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Objectives. Primary gastric diffuse large B-cell lymphoma (PG-DLBCL) is a common phenotype of extranodal non-Hodgkin’s lymphoma (NHL). This research aims to identify a model for predicting overall survival (OS) and cancer-specific survival (CSS) in PG-DLBCL. Methods. A total of 1716 patients diagnosed with PG-DLBCL between 1975 and 2017 were obtained from the SEER database and further randomly divided into the training and validating cohorts at a ratio of 7 : 3. Univariate and multivariate cox analyses were conducted to determine significant variables for the construction of nomogram. The performance of the model was then assessed by the concordance index (C-index), the calibration plot, and the area under the receiver operating characteristic (ROC) curve (AUC). Results. Multivariate analysis revealed that age, race, insurance status, Ann Arbor stage, marital status, chemotherapy, and radiation therapy all showed a significant association with OS and CSS. These characteristics were applied to build a nomogram. In the training cohort, the discrimination of nomogram for OS and CSS prediction was excellent (C-index = 0.764, 95% CI, 0.744–0.784 and C-index = 0.756, 95% CI, 0.732–0.780). The AUC of the nomogram for predicting 3- and 5-year OS was 0.779 and 0.784 and CSS was 0.765 and 0.772. Similar results were also observed in the internal validation set. Conclusions. We have successfully established a novel nomogram for predicting OS and CSS in PG-DLBCL patients with good accuracy, which can help physicians to quickly and accurately complete the evaluation of survival probability, risk stratification, and therapeutic strategy at diagnosis.

Objective. Recent years, there has been a rapid increase in the incidence of esophageal adenocarcinoma (EAC), while the prognosis for patients diagnosed remains poor and has slightly improved. Methods. We extracted 6,466 cases with detailed demographical characteristics including age at diagnosis, sex, ethnicity, marital status, and clinical features, involving tumor grade and stage at diagnosis and treatment modalities (radiation therapy, chemotherapy, and surgery) from the Surveillance, Epidemiology, and End Results (SEER) (1975–2017) dataset. They were further randomly divided into the training and validating cohorts. Univariate and multivariate Cox analyses were conducted to determine significant variables for construction of nomogram. The predictive power of the model was then assessed by Harrell concordance index (C-index) and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Results. Multivariate analysis revealed that age, marital status, insurance, tumor grade, TNM stage, surgery, and chemotherapy all showed a significant association with overall survival (OS) and cancer-specific survival (CSS). These characteristics were employed to build a nomogram. Particularly, the discrimination of nomogram for OS and CSS prediction in the training set were excellent (C-index = 0.762, 95% CI: 0.754–0.770 and C-index = 0.774, 95% CI: 0.766–0.782). The AUC of the nomogram for predicting 2- and 5-year OS was 0.834 and 0.853 and CSS was 0.844 and 0.866. Similar results were observed in the internal validation set. Conclusion. We have successfully established a novel nomogram for predicting OS and CSS in EAC patients with good accuracy, which can help clinicians predict the survival of individual patient survival and provide optimal treatment strategies.

Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p< 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.

A growing body of evidence has indicated that behaviors of cancers are defined by not only intrinsic activities of tumor cells but also tumor-infiltrating immune cells (TIICs) in the tumor microenvironment. However, it still lacks a well-structured and comprehensive analysis of TIICs and its therapeutic value in esophageal cancer (EC). The proportions of 22 TIICs were evaluated between 150 normal tissues and 141 tumor tissues of EC by the CIBERSORT algorithm. Besides, correlation analyses between proportions of TIICs and clinicopathological characters, including age, gender, histologic grade, tumor location, histologic type, LRP1B mutation, TP53 mutation, tumor stage, lymph node stage, and TNM stage, were conducted. We constructed a risk score model to improve prognostic capacity with 5 TIICs by least absolute shrinkage and selection operator (lasso) regression analysis. The risk score=−1.86∗plasma+2.56∗T cell follicular helper−1.37∗monocytes−3.64∗activated dendritic cells−2.24∗resting mast cells (immune cells in the risk model mean the proportions of immune cell infiltration in EC). Patients in the high-risk group had significantly worse overall survival than these in the low-risk group (HR: 2.146, 95% CI: 1.243-3.705, p=0.0061). Finally, we identified Semustine and Sirolimus as two candidate compounds for the treatment of EC based on CMap analysis. In conclusion, the proportions of TIICs may be important to the progression, prognosis, and treatment of EC.

