bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA Profiling Can Classify Acute Leukemias of Ambiguous Lineage as Either Acute Myeloid Leukemia or Acute Lymphoid Leukemia
Authors: de Leeuw David C. , van den Ancker Willemijn , Denkers Fedor , de Menezes Renée X. , Westers Theresia M. , Ossenkoppele Gert J. , van de Loosdrecht Arjan A. , Smit Linda
Published: February 2013

Purpose: Classification of acute leukemia is based on the commitment of leukemic cells to the myeloid or the lymphoid lineage. However, a small percentage of acute leukemia cases lack straightforward immunophenotypical lineage commitment. These leukemias of ambiguous lineage represent a heterogeneous category of acute leukemia that cannot be classified as either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL). The lack of clear classification of acute leukemias of ambiguous lineage as either AML or ALL is a hurdle in treatment choice for these patients.

Experimental Design: Here, we compared the microRNA (miRNA) expression profiles of 17 cases with acute leukemia of ambiguous lineage and 16 cases of AML, B-cell acute lymphoid leukemia (B-ALL), and T-cell acute lymphoid leukemia (T-ALL).

Results: We show that leukemias of ambiguous lineage do not segregate as a separate entity but exhibit miRNA expression profiles similar to AML, B-ALL, or T-ALL. We show that by using only 5 of the most lineage-discriminative miRNAs, we are able to define acute leukemia of ambiguous lineage as either AML or ALL.

Conclusion: Our results indicate the presence of a myeloid or lymphoid lineage-specific genotype, as reflected by miRNA expression, in these acute leukemias despite their ambiguous immunophenotype. miRNA-based classification of acute leukemia of ambiguous lineage might be of additional value in therapeutic decision making. Clin Cancer Res; 19(8); 2187–96. ©2013 AACR.
Zoom Zoom: Racing CARs for Multiple Myeloma
Authors: Maus Marcela V. , June Carl H.
Published: February 2013

Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma. Clin Cancer Res; 19(8); 1917–9. ©2013 AACR.
A Phase II Study of Temozolomide in Patients with Advanced Aerodigestive Tract and Colorectal Cancers and Methylation of theO6-Methylguanine-DNA Methyltransferase Promoter
Authors: Hochhauser Daniel , Glynne-Jones Rob , Potter Vanessa , Grávalos Cristina , Doyle Thomas J. , Pathiraja Kumudu , Zhang Qing , Zhang Ling , Sausville Edward A.
Published: February 2013

Responses of patients with gliomas to temozolomide are determined by O6-methylguanine-DNA methyltransferase (MGMT) and mismatch repair (MMR) pathways. This phase II study (NCT00423150) investigated whether MGMT promoter methylation predicts response in patients with advanced aerodigestive tract and colorectal cancers (CRC). Tumor and serum samples were screened for MGMT promoter methylation. In methylation-positive patients, 150 mg/m2 temozolomide was administered daily on a seven-day-on, seven-day-off schedule for each 28-day cycle. The primary efficacy endpoint was response rate (RR). MMR status was determined by a microsatellite instability assay. Among 740 patients screened, 86 were positive for MGMT promoter methylation and enrolled. Nineteen percent of the screened population (137/740) had confirmed tissue and/or serum MGMT promoter methylation, including 25% (57 of 229) for CRC, 36% (55 of 154) for esophageal cancer, 11% (12 of 113) for head and neck cancer, and 5% (13 of 242) for non–small cell lung carcinoma. Among patients with valid methylation results in both tissue and serum samples, concordance was 81% (339 of 419). The majority of enrolled patients (69 of 86; 80%) had microsatellite stable cancer. Overall RR was 6% (5 of 86 partial responses); all responders had microsatellite stable cancer. Temozolomide resulted in low RRs in patients enriched for MGMT methylation. MGMT methylation status varied considerably in the patient population. Although serum methylation assay is an option for promoter methylation detection, tissue assay remains the standard for methylation detection. The low RR of this cohort of patients indicates that MGMT methylation as a biomarker is not applicable to heterogeneous tumor types, and tumor-specific factors may override validated biomarkers. Mol Cancer Ther; 12(5); 809–18. ©2013 AACR.
A Novel Sulindac Derivative Inhibits Lung Adenocarcinoma Cell Growth through Suppression of Akt/mTOR Signaling and Induction of Autophagy
Authors: Gurpinar Evrim , Grizzle William E. , Shacka John J. , Mader Burton J. , Li Nan , Piazza Nicholas A. , Russo Suzanne , Keeton Adam B. , Piazza Gary A.
Published: February 2013

Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth–inhibitory activity. Here, we studied the basis for the growth-inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2 to 5 μmol/L compared with 44 to 52 μmol/L for sulindac sulfide. SSA also suppressed DNA synthesis and caused a G0–G1 cell-cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer. Mol Cancer Ther; 12(5); 663–74. ©2013 AACR.
ALK Inhibitor PF02341066 (Crizotinib) Increases Sensitivity to Radiation in Non–Small Cell Lung Cancer Expressing EML4-ALK
Authors: Sun Yunguang , Nowak Kamila A. , Zaorsky Nicholas G. , Winchester Chia-Lin , Dalal Kunal , Giacalone Nicholas J. , Liu Ningbo , Werner-Wasik Maria , Wasik Mariusz A. , Dicker Adam P. , Lu Bo
Published: February 2013

Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non–small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK–negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK. Mol Cancer Ther; 12(5); 696–704. ©2013 AACR.
Afatinib Prolongs Survival Compared with Gefitinib in an Epidermal Growth Factor Receptor-Driven Lung Cancer Model
Authors: Ninomiya Takashi , Takigawa Nagio , Ichihara Eiki , Ochi Nobuaki , Murakami Toshi , Honda Yoshihiro , Kubo Toshio , Minami Daisuke , Kudo Kenichiro , Tanimoto Mitsune , Kiura Katsuyuki
Published: February 2013

An irreversible ErbB family blocker is expected to inhibit tumors with activating epidermal growth factor receptor (EGFR) mutations more strongly than reversible EGFR tyrosine kinase inhibitors and to overcome acquired resistance to the T790M secondary mutation. Eleven-week-old transgenic mice with Egfr exon 19 deletion mutation were treated with afatinib, gefitinib, or vehicle for 4 weeks. All mice were sacrificed at 15 weeks of age, and the number of superficial left lung tumors with a long axis exceeding 1 mm was counted. The afatinib-treated group had significantly fewer tumors than the vehicle group (P < 0.01) and tended to have fewer tumors than the gefitinib-treated group (P = 0.06). Pathologically, gefitinib-treated mice had clearer, more nodular tumors than afatinib-treated mice. Immunoblotting showed that afatinib suppressed not only pEGFR but also pHER2, and induced apoptosis for longer periods than gefitinib. Subsequently, when each drug was administered 5 days per week until death, afatinib significantly enhanced mouse survival compared with gefitinib (median survival time: 456 days vs. 376.5 days; log-rank test, P < 0.01). Finally, the combination of afatinib with bevacizumab was found to be superior to either drug alone in exon 19 deletion/T790M and L858R/T790M xenograft tumors. Overall, afatinib was more potent than gefitinib in tumors harboring an exon 19 deletion mutation, and the combination of afatinib with bevacizumab efficiently suppressed tumors harboring the T790M secondary mutation. Mol Cancer Ther; 12(5); 589–97. ©2013 AACR.
Spongian Diterpenoids Inhibit Androgen Receptor Activity
Authors: Yang Yu Chi , Meimetis Labros G. , Tien Amy H. , Mawji Nasrin R. , Carr Gavin , Wang Jun , Andersen Raymond J. , Sadar Marianne D.
Published: February 2013

Androgen receptor is a ligand-activated transcription factor and a validated drug target for all stages of prostate cancer. Antiandrogens compete with physiologic ligands for androgen receptor ligand-binding domain (LBD). High-throughput screening of a marine natural product library for small molecules that inhibit androgen receptor transcriptional activity yielded the furanoditerpenoid spongia-13(16),-14-dien-19-oic acid, designated terpene 1 (T1). Characterization of T1 and the structurally related semisynthetic analogues (T2 and T3) revealed that these diterpenoids have antiandrogen properties that include inhibition of both androgen-dependent proliferation and androgen receptor transcriptional activity by a mechanism that involved competing with androgen for androgen receptor LBD and blocking essential N/C interactions required for androgen-induced androgen receptor transcriptional activity. Structure–activity relationship analyses revealed some chemical features of T1 that are associated with activity and yielded T3 as the most potent analogue. In vivo, T3 significantly reduced the weight of seminal vesicles, which are an androgen-dependent tissue, thereby confirming the on-target activity of T3. The ability to create analogues of diterpenoids that have varying antiandrogen activity represents a novel class of chemical compounds for the analysis of androgen receptor ligand-binding properties and therapeutic development. Mol Cancer Ther; 12(5); 621–31. ©2013 AACR.
Activity of the Fibroblast Growth Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer Cells
Authors: Konecny Gottfried E. , Kolarova Teodora , O'Brien Neil A. , Winterhoff Boris , Yang Guorong , Qi Jingwei , Qi Zhengdong , Venkatesan Natarajan , Ayala Raul , Luo Tong , Finn Richard S. , Kristof Jessica , Galderisi Chad , Porta Diana Graus , Anderson Lee , Shi Michael M. , Yovine Alejandro , Slamon Dennis J.
Published: February 2013

