Arimantas Tamasauskas

Brain Lesions Manifesting as Psychiatric Disorders: Eight Cases

Sometimes patients with organic brain lesions in neurologically silent brain areas might present only with psychiatric symptoms, such as depression, anxiety disorders, schizophrenia, anorexia nervosa, or cognitive dysfunction. This study presents eight cases of patients with brain lesions (four cases of meningiomas, one case of intracerebral cysts, one case of anaplastic oligodendroglioma, one case of multiform glioblastoma, and one case of occlusive hydrocephalus) who, for a significant period of time, were diagnosed and treated for psychiatric disorders (three cases of Alzheimers disease, two cases of schizoaffective disorder, one case of schizophrenia, one case of depression, and one case of organic emotional lability disorder). When neurologic symptoms developed, they underwent neuroimaging studies and organic brain lesions were diagnosed. Further treatment required neurosurgical interventions. These cases show that brain tumors can be neurologically silent for a sufficient period of time and manifest as psychiatric disorders. Therefore, neuroimaging studies are needed when atypical changes in mental status or neurologic symptoms and signs develop.

MGMT, GATA6, CD81, DR4, and CASP8 gene promoter methylation in glioblastoma

BackgroundMethylation of promoter region is the major mechanism affecting gene expression in tumors. Recent methylome studies of brain tumors revealed a list of new epigenetically modified genes. Our aim was to study promoter methylation of newly identified epigenetically silenced genes together with already known epigenetic markers and evaluate its separate and concomitant role in glioblastoma genesis and patient outcome.MethodsThe methylation status of MGMT, CD81, GATA6, DR4, and CASP8 in 76 patients with primary glioblastomas was investigated. Methylation-specific PCR reaction was performed using bisulfite treated DNA. Evaluating glioblastoma patient survival time after operation, patient data and gene methylation effect on survival was estimated using survival analysis.ResultsThe overwhelming majority (97.3%) of tumors were methylated in at least one of five genes tested. In glioblastoma specimens gene methylation was observed as follows: MGMT in 51.3%, GATA6 in 68.4%, CD81 in 46.1%, DR4 in 41.3% and CASP8 in 56.8% of tumors. Methylation of MGMT was associated with younger patient age (p < 0.05), while CASP8 with older (p < 0.01). MGMT methylation was significantly more frequent event in patient group who survived longer than 36 months after operation (p < 0.05), while methylation of CASP8 was more frequent in patients who survived shorter than 36 months (p < 0.05). Cox regression analysis showed patient age, treatment, MGMT, GATA6 and CASP8 as independent predictors for glioblastoma patient outcome (p < 0.05). MGMT and GATA6 were independent predictors for patient survival in younger patients’ group, while there were no significant associations observed in older patients’ group when adjusted for therapy.ConclusionsHigh methylation frequency of tested genes shows heterogeneity of glioblastoma epigenome and the importance of MGMT, GATA6 and CASP8 genes methylation in glioblastoma patient outcome.

Low triiodothyronine syndrome as a predictor of poor outcomes in patients undergoing brain tumor surgery: a pilot study: Clinical article

OBJECT A low triiodothyronine (T3) state is highly prevalent and is associated with a poor prognosis in critically ill patients. The authors investigated, in patients undergoing brain tumor surgery, the direct association of a perioperative low T3 syndrome with clinical outcomes and also with symptoms of depression and anxiety. METHODS Ninety consecutive patients (71% women, median age 55 years), on admission for brain tumor surgery, were evaluated for sociodemographic and clinical characteristics. Their thyroid function profile was assessed on the morning of brain tumor surgery and on the morning after brain tumor surgery. Patients with free T3 concentrations of 3.1 pmol/L or less were considered to have low T3 syndrome. The patients were evaluated for symptoms of depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) before and after surgery and for clinical outcomes using the Glasgow Outcome Scale (GOS) at discharge. RESULTS After brain tumor surgery, free T3 concentrations decreased (p < 0.001) and the proportion of patients with low T3 levels increased from 38% to 54% (p = 0.02). Lower preoperative (rho = 0.30, p = 0.004) and postoperative (rho = 0.33, p = 0.002) free T3 concentrations correlated with low GOS scores at discharge. Preoperative low T3 syndrome (OR 5.49, 95% CI 1.27-23.69, p = 0.02) and postoperative low T3 syndrome (OR 8.73, 95% CI 1.49-51.21, p = 0.02) both increased risk for unfavorable clinical outcomes (GOS scores < 5) at discharge, after adjusting for age, sex, histological diagnosis of brain tumor, preoperative functional impairment, previous treatment for brain tumor, and depressive symptoms. Preoperative low T3 syndrome increased the risk for preoperative (HADS-depression subscale score ≥ 11; OR 4.12, 95% CI 1.16-14.58, p = 0.03) but not postoperative depressive symptoms independently from sociodemographic and clinical factors. CONCLUSIONS Low T3 syndrome is a strong independent predictor of unfavorable clinical outcomes and depressive symptoms, and its diagnosis and preoperative management should be considered in patients undergoing neurosurgery for the treatment of brain tumors.