// Seung Ho Yang 1, 2, 3, * , Shenglan Li 1, 3, * , Guangrong Lu 1 , Haipeng Xue 1, 3 , Dong H. Kim 1, 3 , Jay-Jiguang Zhu 1, ** , Ying Liu 1, 3, ** 1 Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA 2 Department of Neurosurgery, St. Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea 3 Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA * These authors contributed equally to this work ** These authors contributed equally to this work Correspondence to: Jay-Jiguang Zhu, email: jay.jiguang.zhu@uth.tmc.edu Ying Liu, email: ying.liu@uth.tmc.edu Keywords: glioblastoma, metformin, temozolomide resistance, SOX2, global gene expression Received: September 07, 2016 Accepted: October 14, 2016 Published: October 24, 2016 ABSTRACT It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo . Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.

H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

ONC201, a bitopic DRD2 antagonist and allosteric ClpP agonist, has shown encouraging efficacy in H3 K27M-mutant glioma. Given that the thalamus has the highest extra-striatal expression of DRD2, we performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27M-mutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). We analyzed thalamic H3 K27M-mutant glioma patients treated with ONC201 on active clinical trials as of 5/22/19 enrollment (n=19 recurrent and 10 post-radiation, non-recurrent; 5–70 years old). As of 12/18/2019, PFS6 and OS12 are 26.3% and 36.8%, respectively, in the recurrent group. For non-recurrent patients, with median follow up of 21.9 months (8.6–26.6) from diagnosis, median PFS or OS have not been reached. This surpasses historical OS of 13.5 months. Best response by RANO includes 1 CR, 3 PR, 4 SD, 8 PD for recurrent patients and 2 PR, 4 SD, 1 PD for non-recurrent patients (4 on-trial patients experienced regressions that are yet unconfirmed responses). Median duration of response for recurrent patients is 14.0 months (2.0–33.1). Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. In summary, single agent ONC201 administered at recurrence, or adjuvantly following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients who currently have no effective treatments following radiation. Investigations are ongoing to assess whether micro-environmental DRD2 expression explains the early exceptional responses in thalamic H3 K27M-mutant glioma.

Cancer cells have altered cellular metabolism. Mutations in genes associated with key metabolic pathways (e.g., isocitrate dehydrogenase 1 and 2, IDH1/IDH2) are important drivers of cancer, including central nervous system (CNS) tumors. Therefore, we hypothesized that the abnormal metabolic state of CNS cancer cells leads to abnormal levels of metabolites in the CSF, and different CNS cancer types are associated with specific changes in the levels of CSF metabolites. To test this hypothesis, we used mass spectrometry to analyze 129 distinct metabolites in CSF samples from patients without a history of cancer (n = 8) and with a variety of CNS tumor types (n = 23) (i.e., glioma IDH-mutant, glioma-IDH wildtype, metastatic lung cancer and metastatic breast cancer). Unsupervised hierarchical clustering analysis shows tumor-specific metabolic signatures that facilitate differentiation of tumor type from CSF analysis. We identified differences in the abundance of 43 metabolites between CSF from control patients and the CSF of patients with primary or metastatic CNS tumors. Pathway analysis revealed alterations in various metabolic pathways (e.g., glycine, choline and methionine degradation, dipthamide biosynthesis and glycolysis pathways, among others) between IDH-mutant and IDH-wildtype gliomas. Moreover, patients with IDH-mutant gliomas demonstrated higher levels of D-2-hydroxyglutarate in the CSF, in comparison to patients with other tumor types, or controls. This study demonstrates that analysis of CSF metabolites can be a clinically useful tool for diagnosing and monitoring patients with primary or metastatic CNS tumors. Electronic supplementary material The online version of this article (10.1186/s40478-018-0588-z) contains supplementary material, which is available to authorized users.

