Anna Goussia

Estrogen receptor beta (ERβ) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm

Purpose Estrogen receptor β (ERβ) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ERβ in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ERβ expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor α (ERα) and a pure antagonist of ERβ, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ERα. The purpose of this study was to explore the expression of ERβ in astrocytic neoplasms.Methods ERβ expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I–IV) and in adjacent non-neoplastic brain tissue.Results Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ERβ expression paralleled the increase in tumor grade.Conclusions In as much as ERβ is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.

Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary

BackgroundCancer of unknown or uncertain primary is a major diagnostic and clinical challenge, since identifying the tissue-of-origin of metastases is crucial for selecting optimal treatment. MicroRNAs are a family of non-coding, regulatory RNA molecules that are tissue-specific, with a great potential to be excellent biomarkers.MethodsIn this study we tested the performance of a microRNA-based assay in formalin-fixed paraffin-embedded samples from 84 CUP patients.ResultsThe microRNA based assay agreed with the clinical diagnosis at presentation in 70% of patients; it agreed with the clinical diagnosis obtained after patient management, taking into account response and outcome data, in 89% of patients; it agreed with the final clinical diagnosis reached with supplemental immunohistochemical stains in 92% of patients, indicating a 22% improvement in agreement from diagnosis at presentation to the final clinical diagnosis. In 18 patients the assay disagreed with the presentation diagnosis and was in agreement with the final clinical diagnosis, which may have resulted in the administration of more effective chemotherapy. In three out of four discordant cases in which supplemental IHC was performed, the IHC results validated the assay’s molecular diagnosis.ConclusionsThis novel microRNA-based assay shows high accuracy in identifying the final clinical diagnosis in a real life CUP patient cohort and could be a useful tool to facilitate administration of optimal therapy.

The shape and the thickness of the anterior cruciate ligament along its length in relation to the posterior cruciate ligament: a cadaveric study.

PURPOSE The purpose of this study was to evaluate the shape of the native anterior cruciate ligament (ACL) along its length in relation to the posterior cruciate ligament (PCL) and compare it with the size of the 3 commonly used autografts (bone-patellar tendon-bone [BPTB], single-bundle hamstring, and double-bundle hamstring). METHODS With the knee in extension, we filled the intercondylar notch with paraffin, fixing the cruciate ligaments in their natural position, in 8 cadaveric specimens. The ACL-PCL tissue specimen, embedded in paraffin, was removed en bloc. Gross sections were prepared in the coronal plane and were evaluated histologically. The width, thickness, and cross-sectional area of both the ACL and PCL were determined. The dimensions of the semitendinosus tendon (ST), gracilis tendon (GT), and BPTB grafts were measured and compared with those of the native ACL. RESULTS The PCL occupies the largest part of the intercondylar area, leaving only a small space for the ACL in knee extension. The ACL midsubstance has a width of 5 mm, resembling a band shape. Only before its tibial insertion does the ACL fan out and take the form of its tibial attachment. The BPTB graft has a thickness of 5.8 mm, whereas the ST and GT grafts have a thickness of 6.25 mm and 4.5 mm, respectively, and are comparable to the midsubstance of the ACL but undersized in the tibial insertion (P = .0016 for BPTB graft, P = .002 for ST graft, and P = .0003 for GT graft). A quadruple-looped ST-GT graft, with a diameter of 8 mm, is oversized in the midsubstance (P = .0002) but fits better in the tibial attachment. CONCLUSIONS The ACL midsubstance has a width of 5 mm, resembling a band shape. Before its tibial insertion, the ACL fans out like a trumpet, taking the form of its wide tibial attachment. CLINICAL RELEVANCE The dimensions of the native ACL have to be considered in graft selection for anatomic ACL reconstruction.

