Sally Järvelä

Carbonic anhydrase IX in oligodendroglial brain tumors

BackgroundCarbonic anhydrase IX is a hypoxia-induced enzyme that has many biologically important functions, including its role in cell adhesion and invasion.MethodsThis study was set out to investigate the role of CA IX in a series of 86 oligodendroglial brain tumors (71 primary and 15 recurrent; 48 pure oligodendrogliomas and 40 mixed oligoastrocytomas).Results80% of the tumors showed CA IX expression by immunohistochemistry. Tumors with moderate or strong CA IX expression had decreased level of cell proliferation compared to weak or no CA IX expression (median 2.9 vs. 5.8, p = 0.015). CA IX correlated with two antioxidative enzymes, manganese superoxide dismutase (MnSOD) and regulatory gammaglutamylcysteine synthetase (GLCL-R): CA IX expression was significantly higher in MnSOD-positive tumors (p = 0.008) and decreased in GLCL-R-positive tumors (p = 0.044). In Cox multivariate analysis CA IX expression, patient age and histological component (pure oligodendroglioma vs. mixed oligoastrocytoma) showed independent prognostic values (p = 0.009, p = 0.003 and p = 0.022, respectively), CA IX positivity predicting poorer outcome.ConclusionCA IX was proved to be an independent prognostic indicator in oligodendroglial brain tumors, and it also correlates reversely with cell proliferation. It may have a role in the biology of oligodendrogliomas, and most interestingly, as it is mainly expressed in tumor tissue, CA IX could serve as a target molecule for anticancer treatments.

Double-bundle anterior cruciate ligament reconstruction using hamstring autografts and bioabsorbable interference screw fixation: prospective, randomized, clinical study with 2-year results.

Background Conventional anterior cruciate ligament reconstruction techniques have focused on restoration of the anterome-dial bundle only, which, however, may be insufficient in restoring the rotational stability of the knee. Hypothesis Rotational stability of the knee is better when using a double-bundle technique instead of a single-bundle technique for anterior cruciate ligament reconstruction. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods Seventy-seven patients were randomized into 3 different groups for anterior cruciate ligament reconstruction with hamstring tendons: double-bundle with bioabsorbable screw fixation (n = 25), single-bundle with bioabsorbable screw fixation (n = 27), and single-bundle with metallic screw fixation (n = 25). The evaluation methods were clinical examination, KT-1000 arthrometric measurement, and the International Knee Documentation Committee and Lysholm knee scores. Results There were no differences between the study groups preoperatively. Seventy-three patients (95%) were available at a minimum 2-year follow-up (range, 24–35 mo). The rotational stability of the knee, as evaluated by the pivot-shift test, was the best in the patients in the double-bundle group. In addition, the patients in the single-bundle groups had more graft failures than those in the double-bundle group. Concerning the anterior stability of the knee as measured with the KT-1000 arthrometer, the group differences were not statistically significant. No significant differences were found between the groups in knee scores. Conclusion Rotational stability of the knee is better when using the double-bundle technique instead of the single-bundle technique in anterior cruciate ligament reconstruction.

Carbonic anhydrase II in the endothelium of glial tumors: A potential target for therapy

Carbonic anhydrase isozyme II (CA II) is a cytosolic enzyme that is highly expressed in most organs, including the brain, where it is mainly located in the oligodendrocytes. Recent studies have shown that its expression is induced in the endothelium of neovessels in melanoma and esophageal, renal, and lung cancer. Immunological studies further indicate that CA II represents a major target antigen stimulating an autoantibody response in melanoma patients. These results prompted us to investigate endothelial CA II expression in two types of brain cancer: oligodendrogliomas and astrocytomas. A series of 255 astrocytoma and 71 oligodendroglial tumor specimens was immunostained for CA II. The staining results were correlated with a number of different clinicopathological factors and survival data. CA II showed weak or no expression in low-grade tumors, while grade 3 mixed oligoastrocytoma and glioblastoma multiforme were the most positively stained tumor types. Survival analysis indicated that endothelial CA II staining is significantly associated with a poor prognosis in patients with astrocytomas. About 17% of patients with CA II-negative tumors (weak or no endothelial signal) were still alive at the end of the follow-up period of five years. The presence of CA II in the tumor endothelium suggests that it may play an important functional role in tumor metabolism. From a clinical perspective, the results also open new avenues for selecting tumor types for dendritic cell therapy trials.

Characterization of TEM1/endosialin in human and murine brain tumors.

