ET-1 Translational research platform for malignant brain tumors

Introduction: The standard therapy for malignant brain tumors includes surgery and combination therapy with radiation and chemotherapy, but to provide individualized treatment based on the biological and molecular genetic background of the tumor, integrate genetic information with various functional data are required. In this study, we present an overview of our integrated approaches for translational research and clinical management. Methods: In glioma, pre-and intra-operative clinical information, including intraoperative genetic diagnosis, and intraoperative rapid immunohistochemistry is obtained, then a multidisciplinary treatment approach is started based on these integrated data. Specimens collected intraoperatively are cryopreserved for future analysis, and primary cultured cells are routinely collected. The cultured cells are transplanted into the brain of immunodeficient mice to establish patient-derived xenograft model (PDX). Genetic screening, such as IDH, TERT, BRAF, H3F3A mutation and MGMT methylation analysis are routinely assessed within a few days after surgery and used as information for integrated diagnosis. In case of PDX establishment or recurrence, we perform whole exon sequencing or comprehensive genomic assessment to identify genetic abnormalities. If genomic alterations for possible molecular targeted therapy are identified, we assess drug sensitivity test in vitro and in vivo, which are utilized for research to develop optimal molecular targeted therapy. The results, such as the therapeutic effects of molecular targeted drugs, are used for clinical applications. Results: Since the platform was established, we have treated a total of 286 patients, including 189 gliomas and 37 central nervous system lymphomas based on the integrated information. We are currently collecting clinical data to examine if this integrated approach could provide clinical benefit.Conclusion: The translational research system for malignant brain tumors plays an important role in the promotion of clinical and basic research.

The role of neurophysiological assessments during the combined treatment of patients with malignant brain tumors

Introduction. Dynamic monitoring and evaluation of the results of therapy of patients with malignant brain diseases is a complex and urgent problem in modern medicine. The aim of the study was to assess the reliability of the transcranial magnetic stimulation technique as a tool for neurophysiological monitoring in patients with malignant brain tumors. Material and methods. Two groups of patients were formed: adults with large focal solitary lesions of the central nervous system (glioma) (n=20), who underwent radiotherapy, and a control comparison group (n=16). All patients underwent diagnostic transcranial magnetic stimulation before and after treatment. Results. In the main group the application of transcranial magnetic stimulation in dynamics allowed to reveal reliable improvement of conduction along the central motor pathways (increase in amplitude of the evoked motor response). The obtained data of neurophysiological examination correlated with clinical improvement in the patient group. Discussion. Some parameters of the motor evoked response (MEP) changed reliably, as after the radiation treatment performed. Obtained changes (amplitude of MEP and, especially, its threshold) to the greatest extent reflect functional state of cortical motoneurons, as well as their anatomical preservation in case of organic changes. Before therapy in all cases there was a reliable tendency to a smaller amplitude and a higher threshold of cortical MEPs, which reflects a decrease in the functional activity of motor cortex neurons; a slower central motor conduction time also draws attention. These changes had a universal character and were registered in all patients. Conclusion. Diagnostic transcranial magnetic stimulation, taking into account age limitations inherent to it as a technique, is a valuable additional neurophysiological technique. It is safe, inexpensive and does not require expensive consumables, and is applicable to a wide range of diseases.

X-ray radiotherapy and X-ray radio diagnostics of malignant neoplasms

Radiation therapy. A report on the experience of using betatron for the treatment of malignant brain tumors was made by a group of Leningrad scientists - V.M. Ugryumov, V.I. Shamov, T.V. Chaika, and others.

Hoff and Schönbauer (Psychiatrisch-Xeurolog. Wochenschrift No. 11, 1932)

(Hoff u. Schnbauer) (Psychiatrisch-Xeurolog. Wochenschrift No. 11, 1932) in an article on radiotherapy of malignant brain tumors describe two cases of brain glioma, which were operated on and then exposed for several weeks to weak doses of radium.