The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632–42. ©2013 AACR.
Inhibition of Mutant GNAQ Signaling in Uveal Melanoma Induces AMPK-Dependent Autophagic Cell Death
Authors: Ambrosini Grazia , Musi Elgilda , Ho Alan L. , de Stanchina Elisa , Schwartz Gary K.
Published: February 2013

Oncogenic mutations in GNAQ and GNA11 genes are found in 80% of uveal melanoma. These mutations result in the activation of the RAF/MEK signaling pathway culminating in the stimulation of ERK1/2 mitogen-activated protein kinases. In this study, using a siRNA strategy, we show that mutant GNAQ signals to both MEK and AKT, and that combined inhibition of these pathways with the MEK inhibitor selumetinib (AZD6244) and the AKT inhibitor MK2206 induced a synergistic decrease in cell viability. This effect was genotype dependent as autophagic markers like beclin1 and LC3 were induced in GNAQ-mutant cells, whereas apoptosis was the mechanism of cell death of BRAF-mutant cells, and cells without either mutation underwent cell-cycle arrest. The inhibition of MEK/ATK pathways induced activation of AMP-activated protein kinase (AMPK) in the GNAQ-mutant cells. The downregulation of AMPK by siRNA or its inhibition with compound C did not rescue the cells from autophagy, rather they died by apoptosis, defining AMPK as a key regulator of mutant GNAQ signaling and a switch between autophagy and apoptosis. Furthermore, this combination treatment was effective in inhibiting tumor growth in xenograft mouse models. These findings suggest that inhibition of MEK and AKT may represent a promising approach for targeted therapy of patients with uveal melanoma. Mol Cancer Ther; 12(5); 768–76. ©2013 AACR.
Regression of Lung Cancer by Hypoxia-Sensitizing Ruthenium Polypyridyl Complexes
Authors: Yadav Abhishek , Janaratne Thamara , Krishnan Arthi , Singhal Sharad S. , Yadav Sushma , Dayoub Adam S. , Hawkins Doyle L. , Awasthi Sanjay , MacDonnell Frederick M.
Published: February 2013

The ruthenium (II) polypyridyl complexes (RPC), Δ-[(phen)2Ru(tatpp)]Cl2 (Δ-[3]Cl2) and ΔΔ-[(phen)2Ru(tatpp)Ru(phen)2]Cl4 (ΔΔ-[4]Cl4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 44+ cleaves DNA when reduced by glutathione to a radical species and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 32+ also exhibits free radical–mediated DNA cleavage in vitro and that 32+ and 44+ both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 32+ and 44+ (maximum tolerable doses ∼ 65 μmol/kg) is comparable with that for cisplatin (LD50 ∼ 57 μmol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 32+ and 44+ are shown to suppress growth of human non–small cell lung carcinoma (∼83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials. Mol Cancer Ther; 12(5); 643–53. ©2013 AACR.
Molecular Hierarchy of Heparin-Binding EGF-like Growth Factor–Regulated Angiogenesis in Triple-Negative Breast Cancer
Authors: Yotsumoto Fusanori , Tokunaga Eriko , Oki Eiji , Maehara Yoshihiko , Yamada Hiromi , Nakajima Kyoko , Nam Sung Ouk , Miyata Kohei , Koyanagi Midori , Doi Keiko , Shirasawa Senji , Kuroki Masahide , Miyamoto Shingo
Published: February 2013

Heparin-binding EGF-like growth factor (HB-EGF) is one of several proangiogenic factors and represents a possible therapeutic target for patients with triple-negative breast cancer (TNBC). However, the role of HB-EGF in promoting tumor aggressiveness in TNBC remains unclear. To investigate specific genes and pathways involved in TNBC tumorigenesis, we profiled gene expression changes in two TNBC cell lines under two-dimensional culture (2DC) and three-dimensional culture (3DC) and in a tumor xenograft model. We identified simultaneous upregulation of HB-EGF, VEGFA, and angiopoietin-like 4 (ANGPTL4) in 3DC and tumor xenografts, compared with 2DC. We show that HB-EGF regulates the expression of VEGFA or ANGPTL4 via transcriptional regulation of hypoxia-inducible factor-1α and NF-κB. Furthermore, suppression of VEGFA or ANGPTL4 expression enhanced HB-EGF expression, highlighting a unique regulatory loop underlying this angiogenesis network. Targeted knockdown of HB-EGF significantly suppressed tumor formation in a TNBC xenograft model, compared with individual knockdown of either VEGFA or ANGPTL4, by reducing the expression of both VEGFA and ANGPTL4. In patients with TNBC, VEGFA or ANGPTL4 expression was also significantly correlated with HB-EGF expression. Low concentrations of exogenously added HB-EGF strongly activated the proliferation of endothelial cells, tube formation, and vascular permeability in blood vessels, in a similar fashion to high doses of VEGFA and ANGPTL4. Taken together, these results suggest that HB-EGF plays a pivotal role in the acquisition of tumor aggressiveness in TNBC by orchestrating a molecular hierarchy regulating tumor angiogenesis. Mol Cancer Res; 11(5); 506–17. ©2013 AACR.
Gamma Knife Surgery for Refractory Insular Cortex Epilepsy
Authors: Irislimane Myriam , Mathieu David , Bouthillier Alain , Deacon Charles , Nguyen Dang Khoa
Published: February 2013