Screening for psychological distress in neurosurgical brain tumor patients using the Patient Health Questionnaire‐2

Psychological distress is highly prevalent but often undiagnosed in brain tumor patients. We evaluated the psychometric properties of the Patient Health Questionnaire‐2 (PHQ‐2) for screening of distressed neurosurgical brain tumor patients.

High level of Sema3C is associated with glioma malignancy

BackgroundMalignant gliomas are characterized by the tendency of cancerous glial cells to infiltrate into normal brain tissue, thereby complicating targeted treatment of this type of cancer. Recent studies suggested involvement of Sema3C (semaphorin 3C) protein in tumorigenesis and metastasis in a number of cancers. The role of Sema3C in gliomagenesis is currently unclear. In this study, we investigated how expression levels of Sema3C in post-operative glioma tumors are associated with the malignancy grade and the survival of the patient.FindingsWestern blot analysis was used for detection of Sema3C protein levels in 84 different grade glioma samples: 12 grade I astrocytomas, 30 grade II astrocytomas, 17 grade III astrocytomas, and 25 grade IV astrocytomas (glioblastomas). Sema3C mRNA levels in gliomas were analysed by real-time PCR. Several statistical methods have been used to investigate associations between Sema3C protein and mRNA levels and clinical variables and survival outcome. The results demonstrated that protein levels of Sema3C were markedly increased in glioblastomas compared to grade I-III astrocytoma tissues and were significantly associated with the shorter overall survival of patients. High accumulation of Sema3C positively associated with the age of patients and pathological grade, but did not correlate with patient’s gender. Sema3C mRNA levels showed no association with either grade of glioma or patient survival.ConclusionsThe data presented in this work suggest that the increased levels of Sema3C protein may be associated with the progression of glioma tumor and has a potential as a prognostic marker for outcome of glioma patients.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1564066714158642

Glioma Malignancy-Dependent NDRG2 Gene Methylation and Downregulation Correlates with Poor Patient Outcome

Aims: NDRG2 (N-myc downstream regulated gene 2) gene is involved in important biological processes: cell differentiation, growth and apoptosis. Several molecular studies have shown NDRG2 as a promising diagnostic marker involved in brain tumor pathology. The aim of the study was to investigate how changes in epigenetic modification and activity of NDRG2 reflect on glioma malignancy and patient outcome. Methods: 137 different malignancy grade gliomas were used as the study material: 14 pilocytic astrocytomas grade I, 45 diffuse astrocytomas grade II, 29 anaplastic astrocytomas grade III, and 49 grade IV astrocytomas (glioblastomas). Promoter methylation analysis has been carried out by using methylation-specific PCR, whereas RT-PCR and Western-blot analyses were used to measure NDRG2 expression levels. Results: We demonstrated that NDRG2 gene methylation frequency increased whereas expression at both mRNA and protein levels markedly decreased in glioblastoma specimens compared to the lower grade astrocytomas. NDRG2 transcript and protein levels did not correlate with the promoter methylation state, suggesting the presence of alternative regulatory gene expression mechanisms that may operate in a tissue-specific manner in gliomas. Kaplan-Meier analyses revealed significant differences in survival time in gliomas stratified by NDRG2 methylation status and mRNA and protein expression levels. Conclusions: Our findings highlight the usefulness of combining epigenetic data to gene expression patterns at mRNA and protein level in tumor biomarker studies, and suggest that NDRG2 downregulation might bear influence on glioma tumor progression while being associated with higher malignancy grade.

