Showing papers by "Mark D. Johnson published in 2015"

Mechanical Thrombectomy in Cerebral Venous Thrombosis Systematic Review of 185 Cases

Abstract: Background and Purpose—Cerebral venous thrombosis is generally treated with anticoagulation. However, some patients do not respond to medical therapy and these might benefit from mechanical thrombectomy. The aim of this study was to gain a better understanding of the efficacy and safety of mechanical thrombectomy in patients with cerebral venous thrombosis, by performing a systematic review of the literature. Methods—We identified studies published between January 1995 and February 2014 from PubMed and Ovid. We included all cases of cerebral venous thrombosis in whom mechanical thrombectomy was performed with or without intrasinus thrombolysis. Good outcome was defined as normal or mild neurological deficits at discharge (modified Rankin Scale, 0–2). Secondary outcome variables included periprocedural complications and recanalization rates. Results—Our study included 42 studies (185 patients). Sixty percent of patient had a pretreatment intracerebral hemorrhage and 47% were stuporous or comatose. AngioJet...

Belonging to a network—microRNAs, extracellular vesicles, and the glioblastoma microenvironment

Abstract: The complexity of glioblastoma multiforme (GBM) and its distinct pathophysiology belong to a unique brain microenvironment and its cellular interactions. Despite extensive evidence of a role for microRNAs in GBM cells, little is known about microRNA-dependent communication between different cellular compartments of the microenvironment that may contribute to the tumor phenotype. While the majority of microRNAs are found intracellularly, a significant number of microRNAs have been observed outside of cells, often encapsulated in secreted extracellular vesicles (EVs). The function of these circulating/secreted microRNAs has not been explored in the context of the brain tumor microenvironment. Establishing how microRNAs are involved in the regulation of oncogenic signaling networks between tumor cells and stroma is likely to add a needed additional layer of complexity to the tumor network, consisting of intercellular communication. More importantly, microRNA/EV signaling may provide an additional therapeutic target for this deadly disease.

Hypofractionated versus standard radiation therapy with or without temozolomide for older glioblastoma patients.

Abstract: Purpose Older patients with newly diagnosed glioblastoma have poor outcomes, and optimal treatment is controversial. Hypofractionated radiation therapy (HRT) is frequently used but has not been compared to patients receiving standard fractionated radiation therapy (SRT) and temozolomide (TMZ). Methods and Materials We conducted a retrospective analysis of patients ≥65 years of age who received radiation for the treatment of newly diagnosed glioblastoma from 1994 to 2013. The distribution of clinical covariates across various radiation regimens was analyzed for possible selection bias. Survival was calculated using the Kaplan-Meier method. Comparison of hypofractionated radiation (typically, 40 Gy/15 fractions) versus standard fractionation (typically, 60 Gy/30 fractions) in the setting of temozolomide was conducted using Cox regression and propensity score analysis. Results Patients received SRT + TMZ (n=57), SRT (n=35), HRT + TMZ (n=34), or HRT (n=9). Patients receiving HRT were significantly older (median: 79 vs 69 years of age; P P P =.01), lower Karnofsky performance status (AHR: 1.02; 95% CI: 1.01-1.03; P =.01), multifocal disease (AHR: 2.11; 95% CI: 1.23-3.61, P =.007), and radiation alone (vs SRT + TMZ; SRT: AHR: 1.72; 95% CI: 1.06-2.79; P =.03; HRT: AHR: 3.92; 95% CI: 1.44-10.60, P =.007) were associated with decreased overall survival. After propensity score adjustment, patients receiving HRT with TMZ had similar overall survival compared with those receiving SRT with TMZ (AHR: 1.10, 95% CI: 0.50-2.4, P =.82). Conclusions With no randomized data demonstrating equivalence between HRT and SRT in the setting of TMZ for glioblastoma, significant selection bias exists in the implementation of HRT. Controlling for this bias, we observed similar overall survival for HRT and SRT with concurrent TMZ among elderly patients, suggesting the need for a randomized trial to compare these regimens directly.

Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma.