Background: Resection of the epileptogenic insular cortex is surgically challenging. We sought to evaluate the potential of Gamma Knife® surgery (GKS) for the treatment of pharmacoresistant insular cortex epilepsy (ICE) in patients who underwent GKS between 2005 and 2010. Adverse events and effects on seizure frequency were assessed. Methods: Three cases of refractory ICE were treated by GKS between 2005 and 2010. Results: Case 1 had refractory nonlesional ICE, proven by depth electrodes only partially helped by a left posterior insulectomy. Case 2 had refractory ICE due to a left insular cavernoma. Case 3 had refractory ICE, confirmed by an invasive study but complicated by transient dysphasia from contusion of Wernicke's area. The marginal and maximum radiation doses delivered were 20 and 40 Gy, respectively. Treatment volume ranged from 1.2 to 3.2 cm3. Two out of 3 patients experienced significant seizure reduction and the third had a worthwhile improvement (follow-up 30-76 months). Complete antiepileptic drug withdrawal was un-fortunately not possible. Complications included transient lightheadedness and new-onset seizures responsive to medical treatment, both in the same patient. Conclusion: GKS is a promising technique for selected drug-resistant ICE patients. Additional observations are necessary.
A Proposed Method to Comprehensively Define Outcomes in Acoustic Tumor Patients Undergoing CyberKnife Management
Authors: Lin Mei-Chun , Chen Chang-Mu , Tseng Ham-Min , Xiao Furen , Young Yi-Ho
Published: February 2013

Background: Vestibular assessment in patients with acoustic tumor (so-called vestibular schwannoma, VS) via ocular vestibular-evoked myogenic potential (oVEMP) and cervical VEMP (cVEMP) tests are not often discussed in the neurosurgical literature. Objectives: This study conducted physiological and morphological assessments for VS patients before and after CyberKnife radiosurgery. Methods: Twenty patients with unilateral VS underwent a battery of tests comprising facial nerve function test, audiometry, and caloric, oVEMP and cVEMP tests before and 2 years after CyberKnife treatment at a mean dosage of 18 Gy in 3 fractions. Results: The abnormal percentages of caloric, oVEMP and cVEMP tests did not significantly differ before and after Cyberknife treatment, indicating that preservation of the superior and inferior vestibular nerves can be achieved after radiosurgery. Median tumor volumes, 1.49 cm3 before treatment versus 0.97 cm3 at 2 years after treatment, differed significantly. Conclusions: The use of oVEMP and cVEMP tests in VS patients before stereotactic radiosurgery may help to evaluate the tumor origin from the superior or inferior vestibular nerve. It takes a short time and costs less, and it would be practical to make this a routine examination in VS patients having stereotactic radiosurgery.
Variation in Presentation and Presence of DNA Adducts and p53 Mutations in Patients with Endemic Nephropathy - an Environmental Form of the Aristolochic Acid Nephropathy
Authors: Karanović Sandra , Lela Ivana Vuković , Jelaković Bojan , Dickman Kathleen G. , Peić Anamarija Kovač , Dittrich Damir , Knežević Matej , Matijević Vesna , Fernandes Andrea S. , Miller Frederick
Published: February 2013

Background: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. Methods: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. Results: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. Conclusion: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.
An Exceptional Cause of Progressive Dyspnoea in a Renal Transplant Recipient: Hemangioma of the Mitral Valve
Authors: Juric Ivana , Hadzibegovic Irzal , Kes Petar , Biocina Bojan , Milicic Davor , Basic-Jukic Nikolina
Published: February 2013