Digit ratio (2D:4D) in primary brain tumor patients: A case-control study ☆

BACKGROUND The second-to-fourth digit ratio (2D:4D) reflects prenatal estrogen and testosterone exposure, and is established in utero. Sex steroids are implicated in development and progression of primary brain tumors. AIMS To investigate whether there is a link between 2D:4D ratio and primary brain tumors, and age at presentation. METHODS Digital images of the right and left palms of 85 primary brain tumor patients (age 56.96±13.68years; 71% women) and 106 (age 54.31±13.68years; 68% women) gender and age matched controls were obtained. The most common brain tumor diagnoses were meningioma (41%), glioblastoma (20%) and pituitary adenoma (16%). Right and left 2D:4D ratios, and right minus left 2D:4D (Dr-l) were compared between patients and controls, and were correlated with age. RESULTS Right and left 2D:4D ratios were significantly lower in primary brain tumor patients relative to controls (t=-4.28, p<0.001 and t=-3.69, p<0.001, respectively). The Dr-l was not different between brain tumor patients and controls (p=0.27). In meningioma and glioma patients, age at presentation correlated negatively with left 2D:4D ratio (rho=-0.42, p=0.01 and rho=-0.36, p=0.02, respectively) and positively with Dr-l (rho=0.45, p=0.009 and rho=0.65, p=0.04, respectively). CONCLUSIONS Right and left hand 2D:4D ratios are lower in primary brain tumor patients relative to healthy individuals suggesting greater prenatal testosterone and lower prenatal estrogen exposure in brain tumor patients. Greater age at presentation is associated with greater Dr-l and with lower left 2D:4D ratio of meningioma and glioma patients. Due to small sample size our results should be considered preliminary and interpreted with caution.

Psychological distress symptoms' clusters in brain tumor patients: factor analysis of depression and anxiety scales

Adomas Bunevicius*, Sarunas Tamasauskas, Vytenis Deltuva, Arimantas Tamasauskas and Robertas Bunevicius Behavioral Medicine Institute, Lithuanian University of Health Sciences, Palanga, Lithuania Department of Neurosurgery, Lithuanian University of Health Sciences, Kaunas, Lithuania Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Institute of Neurosciences, Lithuanian University of Health Sciences, Kaunas, Lithuania

GATA4 and DcR1 methylation in glioblastomas

BackgroundEpigenetic silencing of tumor suppressor genes plays important role in gliomagenesis. Recently, GATA4 and DcR1 were suggested to be a tumor suppressor genes involved in tumorigenesis in various types of human cancers. However, up to now the methylation frequency of GATA4 and DcR1 genes has not been determined in glioblastoma. In this study, we investigated methylation of GATA4 and DcR1 promoters and their association with patient prognosis in glioblastoma.MethodsMethylation status of GATA4 and DcR1 promoters was investigated by methylation specific PCR in 99 glioblastoma patients. Statistical analyses were conducted to investigate the association between clinical variables and overall survival time.ResultsGATA4 and DcR1 were aberrantly methylated in 23.2% and 27.6% of glioblastoma tumors, but not in normal brain. GATA4 promoter hypermethylation showed significant association with patients age (p = 0.027). Relationship between genes promoter methylation and glioblastoma patient survival was not determined.ConclusionsThe present work demonstrated that GATA4 and DcR1 promoter hypermethylation is tumor specific event in glioblastoma but they promoter methylation cannot be considered as a prognostic marker of glioblastoma survival.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1381170351801852

Association of pre-operative depressive and anxiety symptoms with five-year survival of glioma and meningioma patients: a prospective cohort study

Background Mental symptoms are common and associated with worse health status of brain tumor patients. We evaluated the association of pre-operative depressive and anxiety symptoms with 5-year mortality of glioma and meningioma patients. Methods One-hundred and fifty-two patients (mean age 56.9±14.7 years, 69% women) were evaluated for functional status (Barthel index), and depressive and anxiety symptom severity (Hospital Anxiety and Depression scale or HADS). Patients were categorized as having mild, moderate or severe depressive/anxiety symptoms if they scored ≤7, 8-10 or ≥11 on the HADS, respectively. Information pertaining to histological diagnosis, extent of resection and adjuvant therapies were obtained from medical records. Follow-up continued through November, 2015. Results Forty-three patients were diagnosed with high-grade glioma, 20 with low-grade glioma and 89 with meningioma. Moderate to severe depressive and anxiety symptoms were diagnosed in 28% and 36% of patients, respectively. In meningioma patients, survival was the shortest in patients with severe depressive symptoms (40.32±7.92 months) followed by patients with moderate (46.66±6.05 months) and mild (55.68±1.77 months) depressive symptoms (Log-Rank = 6.211, p = 0.045). After adjusting for patients’ age, gender, functional status, extent of resection, history of depression, and tumor location, laterality and grade, severe depressive symptoms were associated with increased 5-year mortality risk of meningioma patients (HR = 7.083 [95%CI: 1.755–28.588], p = 0.006). Depressive and anxiety symptoms were not associated with mortality of glioma patients Conclusions Depressive and anxiety symptoms are common in glioma and meningioma patients. Pre-operative depressive symptoms are associated with shorter survival of meningioma patients independently from clinical prognostic indicators.