Metformin and Risk of Malignant Brain Tumors in Patients with Type 2 Diabetes Mellitus

The risk of malignant brain tumors associated with metformin use has rarely been investigated in humans. This retrospective cohort study investigated such an association. Patients with new-onset type 2 diabetes mellitus diagnosed from 1999 to 2005 in the nationwide database of Taiwan’s national health insurance were used to enroll study subjects. We first identified an unmatched cohort of 153,429 ever users and 16,222 never users of metformin. A cohort of 16,222 ever users and 16,222 never users matched on propensity score was then created from this unmatched cohort. All patients were followed up from 1 January 2006 until 31 December 2011. The incidence density was calculated and hazard ratios were derived from Cox regression incorporated with the inverse probability of treatment weighting using a propensity score. The results showed that 27 never users and 155 ever users developed malignant brain tumors in the unmatched cohort. The incidence rate was 37.11 per 100,000 person-years in never users and 21.39 per 100,000 person-years in ever users. The overall hazard ratio comparing ever users versus never users was 0.574 (95% confidence interval: 0.381–0.863). The respective hazard ratios comparing the first (<27.13 months), second (27.13–58.33 months), and third (>58.33 months) tertiles of cumulative duration of metformin therapy versus never users were 0.897 (0.567–1.421), 0.623 (0.395–0.984), and 0.316 (0.192–0.518). In the matched cohort, the overall hazard ratio was 0.317 (0.149–0.673) and the respective hazard ratios were 0.427 (0.129–1.412), 0.509 (0.196–1.322), and 0.087 (0.012–0.639) for the first, second, and third tertile of cumulative duration of metformin therapy. In conclusion, this study shows a risk reduction of malignant brain tumors associated with metformin use in a dose–response pattern. The risk reduction is more remarkable when metformin has been used for approximately 2–5 years.

Differences between antioxidant defense parameters and specific trace element concentrations in healthy, benign, and malignant brain tissues

There are only a few reports examining the impact of oxidative stress in patients with benign and malignant brain tumors. In this study we investigated whether there are changes in antioxidant system (AOS) parameters and key trace elements between control, benign and malignant brain tissues. The study also aimed to examine correlations between the analyzed parameters. The study enrolled both types of brain tumors, benign tumors (BT) and malignant tumors (MT). The results were compared with control tissue (CT) without tumor infiltration collected from patients with BT. The following antioxidant parameters were determined: activities of total, manganese-containing, and copper/zinc-containing superoxide dismutase (TotSOD, MnSOD and CuZnSOD), activities of catalase, glutathione peroxidase, glutathione S-transferase, glutathione reductase and acetylcholine esterase (AChE), the concentrations of glutathione and sulfhydryl groups and of manganese (Mn), copper (Cu), zinc (Zn), and selenium (Se). BT and MT had altered activities/levels of multiple AOS parameters as compared to CT, indicating that tumor cells had an altered cell metabolism and changes in AOS represent adaptive response to increased oxidative stress. Low MnSOD and AChE and high GST activities were significant for distinguishing between MT and CT. Malignant tissue was also characterized by lower Mn and Cu concentrations relative to CT and BT. Principal Component Analysis clearly discriminated BT from CT and MT (PC1, 66.97%), while PC2 clearly discriminated CT from BT and MT (33.03%). Most correlative relationships were associated with Se in the BT group and Cu in the MT group. The results of this study reveal differences between the AOS parameters and the essential trace elements between the analyzed groups. The observed dysregulations show that oxidative stress could have an important role in disrupting brain homeostasis and its presence in the pathogenesis of benign and malignant brain tumors.

No effect of deleted in malignant brain tumors 1 deficiency on chemotherapy induced murine intestinal mucositis

Mucositis is a serious adverse effect of chemotherapeutic treatment. During intestinal mucositis, the mucosal barrier is compromised, increasing the risk of severe infections. Mucositis necessitates dose reduction or pauses in treatment, which affect the outcome of the treatment. Deleted in malignant brain tumors 1 (DMBT1) is a secreted scavenger protein with effects on innate immunity and epithelial regeneration. We have previously shown that jejunal DMBT1 expression is increased in piglets during chemotherapeutic treatment. We hypothesized that DMBT1 ameliorates doxorubicin-induced mucositis. Individually-caged Dmbt1+/+ (WT) and Dmbt1−/− (KO) female mouse littermates received intraperitoneal injections of either doxorubicin or saline. They were euthanized after three (D3) or seven days (D7). Weight loss was monitored every day, and serum citrulline levels were measured at termination. Intestinal tissue was analyzed for the expression of DMBT1 and proinflammatory cytokines (IL-1β, IL-6, and TNF). Specimens from the small intestines and colon were scored for inflammation and epithelial and mucosal architecture changes. We detected no effect of DMBT1 on weight loss, serum citrulline levels, expression of proinflammatory cytokines, or histologic damage. We detected a significant increase in crypt depth in WT mice compared to that in KO mice on D3. In conclusion, DMBT1 does not affect doxorubicin-induced mucositis in mice.