Primary cardiac hemangioma is a very rare benign vascular tumor, with valvular hemangiomas being even less frequent as valves are generally avascular structures. We present the first case of mitral valve hemangioma in a renal transplant recipient. Patient presented with progressive dyspnea. Transesophageal echocardiogram (TEE) demonstrated a 0.8x0.9-cm pedunculated tumor mass on the posterior leaflet of the mitral valve. Coronary angiography identified a small artery which filled from the circumflex artery and fed the tumor. The tumor was surgically removed. Histopathological examination revealed a hemangioma. The postoperative course was uneventful with stable graft function.
Wireless Neurochemical Monitoring in Humans
Authors: Kasasbeh Aimen , Lee Kendall , Bieber Allan , Bennet Kevin , Chang Su-Youne
Published: February 2013

Electrochemical techniques have long been utilized to investigate chemical changes in the neuronal microenvironment. Preclinical models have demonstrated the successful monitoring of changes in various neurotransmitter systems in vivo with high temporal and spatial resolution. The expansion of electrochemical recording to humans is a critical yet challenging goal to elucidate various aspects of human neurophysiology and to create future therapies. We have designed a novel device named the WINCS (Wireless Instantaneous Neurotransmitter Concentration Sensing) system that combines rapid scan voltammetry with wireless telemetry for highly resolved electrochemical recording and analysis. WINCS utilizes fast-scan cyclic voltammetry and fixed potential amperometry for in vivo recording and has demonstrated high temporal and spatial resolution in detecting changes in extracellular levels of a wide range of analytes including dopamine, adenosine, glutamate, serotonin, and histamine. Neurochemical monitoring in humans represents a new approach to understanding the neurophysiology of the central nervous system, the neurobiology of numerous diseases, and the underlying mechanism of various neurosurgical therapies. This article addresses the current understanding of electrochemistry, its application in humans, and future directions.
Preoperative Three-Dimensional Model Creation of Magnetic Resonance Brain Images as a Tool to Assist Neurosurgical Planning
Authors: Spottiswoode B.S. , van den Heever D.J. , Chang Y. , Engelhardt S. , Du Plessis S. , Nicolls F. , Hartzenberg H.B. , Gretschel A.
Published: February 2013

Background: Neurosurgeons regularly plan their surgery using magnetic resonance imaging (MRI) images, which may show a clear distinction between the area to be resected and the surrounding healthy brain tissue depending on the nature of the pathology. However, this distinction is often unclear with the naked eye during the surgical intervention, and it may be difficult to infer depth and an accurate volumetric interpretation from a series of MRI image slices. Objectives: In this work, MRI data are used to create affordable patient-specific 3-dimensional (3D) scale models of the brain which clearly indicate the location and extent of a tumour relative to brain surface features and important adjacent structures. Methods: This is achieved using custom software and rapid prototyping. In addition, functionally eloquent areas identified using functional MRI are integrated into the 3D models. Results: Preliminary in vivo results are presented for 2 patients. The accuracy of the technique was estimated both theoretically and by printing a geometrical phantom, with mean dimensional errors of less than 0.5 mm observed. Conclusions: This may provide a practical and cost-effective tool which can be used for training, and during neurosurgical planning and intervention.
Effect of Data Normalization on the Creation of Neuro-Probabilistic Atlases
Authors: D'Haese Pierre-François , Pallavaram Srivatsan , Kao Chris , Neimat Joseph S. , Konrad Peter E. , Dawant Benoit M.
Published: February 2013

In the past 15 years, rapid improvements in imaging technology and methodology have had a tremendous impact on how we study the human brain. During deep brain stimulation surgeries, detailed anatomical images can be combined with physiological data obtained by microelectrode recordings and microstimulations to address questions relating to the location of specific motor or sensorial functions. The main advantage of techniques such as microelectrode recordings and microstimulations over brain imaging is their ability to localize patient physiological activity with a high degree of spatial resolution. Aggregating data acquired from large populations permits to build what are commonly referred to as statistical atlases. Data points from statistical atlases can be combined to produce probabilistic maps. A crucial step in this process is the intersubject spatial normalization that is required to relate a position in one subject's brain to a position in another subject's brain. In this paper, we study the impact of spatial normalization techniques on building statistical atlases. We find that the Talairach or anterior-posterior commissure coordinate system commonly used in the medical literature produces atlases that are more dispersed than those obtained with normalization methods that rely on nonlinear volumetric image registration. We also find that the maps produced using nonlinear techniques correlate with their expected anatomic positions.
Effectiveness of Systemic High-Dose Dexamethasone Therapy for Idiopathic Sudden Sensorineural Hearing Loss
Authors: Egli Gallo Doris , Khojasteh Elham , Gloor Martina , Hegemann Stefan C.A.
Published: February 2013