Abstract: Background Multidimensional genotyping of formalin-fixed paraffin-embedded (FFPE) samples has the potential to improve diagnostics and clinical trials for brain tumors, but prospective use in the clinical setting is not yet routine. We report our experience with implementing a multiplexed copy number and mutation-testing program in a diagnostic laboratory certified by the Clinical Laboratory Improvement Amendments. Methods We collected and analyzed clinical testing results from whole-genome array comparative genomic hybridization (OncoCopy) of 420 brain tumors, including 148 glioblastomas. Mass spectrometry-based mutation genotyping (OncoMap, 471 mutations) was performed on 86 glioblastomas. Results OncoCopy was successful in 99% of samples for which sufficient DNA was obtained (n = 415). All clinically relevant loci for glioblastomas were detected, including amplifications (EGFR, PDGFRA, MET) and deletions (EGFRvIII, PTEN, 1p/19q). Glioblastoma patients ≤40 years old had distinct profiles compared with patients >40 years. OncoMap testing reliably identified mutations in IDH1, TP53, and PTEN. Seventy-seven glioblastoma patients enrolled on trials, of whom 51% participated in targeted therapeutic trials where multiplex data informed eligibility or outcomes. Data integration identified patients with complete tumor suppressor inactivation, albeit rarely (5% of patients) due to lack of whole-gene coverage in OncoMap. Conclusions Combined use of multiplexed copy number and mutation detection from FFPE samples in the clinical setting can efficiently replace singleton tests for clinical diagnosis and prognosis in most settings. Our results support incorporation of these assays into clinical trials as integral biomarkers and their potential to impact interpretation of results. Limited tumor suppressor variant capture by targeted genotyping highlights the need for whole-gene sequencing in glioblastoma.

Epidemiology and self-treatment of travelers' diarrhea in a large, prospective cohort of department of defense beneficiaries.

Abstract: Background Infectious diarrhea is a common problem among travelers. Expert guidelines recommend the prompt use of antibiotics for self-treatment of moderate or severe travelers' diarrhea (TD). There is limited data on whether travelers follow these self-treatment guidelines. We evaluated the risk factors associated with TD, the use of TD self-treatment, and the risk of irritable bowel syndrome (IBS) during travel. Methods Department of Defense beneficiaries traveling outside the United States for ≤6.5 months were enrolled in a prospective cohort study. Participants received pre- and post-travel surveys, and could opt into a travel illness diary and follow-up surveys for symptoms of IBS. Standard definitions were used to assess for TD and IBS. Suboptimal self-treatment was defined as the use of antibiotics (with or without antidiarrheal agents) for mild TD, or the use of antidiarrheals alone or no self-treatment in cases of moderate or severe TD. Results Twenty-four percent of participants (270/1,120) met the criteria for TD. The highest incidence was recorded in Africa [8.6 cases/100 person-weeks, 95% confidence interval (CI): 6.7–10.5]. Two hundred and twelve participants with TD provided information regarding severity and self-treatment: 89 (42%) had mild TD and 123 (58%) had moderate or severe TD. Moderate or severe TD was independently associated with suboptimal self-treatment [OR 10.4 (95% CI: 4.92–22.0)]. Time to last unformed stool did not differ between optimal and suboptimal self-treatment. IBS occurred in 4.5% (7/154) of TD cases and in 3.1% (16/516) of cases without TD (p = 0.39). Among TD cases, a lower incidence of IBS was noted in participants who took antibiotics [4.8% (5/105) vs 2.2% (1/46)] in those who did not, but the difference did not reach statistical significance (p = 0.60). Conclusions Our results suggest the underutilization of antibiotics in travelers with moderate or severe TD. Further studies are needed to systematically evaluate pre-travel instruction and traveler adherence to self-treatment guidelines, and the impact of suboptimal self-treatment on outcomes.

Rapid, Multiplexed Phosphoprotein Profiling Using Silicon Photonic Sensor Arrays

Abstract: Extracellular signaling is commonly mediated through post-translational protein modifications that propagate messages from membrane-bound receptors to ultimately regulate gene expression. Signaling cascades are ubiquitously intertwined, and a full understanding of function can only be gleaned by observing dynamics across multiple key signaling nodes. Importantly, targets within signaling cascades often represent opportunities for therapeutic development or can serve as diagnostic biomarkers. Protein phosphorylation is a particularly important post-translational modification that controls many essential cellular signaling pathways. Not surprisingly, aberrant phosphorylation is found in many human diseases, including cancer, and phosphoprotein-based biomarker signatures hold unrealized promise for disease monitoring. Moreover, phosphoprotein analysis has wide-ranging applications across fundamental chemical biology, as many drug discovery efforts seek to target nodes within kinase signaling pathways. For both fundamental and translational applications, the analysis of phosphoprotein biomarker targets is limited by a reliance on labor-intensive and/or technically challenging methods, particularly when considering the simultaneous monitoring of multiplexed panels of phosphoprotein biomarkers. We have developed a technology based upon arrays of silicon photonic microring resonator sensors that fills this void, facilitating the rapid and automated analysis of multiple phosphoprotein levels from both cell lines and primary human tumor samples requiring only minimal sample preparation.