The nationwide studies on survival change in GBM patients treated with bevacizumab (BEV) after Food and Drug Administration (FDA) approval in May 2009 were limited. We investigated the impacts of BEV on survival in general GBM patient population by conducting a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER), Texas Cancer Registry Limited-Use datasets (TCR), and National Cancer Database (NCDB). The adult patients diagnosed with GBM between 2005 and 2013 were included from SEER (N=14827), TCR (N=2709), and NCDB (N=32731). Patients were categorized into two calendar periods based on date of GBM diagnosis: pre-BEV (2005–2008, P1), and post-BEV (2010–2013, P2). The association between calendar periods and GBM survival was analyzed in SEER, TCR, and NCDB separately, by applying the Kaplan-Meier method and Cox proportional hazards model. A significant increase in median overall survival (OS) was observed from P1 to P2 in SEER (P1: 10, P2: 11, months; P

Aims Hypertensive cardiac hypertrophy is associated with reduced coronary flow reserve, but its impact on coronary flow regulation and vasomotor function remains incompletely understood and requires further investigation. Methods and results Left ventricular hypertrophy was induced in mice by transverse aortic coarctation (TAC) for 4 weeks. The left coronary artery blood velocity (LCABV) and myocardium lactate level were measured following the metabolic activation by isoproterenol. Septal coronary arterioles were isolated and pressurized for functional studies. In TAC mice, the heart-to-body weight ratio was increased by 45%, and cardiac fractional shortening and LCABV were decreased by 51 and 14%, respectively. The resting myocardial lactate level was 43% higher in TAC mice. Isoproterenol (5 µg/g, i.p.) increased heart rate by 20% in both groups of animals, but the corresponding increase in LCABV was not observed in TAC mice. The ventricular hypertrophy was associated with elevation of myocardial endothelin-1 (ET-1), increased vascular expression of rho-kinases (ROCKs), and increased superoxide production in the myocardium and vasculature. In coronary arterioles from TAC mice, the endothelial nitric oxide (NO)-mediated dilation to acetylcholine (ACh) was reversed to vasoconstriction and the vasoconstriction to ET-1 was augmented. Inhibition of ROCK by H-1152 alleviated oxidative stress and abolished enhanced vasoconstriction to ET-1. Both H-1152 and superoxide scavenger Tempol abolished coronary arteriolar constriction to ACh in a manner sensitive to NO synthase blocker NG-nitro-L-arginine methyl ester. Conclusions Myocardial hypertrophy induced by pressure overload leads to cardiac and coronary microvascular dysfunction and ischaemia possibly due to oxidative stress, enhanced vasoconstriction to ET-1 and compromised endothelial NO function via elevated ROCK signalling.

Background and objective Cigarette smoking may increase the risk of developing pancreatic cancer, although its impact on pancreatitis has only been discerned in recent years. However, the results of previous studies differ. We performed a meta-analysis to provide a quantitative pooled risk estimate of the association of cigarette smoking with pancreatitis. Method A literature search of the MEDLINE and Embase databases was conducted, and studies were selected that investigated the association of cigarette smoking with pancreatitis. Summary relative risks (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Results Twenty-two studies were included. The summary RRs (95% CI) associated with ever, current and former smokers for acute and chronic pancreatitis (AP/CP) were as follows: 1.51 (1.10, 2.07)/3.00 (1.46, 6.17), 1.42 (1.08, 1.87)/2.72 (1.74, 4.24), and 1.22 (0.99, 1.52)/1.27 (1.00, 1.62), respectively. Moreover, studies that analyzed both AP and CP were also summarized: 1.73 (1.18, 2.54) for ever smokers, 1.67 (1.03, 2.68) for current smokers and 1.56 (1.16, 2.11) for former smokers, respectively. There was no evidence of publication bias across the studies. Conclusion The evidence suggests a positive association of cigarette smoking with the development of pancreatitis. It is possible that smoking cessation may be a useful strategy for the management of pancreatitis.