Objective: To evaluate the effectiveness of systemic high-dose dexamethasone therapy for sudden sensorineural hearing loss in comparison to the previous treatment regimen at our clinic with systemic prednisone 100 mg daily for 7 days analyzed in a previous study. Methods: We conducted a retrospective review of an electronic patient data base of 79 patients with idiopathic sudden sensorineural hearing loss. The standard treatment was orally applied dexamethasone (1st to 3rd day: 40 mg daily, 4th to 6th day: 10 mg daily) in an ambulant setting. The primary endpoint was change in hearing threshold from the initial audiogram to an audiogram at least 4 weeks later. Factors that were analyzed included patient's age, interval between onset of symptoms and start of treatment, presence or absence of dizziness and tinnitus, the audiogram pattern, severity of hearing loss and hearing in the opposite ear. Hearing gain was expressed either as absolute or relative hearing gain. Functionally relevant recovery of hearing was defined as the final pure-tone average (PTA) of 30 dB or less (or the same as the PTA of the opposite ear ± 10 dB). Furthermore, we calculated the percentage of patients with complete, partial and no recovery as defined in the recently published Clinical Practice Guideline of the American Academy of Otolaryngology - Head and Neck Surgery Foundation. We then compared our results with the previous treatment regimen carried out at our clinic. Results: The average initial PTA hearing loss in the affected ear compared to baseline PTA of the unaffected ear was 51.5 ± 20.9 dB (mean ± SD). The mean absolute hearing gain was 44.4 ± 18.1 dB. The mean relative hearing gain was 86 ± 19%. Of the total, 87% had functionally relevant recovery of hearing. All of our patients showed partial (24%) or complete recovery (76%). No difference in recovery rate could be detected between patients with start of therapy within 24 h and patients with beginning of therapy within 7 days. We found a correlation between the severity of hearing loss and functionally relevant recovery. A mild hearing loss was noted in 34% of patients, with an average relative hearing gain of 89% and a functionally relevant recovery in 96% of them; the 9% of patients with initial deafness showed a mean relative hearing gain of 69% and a functionally relevant recovery in 43%. The audiogram pattern with low- or high-frequency hearing loss showed the best recovery rate; the poorest recovery rate was found in patients with initial deafness. Con-clusion: Application of high-dose orally applied dexamethasone seems to improve the recovery outcomes in comparison to prednisone 100 mg p.o. for 7 days.
Association Between Left Ventricular Ejection Fraction Post-Cardiac Resynchronization Treatment and Subsequent Implantable Cardioverter Defibrillator Therapy for Sustained Ventricular Tachyarrhythmias
Authors: Manfredi Joseph A. , Al-Khatib Sana M. , Shaw Linda K. , Thomas Laine , Fogel Richard I. , Padanilam Benzy , Rardon David , Vatthyam Rosh , Gemma Lee W. , Golden Keith , Prystowsky Eric N.
Published: February 2013

Background—

Although cardiac resynchronization therapy (CRT) can improve left ventricular ejection fraction (LVEF), it is not known whether a specific level of improvement will predict future implantable cardioverter defibrillator (ICD) therapy.

Methods and Results—

CRT-defibrillator (CRT-D) was implanted in 423 patients at 1 institution between October 2, 2001 and January 19, 2007. A retrospective analysis was performed to evaluate the relationship between post–CRT-D LVEF and ICD therapy for ventricular tachyarrhythmias. A landmark population of 270 patients, with post–CRT-D LVEF measured and no ICD therapy within 1 year of device implantation, was followed for subsequent outcomes. Of these, 22 patients (8.2%) had subsequent appropriate ICD therapy over a median follow-up of 1.5 years. The estimated 2-year risk of appropriate ICD therapy is 3.0% (95% confidence interval [95% CI], 0%–6.3%), 2.1% (95% CI, 0%–5.0%), and 1.5% (95% CI, 0%–3.9%) for post–CRT-D LVEF of 45%, 50%, and 55%, respectively. In patients with a primary prevention indication for CRT-D, the estimated 2-year risk is 3.3% (95% CI, 0%–7.3%), 2.5% (95% CI, 0%–6.1%), and 1.9% (95% CI, 0%–5.1%) for post–CRT-D LVEF of 45%, 50%, and 55%, respectively.