BackgroundTEM1/endosialin is an emerging microvascular marker of tumor angiogenesis. We characterized the expression pattern of TEM1/endosialin in astrocytic and metastatic brain tumors and investigated its role as a therapeutic target in human endothelial cells and mouse xenograft models.MethodsIn situ hybridization (ISH), immunohistochemistry (IH) and immunofluorescence (IF) were used to localize TEM1/endosialin expression in grade II-IV astrocytomas and metastatic brain tumors on tissue microarrays. Changes in TEM1/endosialin expression in response to pro-angiogenic conditions were assessed in human endothelial cells grown in vitro. Intracranial U87MG glioblastoma (GBM) xenografts were analyzed in nude TEM1/endosialin knockout (KO) and wildtype (WT) mice.ResultsTEM1/endosialin was upregulated in primary and metastatic human brain tumors, where it localized primarily to the tumor vasculature and a subset of tumor stromal cells. Analysis of 275 arrayed grade II-IV astrocytomas demonstrated TEM1/endosialin expression in 79% of tumors. Robust TEM1/endosialin expression occurred in 31% of glioblastomas (grade IV astroctyomas). TEM1/endosialin expression was inversely correlated with patient age. TEM1/endosialin showed limited co-localization with CD31, αSMA and fibronectin in clinical specimens. In vitro, TEM1/endosialin was upregulated in human endothelial cells cultured in matrigel. Vascular Tem1/endosialin was induced in intracranial U87MG GBM xenografts grown in mice. Tem1/endosialin KO vs WT mice demonstrated equivalent survival and tumor growth when implanted with intracranial GBM xenografts, although Tem1/endosialin KO tumors were significantly more vascular than the WT counterparts.ConclusionTEM1/endosialin was induced in the vasculature of high-grade brain tumors where its expression was inversely correlated with patient age. Although lack of TEM1/endosialin did not suppress growth of intracranial GBM xenografts, it did increase tumor vascularity. The cellular localization of TEM1/endosialin and its expression profile in primary and metastatic brain tumors support efforts to therapeutically target this protein, potentially via antibody mediated drug delivery strategies.

Specific expression profile and prognostic significance of peroxiredoxins in grade II-IV astrocytic brain tumors

BackgroundPeroxiredoxins (Prxs) have recently been suggested to have a role in tumorigenesis.MethodsWe studied the expression of Prx I-VI and their relationship to patient survival in 383 grade II-IV diffuse astrocytic brain tumors.ResultsPrx I positivity was found in 68%, Prx II in 84%, Prx III in 90%, Prx IV in 5%, Prx V in 4% and Prx VI in 47% of the tumors. Prx I and Prx II expression decreased significantly with increasing malignancy grade (p < 0.001 and p < 0.001). Patients with Prx I or Prx II positive tumors were significantly younger than the average age of all the patients (p = 0.014 and p = 0.005). A lower proliferation rate was associated with Prx I and Prx VI positive tumors (p = 0.019 and p = 0.033), and a lower apoptotic rate was found within Prx I and Prx II positive tumors (p < 0.001 and p = 0.007). Patients with Prx I and Prx II positive tumors had a significantly better survival rate than their Prx-negative counterparts (p = 0.0052 and p = 0.0002).ConclusionThe expression of Prx I and Prx II correlates with astrocytic tumor features, such as grade and patient age and proliferation activity (Prx I), and accordingly with patient survival.

All-Inside Meniscal Repair With Bioabsorbable Meniscal Screws or With Bioabsorbable Meniscus Arrows A Prospective, Randomized Clinical Study With 2-Year Results

Background All-inside meniscal repairs have gained popularity in the past few years. However, only a few prospective, randomized clinical studies have been done to compare different all-inside meniscal repair techniques. Hypothesis Meniscal repair with bioabsorbable meniscal screws and arrows results in similar clinical outcome on short-term follow-up. Study Design Randomized controlled trial; Level of evidence, 2. Methods Forty-two patients were prospectively randomized to have all-inside meniscal repair either by using bioabsorbable meniscal screws or bioabsorbable meniscus arrows (21 patients, 23 meniscal repairs in each group) for the fixation. The evaluation methods were clinical examination, Lysholm score, the International Knee Documentation Committee (IKDC) knee score, and magnetic resonance arthrography (MRA) evaluation. The average follow-up time was 27 months (standard deviation, 8). Results There were no differences between the study groups preoperatively. All 42 patients (100%) were available for the follow-up. However, during the follow-up, 11 patients had clinical failure, confirmed at second-look arthroscopy, of the repair leading to partial meniscal resection. Four failures (all on the medial meniscus) were observed with the use of meniscal screw fixation (17%), and 7 (4 on the medial meniscus, and 3 on the lateral meniscus) with the use of meniscus arrow fixation (30%) (P = .242). Six patients with meniscus arrows (29%) had chondral damage on the femoral condyles evaluated by MRA or at second-look arthroscopy, while none of the patients with the meniscal screws had the same (P = .018). However, the Lysholm and the IKDC scores were similar in both groups at follow-up. Conclusion All-inside meniscal repair with bioabsorbable meniscal screws and arrows resulted in similar clinical outcome, although significantly more chondral damage was observed when using bioabsorbable meniscus arrows for fixation.

Antioxidant enzymes in oligodendroglial brain tumors: association with proliferation, apoptotic activity and survival.

