Postoperative recurrence and the role of adjuvant chemotherapy in patients with pulmonary large-cell neuroendocrine carcinoma

ObjectivesThe prognosis for patients with large-cell neuroendocrine carcinoma is generally very poor. In this study, we describe the clinical features of recurrent tumors of large-cell neuroendocrine carcinoma and discuss the role of adjuvant chemotherapy and management of recurrence in patients with large-cell neuroendocrine carcinoma.MethodsWe retrospectively analyzed clinical data from 79 patients and evaluated the prognosis of patients with platinum-based adjuvant chemotherapy, recurrence patterns, patient response to chemotherapy or radiation therapy, and prognosis in patients who experienced relapse.ResultsOf 72 patients, 36 had confirmed recurrent tumors upon follow-up examinations. Of those with recurrent tumors, 33 patients (91.7%) had their first recurrent tumors within 3 years. Patients who underwent platinum-based adjuvant chemotherapy had a significantly lower rate of tumor recurrence and a higher rate of disease-free survival than those who had non–platinum-based adjuvant chemotherapy or no adjuvant chemotherapy. Multivariate analyses revealed that platinum-based adjuvant chemotherapy, pathologic stage, and the presence of second cancer are independent prognostic factors. Three patients with limited resection of the primary tumor had poor prognosis with recurrence. Postoperatively, 11 of the 36 patients without recurrence (30.6%) had metachronous second primary cancers, of which 4 patients had more than 1 site.ConclusionsPatients with large-cell neuroendocrine carcinoma had frequent recurrence following resection of the primary tumor, and those without recurrence often developed metachronous second primary cancers. Platinum-based adjuvant chemotherapy after surgery may be useful for preventing recurrence in patients with large-cell neuroendocrine carcinoma

A prospective compound screening contest identified broader inhibitors for Sirtuin 1

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified

MicroRNA signature constituted of miR-30d, miR-93, and miR-181b is a promising prognostic marker in primary central nervous system lymphoma.

MicroRNAs (miRNAs) are small RNA molecules that inhibit gene function by suppressing translation of target genes. However, in primary central nervous system lymphoma (PCNSL), the biological significance of miRNAs is largely unknown, although some miRNAs are known to be prognosis markers. Here, we analyzed 847 miRNAs expressed in 27 PCNSL specimens using microarray profiling and surveyed miRNA signature for prognostic prediction. Of these, 16 miRNAs were expressed in 27 PCNSL specimens at a frequency of 48%. Their variable importance measured by Random forest model revealed miR-192, miR-486, miR-28, miR-52, miR-181b, miR-194, miR-197, miR-93, miR-708, and let-7g as having positive effects; miR-29b-2*, miR-126, and miR-182 as having negative effects; and miR-18a*, miR-425, and miR-30d as neutral. After principal component analysis, the prediction formula for prognosis, consisting of the expression values of the above-mentioned miRNAs, clearly divided Kaplan-Meier survival curves by the calculated Z-score (HR = 6.4566, P = 0.0067). The 16 miRNAs were enriched by gene ontology terms including angiogenesis, cell migration and proliferation, and apoptosis, in addition to signaling pathways including TGF-β/SMAD, Notch, TNF, and MAPKinase. Their target genes included BCL2-related genes, HMGA2 oncogene, and LIN28B cancer stem cell marker. Furthermore, three miRNAs including miR-181b, miR-30d, and miR-93, selected from the 16 miRNAs, also showed comparable results for survival (HR = 8.9342, P = 0.0007), suggestive of a miRNA signature for prognostic prediction in PCNSL. These results indicate that this miRNA signature is useful for prognostic prediction in PCNSL and would help us understand target pathways for therapies in PCNSL

miR-101, miR-548b, miR-554, and miR-1202 are reliable prognosis predictors of the miRNAs associated with cancer immunity in primary central nervous system lymphoma.

MicroRNAs (miRNAs) inhibit protein function by silencing the translation of target mRNAs. However, in primary central nervous system lymphoma (PCNSL), the expression and functions of miRNAs are inadequately known. Here, we examined the expression of 847 miRNAs in 40 PCNSL patients with a microarray and investigated for the miRNA predictors associated with cancer immunity-related genes such as T helper cell type 1/2 (Th-1/Th-2) and regulatory T cell (T-reg) status, and stimulatory and inhibitory checkpoint genes, for prognosis prediction in PCNSL. The aim of this study is to find promising prognosis markers based on the miRNA expression in PCNSL. We detected 334 miRNAs related to 66 cancer immunity-related genes in the microarray profiling. Variable importance measured by the random survival forest analysis and Cox proportional hazards regression model elucidated that 11 miRNAs successfully constitute the survival formulae dividing the Kaplan-Meier curve of the respective PCNSL subgroups. On the other hand, univariate analysis shortlisted 23 miRNAs for overall survival times, with four miRNAs clearly dividing the survival curves-miR-101/548b/554/1202. These miRNAs regulated Th-1/Th-2 status, T-reg cell status, and immune checkpoints. The miRNAs were also associated with gene ontology terms as Ras/MAP-kinase, ubiquitin ligase, PRC2 and acetylation, CDK, and phosphorylation, and several diseases including acquired immunodeficiency syndrome, glioma, and those related to blood and hippocampus with statistical significance. In conclusion, the results demonstrated that the four miRNAs comprising miR-101/548b/554/1202 associated with cancer immunity can be a useful prognostic marker in PCNSL and would help us understand target pathways for PCNSL treatments