Conclusions—

When a CRT responder demonstrates near normalization in LVEF to ≥45%, the incidence of ICD therapy for ventricular arrhythmias becomes low. Future studies are needed to determine whether an ICD is still needed in some of these patients at the time of generator replacement.
Economic and Safety Implications of Introducing Fast Tracking in Congenital Heart Surgery
Authors: Lawrence Emily J. , Nguyen Khanh , Morris Shaine A. , Hollinger Ingrid , Graham Dionne A. , Jenkins Kathy J. , Bodian Carol , Lin Hung-Mo , Gelb Bruce D. , Mittnacht Alexander J.C.
Published: February 2013

Background—

The feasibility of fast-tracking children undergoing congenital heart disease surgery has not been assessed adequately. Current knowledge is based on limited single-center experiences without contemporaneous control groups.

Methods and Results—

We compared administrative data for atrial septal defect (ASD) and ventricular septal defect (VSD) surgeries in children 2 months to 19 years of age at the Mount Sinai Medical Center (MSMC) with data from comparable patients at 40 centers contributing to the Pediatric Health Information System. Three-year blocks, early in and after fast tracking had been implemented at the MSMC, were examined. Seventy-seven and 89 children at MSMC undergoing ASD and VSD closure, respectively, were compared with 3103 ASD and 4180 VSD patients nationally. With fast tracking fully implemented, median length of stay at the MSMC decreased by 1 day compared with the earlier era (length of stay, 1 and 3 days for ASD and VSD, respectively). Nationally, median length of stay remained unchanged (3 days for ASD and 4 days for VSD) in the observed time periods. Hospitalization costs fell by 33% and 35% at MSMC (ASD and VSD, respectively), whereas they rose by 16% to 17% nationally. When analyzed in multiple regression models, the decrease in both length of stay and cost remained significantly greater at MSMC compared with nationally (
P
<0.0001 for all). Hospital mortality and 2-week readmission rates were unchanged at MSMC between the 2 time periods and were not different from the national rates.

Conclusion—

Shorter length of stay and cost savings compared with national data were observed after implementation of fast tracking.
Donor Brain Death Exacerbates Complement-Dependent Ischemia/Reperfusion Injury in Transplanted Hearts
Authors: Atkinson Carl , Floerchinger Bernhard , Qiao Fei , Casey Sarah , Williamson Tucker , Moseley Ellen , Stoica Serban , Goddard Martin , Ge Xupeng , Tullius Stefan G. , Tomlinson Stephen
Published: February 2013

Background—

Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors.

Methods and Results—

Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors.

Conclusions—

BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury.
Safety of Thrombolysis in Stroke Mimics
Authors: Zinkstok Sanne M. , Engelter Stefan T. , Gensicke Henrik , Lyrer Philippe A. , Ringleb Peter A. , Artto Ville , Putaala Jukka , Haapaniemi Elena , Tatlisumak Turgut , Chen Yaohua , Leys Didier , Sarikaya Hakan , Michel P. , Odier Céline , Berrouschot Jörg , Arnold Marcel , Heldner Mirjam R. , Zini Andrea , Fioravanti Valentina , Padjen Visnja , Beslac-Bumbasirevic Ljiljana , Pezzini Alessandro , Roos Yvo B. , Nederkoorn Paul J.
Published: February 2013

Background and Purpose—

Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients.

Methods—

In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes.

Results—

One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5–2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0–5.0) compared with 7.9% (95% confidence interval, 7.2–8.7) in ischemic strokes.

Conclusions—

In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.
Atrial Fibrillation is Associated With Reduced Brain Volume and Cognitive Function Independent of Cerebral Infarcts
Authors: Stefansdottir Hrafnhildur , Arnar David O. , Aspelund Thor , Sigurdsson Sigurdur , Jonsdottir Maria K. , Hjaltason Haukur , Launer Lenore J. , Gudnason Vilmundur
Published: February 2013

Background and Purpose—

Atrial fibrillation (AF) has been associated with cognitive decline independent of stroke, suggesting additional effects of AF on the brain. We aimed to assess the association between AF and brain function and structure in a general elderly population.

Methods—

This is a cross-sectional analysis of 4251 nondemented participants (mean age, 76±5 years) in the population-based Age, Gene/Environment Susceptibility-Reykjavik Study. Medical record data were collected for the presence, subtype, and time from first diagnosis of AF; 330 participants had AF. Brain volume measurements, adjusted for intracranial volume, and presence of cerebral infarcts were determined with magnetic resonance imaging. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. In a multivariable linear regression model, adjustments were made for demographic factors, cardiovascular risk factors, and cerebral infarcts.

Results—

Participants with AF had lower total brain volume compared with those without AF (
P
<0.001). The association was stronger with persistent/permanent than paroxysmal AF and with increased time from the first diagnosis of the disease. Of the brain tissue volumes, AF was associated with lower volume of gray and white matter hyperintensities (
P
<0.001 and
P
=0.008, respectively), but not of white matter hyperintensities (
P
=0.49). Participants with AF scored lower on tests of memory.