A major role for microRNAs in glioblastoma cancer stem-like cells

Abstract: Studies have demonstrated that miRNAs contribute to the maintenance and phenotype of in several cancer types. This review will focus on the roles of a few well studied miRNAs in cancer stem-like cells of glioblastoma.

Salvage whole brain radiotherapy or stereotactic radiosurgery after initial stereotactic radiosurgery for 1-4 brain metastases.

Abstract: Patients with limited brain metastases are often candidates for stereotactic radiosurgery (SRS) or whole brain radiotherapy (WBRT). Among patients who receive SRS, the likelihood and timing of salvage WBRT or SRS remains unclear. We examined rates of salvage WBRT or SRS among 180 patients with 1–4 newly diagnosed brain metastases who received index SRS from 2008–2013. Competing risks multivariable analysis was used to examine factors associated with time to WBRT. Patients had non-small cell lung (53 %), melanoma (23 %), breast (10 %), renal (6 %), or other (8 %) cancers. Median age was 62 years. Patients received index SRS to 1 (60 %), 2 (21 %), 3 (13 %), or 4 (7 %) brain metastases. Median survival after SRS was 9.7 months (range, 0.3–67.6 months). No further brain-directed radiotherapy was delivered after index SRS in 55 % of patients. Twenty-seven percent of patients ever received salvage WBRT, and 30 % ever received salvage SRS; 12 % of patients received both salvage WBRT and salvage SRS. Median time to salvage WBRT or salvage SRS were 5.6 and 6.1 months, respectively. Age ≤60 years (adjusted hazard ratio [AHR] = 2.80; 95 % CI 1.05–7.51; P = 0.04) and controlled/absent extracranial disease (AHR = 6.76; 95 % CI 1.60–28.7; P = 0.01) were associated with shorter time to salvage WBRT. Isolated brain progression caused death in only 11 % of decedents. In summary, most patients with 1–4 brain metastases receiving SRS never require salvage WBRT or SRS, and the remainder do not require salvage treatment for a median of 6 months.

Computational fluid dynamics of computed tomography angiography to detect the hemodynamic impact of intracranial atherosclerotic stenosis

Abstract: In symptomatic intracranial atherosclerotic stenosis (ICAS), its hemodynamic impact may affect the risk of stroke recurrence, in addition to the degree of luminal stenosis. We therefore conducted a pilot study to evaluate the feasibility to delineate the hemodynamic impact of symptomatic ICAS lesions using computational fluid dynamics (CFD) models reconstructed based on computed tomography angiography (CTA) source images. Three-dimensional CFD models were reconstructed based on routine CTA source images of patients with a symptomatic ICAS lesion. The anatomic features and hemodynamic impact of target ICAS lesions were evaluated on the CFD models. The hemodynamic impact of a lesion was evaluated using distal to proximal pressure ratio (PR) and pressure gradient (PG) across the lesion. PG was defined as pressure drop across the lesion divided by length of the lesion. Among the 10 cases recruited, CTA source images of 9 cases were successfully processed to CFD models. The hemodynamic characteristics of the ICAS lesions could be quantitatively evaluated on the CFD models, such as the pressures, blood flow velocities, wall shear stress and shear strain rates. The median PR was 0.58 and the median PG was 93 mmHg/cm. PRs and PGs varied in cases with similar degrees of stenoses with different lesion lengths and proximal vessel diameters. This pilot study demonstrated the feasibility to quantitatively assess the hemodynamic impact of ICAS using CFD models reconstructed based on routine CTA. Further studies are required to improve the models built in this pilot study, and to evaluate the ultimate value of this technique in clinical assessment and risk stratification of patients with symptomatic ICAS.

Incidence, risk factors, and reasons for hospitalization among glioblastoma patients receiving chemoradiation.