The Role of C-11 Methionine PET for Non-invasive Grading Between Oligodendroglial Tumor and Other Brain Tumors

PURPOSE: Several studies have shown that the prognosis of oligodendroglial tumor is dependent on their histological grade. C-11 methionine (MET) PET imaging is one of sensitive techniques for visualizing primary brain tumors. The aim of this study was to evaluate the relationship between the uptake of MET and histopathologic grading especially based on oligodendroglial tumor versus other brain tumors.METHOD AND MATERIALS: Cerebral uptake of MET was determined in 30 patients with histologically proven gliomas (22 male patients and 9 female patients: meanage,46.9y; range, 14-75y). Grade I, II, III and IV lesions based on WHO grading class were 3,10,9, and 8 lesions, respectively. There were 3 oligodendroglioma (grade II) and 1 anaplastic oligodendroglioma (grade III) in our cases. Ecat Exact HR+ PET scanner and Biograph DUO PET/CT were used for imaging in this study. A semiquantitative methionine uptake ratio (TNR; Tumor to normal tissue ratio) was correlated with tumor grade. RESULTS: There was a significant difference in TNR between grade III and IV lesions, but no significant difference between grade II and III in whole cases. In oligodendroglial tumors, 3 grade II lesions tended to show higher TNR than a grade III lesion. There was a significant difference in TNR between grade II and III lesions except oligodendroglial tumors from the cases. Oligodendroglioma might represent different metabolic demand for MET uptake from the other gliomas. CONCLUSION: MET PET was sensitive for histopathologic grading of gliomas except oligodedroglial tumors. We must pay much attention to primary staging of oligodendroglial tumors using MET PET. CLINICAL RELEVANCE/APPLICATION: Non-invasive grading technique for oligodendroglial tumor and other brain tumors using methionine PET94rd Scientific Assembly and Annual Meetin

Operation of a P300-based brain-computer interface by patients with spinocerebellar ataxia

Objective: We investigated the efficacy of a P300-based brain-computer interface (BCI) for patients with spinocerebellar ataxia (SCA), which is often accompanied by cerebellar impairment. Methods: Eight patients with SCA and eight age- and gender-matched healthy controls were instructed to input Japanese hiragana characters using the P300-based BCI with green/blue flicker. All patients depended on some assistance in their daily lives (modified Rankin scale: mean 3.5). The chief symptom was cerebellar ataxia; no cognitive deterioration was present. A region-based, two-step P300-based BCI was used. During the P300 task, eight-channel EEG data were recorded, and a linear discriminant analysis distinguished the target from other nontarget regions of the matrix. Results: The mean online accuracy in BCI operation was 82.9% for patients with SCA and 83.2% for controls; no significant difference was detected. Conclusion: The P300-based BCI was operated successfully not only by healthy controls but also by individuals with SCA. Significance: These results suggest that the P300-based BCI may be applicable for patients with SCA. Keywords: BCI, BMI, P300, Visual stimuli, Spinocerebellar ataxi

Glucose and Methionine Uptake by Rat Brain Tumor Treated with Prodrug-Activated Gene Therapy

The effect of aciclovier(ACV) on the metabolism of rat 9I-gliosarcoma cells expressing the herpes simples virus-thymidine kinase gene was studied using 2-deoxy-2-[18F]fluoro-D-glucose(FDG) and L-[methyl-11C]methionine. Though the average weight of the tumors treated with ACV was significantly lower than that of the saline-injected control group, FDG and methionine uptake per weight of tumor tissue was not different between the two groups. This result exhibits a striking contrast to the metabolic pattern observed after radiation therapy, suggesting the different pathways regarding tumor cell death between the therapies

Urokinase-targeted fusion by oncolytic Sendai virus eradicates orthotopic glioblastomas by pronounced synergy with interferon-beta gene

Glioblastoma multiforme (GM), the most frequent primary malignant brain tumor, is highly invasive due to the expression of proteases, including urokinase-type plasminogen activator (uPA). Here, we show the potential of our new and powerful recombinant Sendai virus (rSeV) showing uPA-specific cell-to-cell fusion activity [rSeV/dMFct14 (uPA2), named "BioKnife"] for GM treatment, an effect that was synergistically enhanced by arming BioKnife with the interferon-beta (IFN-beta) gene. BioKnife killed human GM cell lines efficiently in a uPA-dependent fashion, and this killing was prevented by PA inhibitor-1. Rat gliosarcoma 9L cells expressing both uPA and its functional receptor uPAR (9L-L/R) exhibited high uPA activity on the cellular surface and were highly susceptible to BioKnife. Although parent 9L cells (9L-P) were resistant to BioKnife and to BioKnife expressing IFN-beta (BioKnife-IFNbeta), cell-cell fusion of 9L-L/R strongly facilitated the expression of IFN-beta, and in turn, IFN-beta significantly accelerated the fusion activity of BioKnife. A similar synergy was seen in a rat orthotopic brain GM model with 9L-L/R in vivo; therefore, these results suggest that BioKnife-IFNbeta may have significant potential to improve the survival of GM patients in a clinical setting