone samples to assess whether differences exist between orthotopic and heterotopic bone. Heterotopic bone tissues contained lower amounts of glycosaminoglycans compared to normal femoral bone. Structural analysis of chondroitin sulfate (CS) revealed that both heterotopic and normal femoral bones were composed mainly of 6-sulfated disaccharides. Quantitative differences in the disaccharide composition of CS, such as the decrease of 6-sulfated disaccharides in heterotopic bone with a concurrent increase of 4-sulfated and nonsulfated disaccharides, were found between ectopic bone and normal femoral bone. The proteoglycans decorin and aggrecan were both detected in all bone samples using specific antibodies. The detection of minor amounts of aggrecan in mature human bone, such as femoral bone, as well as in ectopic bone is described for the first time. These results may elucidate the phenomenon of ectopic bone formation and assist in early detection.

p75 and TrkC neurotrophin receptors demonstrate a different immunoreactivity profile in comparison to TrkA and TrkB receptors in human normal pituitary gland and adenomas.

BACKGROUND/AIMS: Recent knowledge indicates that neurotrophins play a significant role in neuroendocrine systems through their specific receptors TrkA, TrkB, TrkC and low-affinity p75(NTR) receptor. TrkA and TrkB receptors have been previously detected in numerous endocrine cells in human anterior pituitary and adenomas. In the present study, the localization of p75(NTR) and TrkC along with TrkA and TrkB receptors was investigated. METHODS: Semi-serial paraffin-embedded sections of 5 human normal pituitaries and 30 adenomas were immunostained using specific antibodies. RESULTS: Expression of p75(NTR) receptor was demonstrated in the intricate capillary and reticulin network in the anterior pituitary and in the pericapillary tissue and pituicytes in the posterior lobe. p75(NTR) immunoreactivity was absent from all adenomas. In normal anterior pituitary, a few scattered cells showed weak TrkC immunoreactivity in contrast to a high percentage of endocrine cells distributed throughout the pars distalis and pars intermedia which exhibited strong TrkA and/or intermediate TrkB immunoreactivity. Double immunohistochemistry demonstrated TrkA immunoreactivity in more than 80% of lactotropes and 70% of corticotropes and to a lesser extent in other cell types. Furthermore, in the majority of adenomas, independently of type, sex and age, a high percentage of TrkA- and/or TrkB-positive cells was detected. Interestingly, TrkC expression appeared to be increased in some adenomas compared to normal pituitary. Endothelial cells and perivascular connective tissue were always TrkB-immunostained. CONCLUSION: The above findings support a potential role of all neurotrophins, through their different receptors, in pituitary functions.

Neurotrophin receptors expression and JNK pathway activation in human astrocytomas.

BACKGROUND: Neurotrophins are growth factors that regulate cell growth, differentiation and apoptosis in the nervous system. Their diverse actions are mediated through two different transmembrane - receptor signaling systems: Trk receptor tyrosine kinases (TrkA, TrkB, TrkC) and p75NTR neurotrophin receptor. Trk receptors promote cell survival and differentiation while p75NTR induces, in most cases, the activity of JNK-p53-Bax apoptosis pathway or suppresses intracellular survival signaling cascades. Robust Trk activation blocks p75NTR -induced apoptosis by suppressing the JNK-p53-Bax pathway. The aim of this exploratory study was to investigate the expression levels of neurotrophin receptors, Trks and p75NTR, and the activation of JNK pathway in human astrocytomas and in adjacent non-neoplastic brain tissue. METHODS: Formalin-fixed paraffin-embedded serial sections from 33 supratentorial astrocytomas (5 diffuse fibrillary astrocytomas, WHO grade II; 6 anaplastic astrocytomas, WHO grade III; 22 glioblastomas multiforme, WHO grade IV) were immunostained following microwave pretreatment. Polyclonal antibodies against TrkA, TrkB, TrkC and monoclonal antibodies against p75NTR and phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were used. The labeling index (LI), defined as the percentage of positive (labeled) cells out of the total number of tumor cells counted, was determined. RESULTS: Moderate to strong, granular cytoplasmic immunoreactivity for TrkA, TrkB and TrkC receptors was detected in greater than or equal to 10% of tumor cells in the majority of tumors independently of grade; on the contrary, p75NTR receptor expression was found in a small percentage of tumor cells (approximately 1%) in some tumors. The endothelium of tumor capillaries showed conspicuous immunoreactivity for TrkB receptor. Trk immunoreactivity seemed to be localized in some neurons and astrocytes in non-neoplastic tissue. Phosphorylated forms of JNK (pJNK) and c-Jun (pc-Jun) were significantly co-expressed in a tumor grade-dependent manner (p < 0.05). Interestingly, a statistically significant (p < 0.05) reverse relationship between Trk receptors LIs and pc-Jun/pJNK LIs was noted in some glioblastomas multiforme. CONCLUSION: In the context of astrocytomas, Trk receptors (TrkA, TrkB, TrkC) expression may promote tumor growth independently of grade. Furthermore, activation of JNK pathway may contribute to progression towards malignancy. Considering the fact that regional tumor heterogeneity may be a limiting factor for immunohistochemical studies, the significance of the reverse relationship between Trk receptors and pc-Jun/pJNK LIs with respect to biological behavior of human astrocytomas requires further evaluation.