Conclusions—

AF is associated with smaller brain volume, and the association is stronger with increasing burden of the arrhythmia. These findings suggest that AF has a cumulative negative effect on the brain independent of cerebral infarcts.
Assessing Human Rights in Russia: Not to Miss the Forest for the Trees A Response to Preclik, Schönfeld and Hallinan
Authors: Starzhenetskii Vladislav
Published: February 2013

Looking fourteen years into the past, Russia has made enormous progress in reforming its legal system in order to ensure human-rights protection under the Convention. This process of reform is still ongoing. The causes of the existing difficulties in the area of human-rights protection are better explained in terms of difficulties with implementation of standards in the Russian legal system rather than any antagonism between Russian and European human-rights attitudes. There are several groups of violations of the ECHR that need to be analyzed separately because of the different nature of the problems. Some of them reflect structural and practical problems of the Russian legal system immanent in a transition period of reforms and of the dismantling of old regulations and attitudes; others may be accounted for by the lack of proper (efficient, adequate and balanced) measures and solutions to address the numerous new challenges that Russian society is facing after the collapse of the Soviet Union. There are many examples that provide evidence that Russia is trying to amend its legal and political system to meet the requirements of the Convention.
When Jurisprudence Becomes Law: How Italian Colonial Judges in Libya Turned Islamic Law and Customary Practice into Binding Legal Precedent
Authors: Gazzini Claudia
Published: February 2013

Abstract

This paper considers the way in which Italian authorities introduced jurisprudence of the Court of Appeals as a source of law in Libya from 1911 to 1943. Aimed at resolving the tensions that resulted from the interplay between local customs, Islamic law, and the Italian legal codes, such a recourse to jurisprudence was a clear departure from Italy’s own code-based legal system. This judicial innovation was also a change from the practices introduced in British and French colonies, where the codification of a hybrid European-local law had become the norm. Divided into three parts—jurisprudence as source of law in Italy, its uses in the colonies, and jurisprudence in practice (through the analysis of the sentences on shuf ʿa, the customary right of pre-emption)—this article illustrates Italian jurisprudential law in Libya as an example of the theoretical problems and practical advantages of legal pluralism in a colonial context.

Cet article examine comment les autorités italiennes ont introduit la jurisprudence émanant de la Cour d’appel en tant que source de droit en Libye de 1911 à 1943. Destiné à résoudre les tensions qui ont résulté de l’interaction entre les coutumes locales, le droit islamique et les codes juridiques italiennes, un tel recours à la jurisprudence était clairement une rupture avec le système basé sur les codes juridiques en usage en Italie. Cette innovation judiciaire était également différente des pratiques introduites dans les colonies britanniques et française, où la codification d’un hybride euro-locale était devenue la norme. Divisé en trois parties—la jurisprudence comme source de droit en Italie, ses utilisations dans les colonies, et la jurisprudence dans la pratique (à travers l’analyse des décisions sur le shuf ʿa, droit coutumier de préemption)—cet article illustre le droit jurisprudentiel italien en Libye comme un exemple des problèmes théoriques et des avantages pratiques du pluralisme juridique dans un contexte colonial.
The Time of Dishonour: Land and Murder under Colonial Rule in the Tian Shan
Authors: Jacquesson Svetlana
Published: February 2013

Abstract

In this article I try to uncover the reasons for false accusations of murder, instigated murders, and staged murders among the Tian Shan Kyrgyz under Russian colonial rule. Towards this end, I read, contrapuntally, field data, ethnohistorical accounts, colonial statutory laws, and colonial ethnography. I argue that colonial interventions—namely, the hybrid adjudication of murders, the newly designed system of self-government, and the imposition of an arbitrary land-rights regime—correlated in unexpected ways and triggered instigated and staged murders and false accusations of murder as an extreme recourse in defence of land-use rights. I conclude by relating the particular legal setting of Russian colonial rule to its representation as “the time of dishonour.”

Dans cet article j’essaie d’élucider les fausses accusations de meurtre, les meurtres prémédités et les meurtres simulés attestés parmi les Kirghiz du Tian Shan à l’époque colonial. A cette fin, j’analyse des récits ethno-historiques, les lois statutaires coloniales et les écrits des ethnographes coloniaux. Je soutiens que des interventions coloniales, telles le jugement hybride des meurtres, le système d’auto-gouvernance nouvellement introduit et la gestion ambiguë de la terre, se combinent de façon inattendue pour produire les meurtres bizarres comme ultime remède aux injustices terriennes. Dans les conclusions, je relie l’environnement légal de la domination coloniale à sa représentation comme “le temps de déshonneur.”