Primary central nervous system lymphoma in China: a single-center retrospective analysis of 167 cases.

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin's lymphoma and a limited number of cases have been reported from China. This study aimed to investigate the clinicopathological features of newly diagnosed PCNSLs from a single center in eastern China and to identify the potential prognostic factors for overall survival (OS) and progression-free survival (PFS). All consecutive patients with histopathologically diagnosed PCNSLs at our center between January 2003 and October 2017 were recruited. Demographic and clinicopathological data were collected and reviewed retrospectively. The potential risk factors for OS and PFS were identified using the log-rank test and Cox regression analysis. A total of 167 immunocompetent cases were enrolled. The median age was 58 years (range 17-96 years), and the male:female ratio was 3:2. Headache (n = 65; 39%) and cerebral hemisphere (n = 96; 57%) were the most common presenting complaint and location, respectively. Out of 167 cases, 150 cases were diffuse large B cell lymphomas. With a median follow-up of 25 months (range 1-152 ), the median OS and PFS were 37 months (95% CI, 25-49) and 17 months (95% CI, 13-20), respectively. Residual tumor after operation, chemotherapy without HD-MTX and palliative treatment was revealed as independent prognostic markers. Moreover, ECOG > 3, multifocal lesions, and palliative treatment were revealed as unfavorable independent prognostic markers for PFS. In conclusion, Chinese patients with PCNSL have distinct characteristics. Further studies are warranted to confirm the prognostic value of these factors and to optimize treatments for these patients.

Correlation Between Tumor Location and Clinical Properties of Glioblastomas in Frontal and Temporal Lobes.

BACKGROUND: Tumor location is a major prognostic factor in glioblastomas and may be associated with clinical properties. This study established and analyzed the correlation between tumor location and clinical properties of glioblastomas in frontal and temporal lobes. METHODS: This retrospective study determined the location of glioblastomas in the frontal lobe (FL) or temporal lobe (TL) based on preoperative magnetic resonance imaging. Clinical, radiologic, and molecular characteristics of FL and TL glioblastomas were compared to define their clinical properties, including sex, age, sides, relationship to ventricle, imaging subtypes, volume, isocitrate dehydrogenase mutation, promoter methylation of O6-methylguanine-DNA methyltransferase, progression-free survival, and overall survival. RESULTS: The study enrolled 406 patients (182 [44.83%] in FL group and 224 [55.17%] in TL group) with a mean age of 69.8 years. Compared with FL group, TL group had higher incidence of female patients (P = 0.024), tumor location distant to the ventricle (P = 0.006), isocitrate dehydrogenase mutations (P = 0.021), promoter methylation of O6-methylguanine-DNA methyltransferase (P = 0.012), and prolonged progression-free survival and overall survival (P < 0.05). No significant differences were observed between groups with respect to age ≥60 years at study entry (P = 0.668), sides (P = 0.879), imaging subtypes (P = 0.362), or volume (P = 0.709). CONCLUSIONS: This study demonstrated that different tumor locations are associated with diverse clinical properties of glioblastomas in FL and TL. This information will aid in increasing understanding of glioblastoma biology for application in baseline comparisons in future clinical trials.

Long noncoding RNA lncHERG promotes cell proliferation, migration and invasion in glioblastoma.

Long noncoding RNAs have recently been proven to regulate tumorgenesis in many cancers. However, their biological functions in glioblastoma remain largely unknown. Here we found an uncharacteristic lncRNA lncHERG that is highly expressed in human glioblastoma (GBM). We found that lncHERG knockdown inhibited cell proliferation, migration and invasion in glioblastoma in vitro and in vivo. Moreover, the higher expression of lncHERG in patients with glioblastoma indicated lower survival rate and poorer prognosis. Mechanistically, we found that lncHERG can serve as a sponge for miR-940 which is a tumor suppressor in cervical cancer and whose function has not been defined in glioblastoma. We showed that miR-940 was down-regulated in glioblastoma tissues compared to peritumor tissues. LncHERG knockdown impaired cell proliferation, migration and invasion while inhibition of miR-940 in the meantime reversed this trend. In conclusion, our study highlights the essential role of lncHERG in glioblastoma by acting as a competing endogenous RNA of miR-940, which may serve as a new prognostic biomarker in glioblastoma.