Fast cell cycle analysis for intraoperative characterization of brain tumor margins and malignancy

Flow cytometry, although indispensable for the characterization of hematologic malignancies, has not been extensively evaluated in solid tumors. To date intraoperative pathology evaluation of frozen sections of tissue obtained during surgery is the gold standard for intraoperative diagnosis. We investigated the value of a modified rapid protocol for cell cycle analysis for the intraoperative characterization of intracranial lesions and their surgical margins. We investigated patients who underwent surgery for an intracranial lesion suspicious for a tumor. DNA analysis and frozen sections were performed on tumor samples that were taken during surgery. Thirty-one patients met the inclusion criteria for the study. There was a significant difference in G0/G1 phase between high-grade and low-grade tumors. Receiver operating characteristic (ROC) analysis provided 75% of G0/G1 fraction as the optimal cutoff value thresholding the discrimination between low and high-grade tumors. There was a significant difference in S-phase and mitoses fraction between high-grade and low-grade tumors. ROC analysis indicated 6% of S-phase and 9.7% of mitoses as the optimal cutoff values thresholding the discrimination between these two groups. In the glioblastoma patients, we also analyzed the perilesional tissue and found significant differences between tumor mass and margins regarding the G0/G1 phase, the S-phase and mitoses fraction. In conclusion rapid cell cycle analysis is a method capable of differentiating low from high-grade tumors and delineating tumor margins in gliomas. Thus, the role of cell cycle analysis in brain tumors warrants further investigation.

Influence of glioma's multidrug resistance phenotype on (99m)Tc-tetrofosmin uptake.

PurposeMultidrug resistance (MDR) remains a major obstacle to successful chemotherapeutic treatment of cancer. Several chemotherapeutic and radiopharmaceutical agents are substrates of the pumps encoded by the MDR genes, and therefore, their accumulation is prevented. We evaluated in vivo whether [99mTc]tetrofosmin (99mTc-TF) uptake is influenced by the MDR profile of gliomas.ProceduresEighteen patients with histologically confirmed glioma were included in the study. Brain single-photon emission computed tomography by 99mTc-TF was performed within a week prior to surgical excision, and the expression of MRP5 was assessed by immunohistochemistry. Radiotracer accumulation was assessed by a semiquantitative method, calculating the lesion-to-normal uptake ratio.ResultsUsing Spearmans ρ analysis, we found no correlation between tracer uptake expressed as lesion-to-normal and MRP5 expression. There was a significant correlation between glioma aggressiveness as assessed by Ki-67/MIB-1 and MRP5 expression.ConclusionThe present data suggest that 99mTc-TF uptake is not influenced by gliomas MDR phenotype. Thus, 99mTc-TF constitutes a suitable radiotracer for imaging gliomas.

Low grade fibromyxoid sarcoma: a case report and review of the literature

Low grade fibromyxoid sarcoma (LGFMS) is a distinctive variant of fibrosarcoma with a high metastasizing potential and sometimes long interval between tumour presentation and metastasis. We present the case of a 50-year-old male who developed a large mass in the posterior aspect of his lower left thigh. The tumor was excised with preservation of the neurovascular structures surrounded by the mass. The tumour measured 11 × 10 × 9 cm and on pathology evaluation was diagnosed as LGFMS. Due to the relative rarity of LGFMS, there is no dedicated protocol regarding follow-up recommendations. In order to early diagnose possible metastasis it is important to inform the patients about the longstanding metastatic potential of the disease.

Comparison of diffusion tensor, dynamic susceptibility contrast MRI and 99mTc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma

INTRODUCTION Treatment induced necrosis is a relatively frequent finding in patients treated for high-grade glioma. Differentiation by imaging modalities between glioma recurrence and treatment induced necrosis is not always straightforward. This is a comparative study of diffusion tensor imaging (DTI), dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain single-photon emission computed tomography (SPECT) for differentiation of recurrent glioma from treatment induced necrosis. METHODS A prospective study was made of 30 patients treated for high-grade glioma who had suspected recurrent tumor on follow-up MRI. All had been treated by surgical resection of the tumor followed by standard postoperative radiotherapy with chemotherapy. No residual tumor had been found on brain imaging immediately after the initial treatment. All the patients were studied with dynamic susceptibility contrast brain MRI and, within a week, (99m)Tc-Tetrofosmin brain SPECT. RESULTS Both (99m)Tc-Tetrofosmin brain SPECT and dynamic susceptibility contrast MRI could discriminate between tumor recurrence and treatment induced necrosis with 100% sensitivity and 100% specificity. An apparent diffusion coefficient (ADC) ratio cut-off value of 1.27 could differentiate recurrence from treatment induced necrosis with 65% sensitivity and 100% specificity and a fractional anisotropy (FA) ratio cut-off value of 0.47 could differentiate recurrence from treatment induced necrosis with 57% sensitivity and 100% specificity. A significant correlation was demonstrated between (99m)Tc-Tetrofosmin uptake ratio and rCBV (P=0.003). CONCLUSIONS Dynamic susceptibility contrast MRI and brain SPECT with (99m)Tc-Tetrofosmin had the same accuracy and may be used to detect recurrent tumor following treatment for glioma. DTI also showed promise for the detection of recurrent tumor, but was inferior to both dynamic susceptibility contrast MRI and brain SPECT.

Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices.

Abstract CD44 has diverse functions in cell–cell and cell–matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10–50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.

Correlation of diffusion tensor, dynamic susceptibility contrast MRI and 99mTc-Tetrofosmin brain SPECT with tumour grade and Ki-67 immunohistochemistry in glioma

OBJECTIVE Assessment of the grade and type of glioma is of paramount importance for prognosis. Tumour proliferative potentials may provide additional information on the behaviour of the tumour, its response to treatment and prognosis. The purpose of this study was to investigate the correlation between diffusion tensor imaging (DTI), dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) and (99m)Tc-Tetrofosmin brain single-photon emission computed tomography (SPECT), and the tumour grade and Ki-67 labelling index in newly diagnosed gliomas. METHODS Study was made of patients with suspected glioma on brain MRI between December 2010 and January 2012, by DTI, DSC MRI and (99m)Tc-Tetrofosmin brain SPECT. The proliferative activity of each tumour was measured by deriving the Ki-67 proliferation index from immunohistochemical staining of tumour specimens. RESULTS Glioma was newly diagnosed in 25 patients (17 men, 8 women, aged 19-79 years, median 55 years). The Ki-67 index ranged from 1% to 80% (mean 19.4%). On evaluation of the relationship between the (99m)Tc-Tetrofosmin tumour uptake by gliomas was found to be significantly correlated with cellular proliferation (rho=0.924, p<0.0001). Regarding DTI, significant negative correlation was demonstrated between the apparent diffusion coefficient (ADC) ratio and the Ki-67 index (rho=-0.545, p=0.0087). Significant correlation was also observed between the fractional anisotropy (FA) ratio and the Ki-67 index (rho=0.489, p=0.02). Strong correlation was found between relative cerebral blood volume (rCBV) and Ki-67 index (rho=0.853, p<0.0001), and between the (99m)Tc-Tetrofosmin lesion-to-normal (L/N) uptake ratio and rCBV (rho=0.808, p ≤ 0.0001). Significant negative correlation was demonstrated between the (99m)Tc-Tetrofosmin L/N ratio and ADC ratio (rho=-0.513, p=0.014). These imaging techniques were able to distinguish between low-grade and high-grade gliomas. CONCLUSIONS Findings on DSC MRI and brain SPECT with (99m)Tc-Tetrofosmin metrics were more closely correlated with glioma cellular proliferation.

DNA content is associated with malignancy of intracranial neoplasms.

OBJECTIVE Flow cytometry has been applied to analyze the DNA-content distribution of tumors, in order to relate this to clinical and biological parameters of tumor behavior. Herewith, we investigated the value of cell cycle analysis in the characterization of intracranial lesions and its possible prognostic role. METHODS DNA analysis was performed in tumor samples that were taken during surgery over a five year period. Diagnosed tumors were graded according to the World Health Organization 2007 classification scheme. RESULTS Fifty-six patients were included in the study. There was a significant difference in G0/G1 phase and S-phase between low-grade and high-grade gliomas. There were 12 (57%) diploid and 9 (43%) aneuploid tumors. All aneuploid tumors were glioblastomas. Patients with G0/G1 value ≤ 69% and S phase value greater than 6% were associated with worse survival. As regards meningiomas, there was a significant difference in G0/G1 phase, S phase and mitoses fraction between benign and both atypical and anaplastic meningiomas. Aneuploidy was observed in the anaplastic tumors and in 2/4 atypical meningiomas. CONCLUSION The results of the present study, showed that cell cycle analysis could differentiate low from high grade gliomas and benign from atypical/anaplastic meningiomas. Furthermore, a prognostic significance was found in glioma patients. The role of cell cycle analysis in brain tumors thus warrants further investigation.