SummaryPurpose of the study was to investigate the relationship between antioxidant enzyme expression and clinicopathological features in oligodendroglial tumors. The expression of antioxidant enzymes and related proteins (AOEs),␣manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR) and gammaglutamylcysteine synthetase catalytic and regulatory subunits (GLCL-C and GLCL-R), was studied in 85 oligodendroglial tumors. The material included 71 primary (43 grade II and 28 grade III) and 14 recurrent (6 grade II and 8 grade III) tumors. Fifty-seven cases were pure oligodendrogliomas and 28 were mixed oligoastrocytomas. Immunoreactivity for MnSOD was found in 89%, Trx in 29%, TrxR in 76%, GLCL-C in 70% and GLCL-R in 68% of cases. Increased Trx expression was associated with higher tumor grade, cell proliferation and apoptosis (P=0.006, P=0.001 and P=0.003, Mann–Whitney test). Pure oligodendrogliomas showed more intense staining than oligoastrocytomas, especially for MnSOD (P=0.002, Mann–Whitney test). In the total series Trx was associated with poor prognosis in univariate survival analysis (P=0.0343, log-rank test) and furthermore in Cox multivariate analysis (P=0.009) along with age (P=0.002). The results suggest that the expression of Trx has a correlation to patient outcome and that there may be some association between AOEs, like MnSOD and Trx, and clinicopathological features of oligodendrogliomas.

Double-bundle versus single-bundle anterior cruciate ligament reconstruction.

According to the 20 prospective, randomized studies found from the English literature and included into this review, 6 studies (30%) did not find any significant differences in the clinical results between double-bundle and single-bundle anterior cruciate ligament reconstructions. However, 14 studies (70%) reported significantly better results with the double-bundle technique than with the single-bundle technique. In addition, none of the studies found that the single-bundle technique had better results in any of these evaluations than the double-bundle technique.

Double-Bundle Versus Single-Bundle Anterior Cruciate Ligament Reconstruction: A Prospective Randomized Study With 10-Year Results:

Background: A long-term follow-up comparing double-bundle and single-bundle techniques for anterior cruciate ligament (ACL) reconstruction has not been reported before. Hypothesis: Double-bundle ACL reconstruction may have fewer graft ruptures, lower rates of osteoarthritis (OA), and better stability than single-bundle reconstruction. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Ninety patients were randomized for double-bundle ACL reconstruction with bioabsorbable screw fixation (DB group; n = 30), single-bundle ACL reconstruction with bioabsorbable screw fixation (SBB group; n = 30), and single-bundle ACL reconstruction with metallic screw fixation (SBM group; n = 30). Evaluation methods consisted of a clinical examination, KT-1000 arthrometer measurements, International Knee Documentation Committee (IKDC) and Lysholm knee scores, and a radiographic examination of both the operated and contralateral knees. Results: Eighty-one patients (90%) were available at the 10-year follow-up. Eleven patients (1 in the DB group, 7 in the SBB group, and 3 in the SBM group) had a graft failure during the follow-up and went on to undergo revision ACL surgery (P = .043). In the remaining 70 patients at 10 years, no significant group differences were found in the pivot-shift test findings, KT-1000 arthrometer measurements, or knee scores. The most OA findings were found in the medial compartment of the knee, with 38% of the patients in the operated knee and 28% of the patients in the contralateral nonoperated knee. However, no significant group difference was found. The most severe OA changes were in the patients who had the longest delay from the primary injury to ACL reconstruction (P = .047) and in the patients who underwent partial meniscal resection at the time of ACL reconstruction (P = .024). Conclusion: Double-bundle ACL reconstruction resulted in significantly fewer graft failures than single-bundle ACL reconstruction during the follow-up. Knee stability and OA rates were similar at 10 years. The most severe OA changes were found in the patients who had the longest delay from the primary injury to ACL reconstruction and in the patients who underwent partial meniscal resection at the time of ACL reconstruction.

Peroxiredoxins and their expression in ependymomas

Aims Peroxiredoxins I–VI (Prxs) have recently been shown to have a role in the tumorigenesis of astrocytic brain tumours. In some tumour types they are associated with Nrf2 (transcription factor NF-E2-related factor), a sensor of oxidative stress, and DJ-1 (also known as PARK7), a protein known to stabilise Nrf2. Methods We investigated the immunohistochemical expression of Prxs I–VI, Nrf2 and DJ-1 in a total of 76 ependymomas and their relationship with clinicopathological features of these tumours. Results There was a significant expression of all Prxs except Prx IV in the ependymomas. Strong nuclear and cytoplasmic expression of Nrf2 could be detected in these tumours. Prx I expression was significantly associated with cytoplasmic and nuclear Nrf2 expression. Prx I expression was also associated with tumour site, with cerebellar ependymomas having a lower expression of Prx I than other tumours. DJ-1 did not associate with Prxs but nuclear DJ-1 had an inverse association with nuclear Nrf2. Cytoplasmic DJ-1 associated with worse survival in ependymoma patients. Conclusions This study indicates that oxidative mechanisms as reflected by Nrf2 expression are highly activated in ependymomas. Prxs, especially Prx I, were associated with Nrf2 expression, suggesting a role for Nrf2 in Prx I synthesis in ependymomas. While DJ-1 did not associate with any of the Prxs, its expression was associated with worsened patient survival and could have a role as a prognostic marker in ependymomas.