Abstract: Despite a high symptom burden, little is known about the incidence or predictors of hospitalization among glioblastoma patients, including risks during chemoradiation (CRT). We studied 196 consecutive newly diagnosed glioblastoma patients treated at our institution from 2006-2010. Toxicity data were reviewed during and after the CRT phase, defined as the period between diagnosis and 6 weeks after radiotherapy completion. Logistic regression and proportional hazards modeling identified predictors of hospitalization and overall survival (OS). Median age was 59 years (range, 23-90) and 83 % had Karnofsky performance status (KPS) score ≥ 70. Twenty-six percent of patients underwent gross total resection, 77 % received ≥ 59.4 Gy of radiotherapy, and 89 % received concurrent temozolomide. Median OS was 15.6 months (IQR, 8.5-26.8 months). Forty-three percent of patients were hospitalized during the CRT phase; OS was 10.7 vs. 17.8 months for patients who were vs. were not hospitalized, respectively (P < .001). Nearly half of the hospitalizations were due to generalized weakness (17 % of hospitalizations), seizures (16 %), or venous thromboembolism (13 %). On multivariate analysis, age (odds ratio [OR], 1.03; 95 % CI, 1.002-1.060; P = .034) and KPS (OR, 0.95; 95 % CI, 0.93-0.97; P < .001) were associated with risk of hospitalization. Hospitalization during the CRT phase was associated with decreased OS (adjusted hazard ratio, 1.47; 95 % CI, 1.01-2.13; P = .043), after adjustment for known prognostic factors. Hospitalization during the CRT phase is common among glioblastoma patients in the temozolomide era and is associated with shorter overall survival.

A small subunit processome protein promotes cancer by altering translation

Abstract: Dysregulation of ribosome biogenesis or translation can promote cancer, but the underlying mechanisms remain unclear. UTP18 is a component of the small subunit processome, a nucleolar multi-protein complex whose only known function is to cleave pre-ribosomal RNA to yield the 18S ribosomal RNA component of 40S ribosomal subunits. Here, we show that UTP18 also alters translation to promote stress resistance and growth, and that UTP18 is frequently gained and overexpressed in cancer. We observed that UTP18 localizes to the cytoplasm in a subset of cells, and that serum withdrawal increases cytoplasmic UTP18 localization. Cytoplasmic UTP18 associates with the translation complex and Hsp90 to upregulate the translation of IRES-containing transcripts such as HIF1a, Myc and VEGF, thereby inducing stress resistance. Hsp90 inhibition decreases cytoplasmic UTP18 and UTP18-induced increases in translation. Importantly, elevated UTP18 expression correlates with increased aggressiveness and decreased survival in numerous cancers. Enforced UTP18 overexpression promotes transformation and tumorigenesis, whereas UTP18 knockdown inhibits these processes. This stress adaptation mechanism is thus co-opted for growth by cancers, and its inhibition may represent a promising new therapeutic target.

Successful Integration of Nonclinical and Clinical Findings in Interpreting the Clinical Relevance of Rodent Neoplasia with a New Chemical Entity

Abstract: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM.

miR-505 Downregulates 6-Phosphofructo-2-Kinase/ Fructose-2,6-Biphosphatase 4 to Promote Cell Death in Glioblastoma

Abstract: Aim: The glycolytic enzyme, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), mediates shifts in glycolytic flux and is important for glioblastoma cell survival. This study aimed to identify micro-RNAs that alter PFKFB4 expression to regulate glioblastoma cell survival. Methods: Western blot analyses, luciferase reporter assays, and public database analyses were used to predict and validate the regulation of PFKFB4 mRNA expression by miR-505 in glioblastoma. Cell growth and apoptosis assays were performed to determine the effects of miR-505 on the growth and survival of primary glioblastoma stem-like cells (GSCs) and established glioblastoma cell lines. In addition, the correlations between patient survival and the expression of miR-505 and PFKFB4 mRNA in glioblastoma specimens were examined. Results: Using micro-RNA target prediction programs, a miR-505 binding site in the 3'-UTR of the PFKFB4 mRNA transcript was identified, and query of a public CLIP-Seq database indicated that PFKFB4 binds this site in living cells. It was found that fusion of the PFKFB4 3'-UTR to luciferase conferred regulation of luciferase activity by PFKFB4. In addition, Western blots revealed that miR-505 significantly decreased PFKFB4 protein expression in established glioblastoma cell lines and primary GSCs. Enforced PFKFB4 overexpression increased the growth of primary GSCs and established glioblastoma multiforme cell lines, and miR-505 antagonized this effect. By downregulating PFKFB4, miR-505 increased production of reactive oxygen species, thereby repressing glioblastoma cell growth and promoting glioblastoma cell death. Importantly, patient survival was positively correlated with miR-505 expression and negatively correlated with PFKFB4 mRNA expression in primary glioblastoma specimens. Conclusion: It was showed that miR-505 downregulates PFKFB4 expression in glioblastoma, thereby decreasing glioblastoma cell survival. Targeting PFKFB4 via miR-505 may represent a promising therapeutic approach in glioblastoma.