TERT promoter mutated WHO grades II and III gliomas are located preferentially in the frontal lobe and avoid the midline.

The promoter region of telomerase reverse transcriptase (TERTp) and isocitrate dehydrogenase (IDH) have been regarded as biomarkers with distinct clinical and phenotypic features. Investigated the possible correlations between tumor location and genetic alterations would enhance our understanding of gliomagenesis and heterogeneity of glioma. We examined mutations of TERTp and IDH by direct sequencing and fluorescence in-situ hybridization in a cohort of 225 grades II and III diffuse gliomas. Correlation analysis between molecular markers and tumor locations was performed by Chi-square tests/Fisher's exact test and multivariate logistic regression analysis. We found gliomas in frontal lobe showed higher frequency of TERTp mutation (P=0.0337) and simultaneously mutations of IDH and TERTp (IDH (mut)-TERTp(mut)) (P=0.0281) than frequency of biomarkers mutation of tumors in no-Frontal lobes, while lower frequency of TERTp mutation (P<0.0001) and simultaneously wild type of IDH and TERTp (IDH (wt)-TERTp(wt)) (P<0.0001) in midline than no-midline lobes. Logistic regression analysis indicated that locations of tumors associated with TERTp mutation (OR=0.540, 95% CI 0.324-0.900, P=0.018) and status of combinations of IDH and TERTp (IDH (mut)-TERTp (mut) vs. IDH (wt)-TERTp (wt) OR=0.162, 95% CI 0.075-0.350, P<0.001). In conclusion, grades II and III gliomas harboring TERTp mutation were located preferentially in the frontal lobe and rarely in midline. Association of IDH-TERTp status and tumor location suggests their potential values in molecular classification of grades II and III gliomas.

Brain ischemia induces regeneration of interneurons but not projection neurons.

PURPOSE: How injured long-distance neural tracts are reestablished following ischemic brain injury remains unclear. Theories surrounding reconnection include the growth of newly formed axons from newborn neurons, modification of local circuits and a beneficial influence from neurotrophic factors. This research aimed to find the developing new born neurons and the neurotrophic factors they secreted in a middle cerebral artery occlusion (MCAO) rat model to explain the roles of neural progenitor cells in post-ischemic neurogenesis. METHODS: Fifty-three male Sprague-Dawley rats underwent the MCAO procedure or sham operation. Double labeling of specific neuron markers (calbindin and N-200) and a dividing cell marker (BrdU) were used to identify newly formed neurons. Neurotrophic factors were examined in the cerebrospinal fluid in post-ischemic rats using enzyme-linked immunosorbent assay. RESULTS: Ischemic injury induced activation of neurogenesis. The newborn neurons differentiated into calbindin-positive interneurons, but not N-200 positive projection neurons. The concentration of neurotrophic factors was elevated and was in accordance with the neurogenesis seen in ischemic animal models. CONCLUSION: Our research indicates that the recovery of neural function is not ascribed to the reestablishment of damaged projection tracts, but to the modulation of local circuits and beneficial effects of neurotrophins produced by neural progenitor cells.

The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice.

AIM: To determine whether Nrf2 signaling pathway activation could attenuate oxidative stress and neuronal damage following traumatic brain injury (TBI). METHODS: Controlled cortical impact (CCI) injury was performed in Sprague-Dawley rats and Nrf2-knockout or control mice. Sulforaphane (SFN), a potent Nrf2 activator, was used to activate Nrf2. Oxidative stress, lesion volume, neuron degeneration, and neurologic dysfunction were determined using biochemical, histopathological and neuroethologic approaches. Protein and mRNA levels of Nrf2 and the antioxidant enzymes heme oxygenase 1 (HO-1) and NAD(P)H:quinine oxidoreductase 1 (NQO1) were assessed using Western blot analysis and RT-PCR. RESULTS: Activation of Nrf2 by SFN( 5 mg/kg, ip) induced the nuclear translocation and activation of Nrf2, which resulted in an up-regulation of Nrf2-dependent antioxidant enzymes and a reduction of oxidative damage after TBI. In accordance with these biochemical changes, SFN also significantly reduced neuronal death, contusion volume, and neurological dysfunction after TBI. Furthermore, Nrf2-knockout mice showed more severe oxidative stress and neurologic deficits after TBI and did not benefit from the effects of SFN. CONCLUSION: Nrf2 plays a pivotal role in cell defenses against the oxidative stress of TBI. In addition, pharmacological activation of the Nrf2 signaling pathway by small molecule inducers such as SFN attenuated oxidative stress and neuronal damage following TBI.