PURPOSE Although endothelin-1 (ET-1) is a potent vasoconstrictor peptide implicated in several retinal pathologies, the underlying mechanism of vasoconstriction is understood incompletely. We addressed this issue by assessing the contributions of extracellular calcium (Ca²⁺), L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) to ET-1-induced constriction of porcine retinal arterioles, all of which have been implicated commonly in vascular smooth muscle contraction. METHODS Porcine retinal arterioles (~50-100 μm) were isolated for vasomotor study and molecular assessment of ROCK isoforms. RESULTS Isolated arterioles developed stable basal tone at 55 cmH₂O luminal pressure and constricted to ET-1 (0.1 nM) with a 40 ± 6% reduction in resting diameter in 20 minutes. In the absence of extraluminal Ca²⁺, arterioles lost basal tone and failed to constrict to ET-1. Although L-VOCC inhibitor nifedipine reduced basal tone and blocked vasoconstriction to PKC activator PDBu, vasoconstriction to ET-1 was unaffected. The broad-spectrum PKC inhibitor Go-6983 abolished vasoconstriction to PDBu, but did not alter ET-1-induced vasoconstriction or basal tone. Incubation of arterioles with ROCK inhibitor H-1152 abolished basal tone and vasoconstrictions to ET-1 and PDBu. Both ROCK1 and ROCK2 isoforms were expressed in the retinal arteriolar wall. CONCLUSIONS Extracellular Ca²⁺ entry via L-VOCCs and basal ROCK activity play important roles in the maintenance of basal tones of porcine retinal arterioles. ET-1-induced constriction is mediated by extracellular Ca²⁺ entry independent of L-VOCCs and by ROCK activation without the involvement of PKC. However, direct PKC activation can cause vasoconstriction via L-VOCC and ROCK signaling.

Phospholipase C beta 1 (PLCβ1) expresses in gliomas and cultured glial cells, but its expression is barely detectable in normal glial cells. We analyzed data from Gene Expression Omnibus (GEO-GDSxxx), The Cancer Genome Atlas (TCGA), and the Repository for Molecular Brain Neoplasia Data (REMBRANDT) to explore the potential role of PLCβ1 as a biomarker in high-grade glioma (HGG). PLCβ1 expression is significantly higher in grade III gliomas than that in grade IV gliomas from GDS1815 (n = 24 vs. 76), GDS1962 (n = 19 vs. 81), and GDS1975 (n = 26 vs. 59). In GDS1815, PLCβ1 expression correlates with several known proneural (PN) signature genes; its expression from PN subtype (n = 15) is significantly higher than that from mesenchymal (Mes) subtype (n = 33) HGG. In GDS1962, PLCβ1 expression is the highest in nontumor brain tissue (n = 23) and is significantly higher than its expression in grade II gliomas [astrocytomas (n = 7) and oligodendrogliomas (n = 37)]. A Kaplan-Meier survival curve from a REMBRANDT cohort demonstrates that glioma patients with intermediate PLCβ1 expression (n = 103) survived significantly longer than PLCβ1 downregulated (2X) groups (n = 226). From TCGA data, PLCβ1 RNA-Seq signal inversely correlates with the pathological grades, and PLCβ1 expression in PN (n = 8) is of significantly higher levels than that in Mes (n = 8) subtypes of glioblastoma. The top 50 % of PLCβ1 expression subgroup (n = 294) of gliomas (grades II to IV merged) survived significantly longer than the low 50 percentile of the PLCβ1 expression subgroup (n = 293). p values are less than 0.05 for all these analyses. We conclude that PLCβ1 is a candidate signature gene for PN subtype HGG, and its expression inversely correlates with glioma pathological grade and is a potential prognostic factor. Electronic supplementary material The online version of this article (doi:10.1007/s12035-015-9518-2) contains supplementary material, which is available to authorized users.