Implantation of neural stem cells embedded in hyaluronic acid and collagen composite conduit promotes regeneration in a rabbit facial nerve injury model.

The implantation of neural stem cells (NSCs) in artificial scaffolds for peripheral nerve injuries draws much attention. NSCs were ex-vivo expanded in hyaluronic acid (HA)-collagen composite with neurotrophin-3, and BrdU-labeled NSCs conduit was implanted onto the ends of the transected facial nerve of rabbits. Electromyography demonstrated a progressive decrease of current threshold and increase of voltage amplitude in de-innervated rabbits after implantation for one, four, eight and 12 weeks compared to readouts derived from animals prior to nerve transection. The most remarkable improvement, observed using Electrophysiology, was of de-innervated rabbits implanted with NSCs conduit as opposed to de-innervated counterparts with and without the implantation of HA-collagen, NSCs and HA-collagen, and HA-collagen and neurotrophin-3. Histological examination displayed no nerve fiber in tissue sections of de-innervated rabbits. The arrangement and S-100 immunoreactivity of nerve fibers in the tissue sections of normal rabbits and injured rabbits after implantation of NSCs scaffold for 12 weeks were similar, whereas disorderly arranged minifascicles of various sizes were noted in the other three arms. BrdU+ cells were detected at 12 weeks post-implantation. Data suggested that NSCs embedded in HA-collagen biomaterial could facilitate re-innervations of damaged facial nerve and the artificial conduit of NSCs might offer a potential treatment modality to peripheral nerve injuries.

Induction of functional recovery by co-transplantation of neural stem cells and Schwann cells in a rat spinal cord contusion injury model.

OBJECTIVE: To study the transplantation efficacy of neural stem cells (NSCs) and Schwann cells (SC) in a rat model of spinal cord contusion injury. METHODS: Multipotent neural stem cells (NSCs) and Schwann cells were harvested from the spinal cords of embryonic rats at 16 days post coitus and sciatic nerves of newborn rats, respectively. The differential characteristics of NSCs in vitro induced by either serum-based culture or co-culture with SC were analyzed by immunofluorescence. NSCs and SCs were co-transplanted into adult rats having undergone spinal cord contusion at T9 level. The animals were weekly monitored using the Basso-Beattie-Bresnahan locomotor rating system to evaluate functional recovery from contusion-induced spinal cord injury. Migration and differentiation of transplanted NSCs were studied in tissue sections using immunohistochemical staining. RESULTS: Embryonic spinal cord-derived NSCs differentiated into a large number of oligodendrocytes in serum-based culture upon the withdrawal of mitogens. In cocultures with SCs, NSCs differentiated into neuron more readily. Rats with spinal cord contusion injury which had undergone transplantation of NSCs and SCs into the intraspinal cavity demonstrated a moderate improvement in motor functions. CONCLUSIONS: SC may contribute to neuronal differentiation of NSCs in vitro and in vivo. Transplantation of NSCs and SCs into the affected area may be a feasible approach to promoting motor recovery in patients after spinal cord injury.

Modulation and impact of class I major histocompatibility complex by neural stem cell-derived neurotrophins on neuroregeneration.

Transplantation of neural stem cells (NSC) has shown to elicit functional recovery in experimental animal and human models of neural disorders pertaining to cell loss or degeneration. However, the underlying mechanisms of the regimen are not well understood. The scenarios lead to the speculation of neuroregeneration and replacement of lost neurons in both the central nervous system (CNS) and the peripheral nervous system (PNS). The repair per se is extremely complex involving the re-building and modulation of synapses, neurites, neural cells and glial cells. Neurotrophins, which nourish the CNS and the PNS, may attribute to the functional improvement after neural stem cell transplantation. Recent studies suggested the CNS plasticity may be modulated by the class I major histocompatibility complex (MHC), which are in turn regulated by neurotrophins. Based upon these findings, we speculate that the neurotrophins derived from the transplanted NSC may modulate the expression of the major histocompatibility complex in the injured microenvironment to facilitate neurological recovery. The proposition may have clues on the development of novel treatment modality to cure CNS injury.