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PubMed | Experimental Epilepsy Research, Institute of Neuropathology Center for Biological Signalling Studies, Oncology and Stem Cell Transplantation. and Albert Ludwigs University of Freiburg
Type: | Journal: Cerebral cortex (New York, N.Y. : 1991) | Year: 2016

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex with strong epileptogenic potential. To investigate the underlying pathomechanisms, we performed a whole human transcriptome screening to compare the gene expression pattern of dysplastic versus nondysplastic temporal neocortex. Tissue obtained from FCD IIIa cases (mean age 20.5 years) who had undergone surgical treatment, due to intractable epilepsy, was compared with nondysplastic specimens (mean age 19.9 years) by means of Affymetrix arrays covering 28 869 genes. We found 211 differentially expressed genes (DEX) among which mainly genes important for oligodendrocyte differentiation and myelination were downregulated in FCD IIIa. These findings were confirmed as functionally important by Database for Annotation, Visualization, and Integrated Discovery (DAVID) analysis. The reduced expression of myelin-associated transcripts was confirmed for FCD Ia, IIa, and IIIa by real-time RT-qPCR. In addition, we found that the density of myelin basic protein mRNA-expressing oligodendrocytes and of 2,3-cyclic nucleotide 3-phosphodiesterase-positive myelin fibers was significantly reduced in dysplastic cortex. Moreover, high-resolution confocal imaging and 3D reconstruction revealed that the myelin fiber network was severely disorganized in dysplastic neocortex, indicating a disturbance of myelin sheath formation and maintenance in FCD.


PubMed | University of Tübingen, Klinikum Oldenburg, University of Bonn, Hannover Medical School and 17 more.
Type: Journal Article | Journal: Annals of hematology | Year: 2016

The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45mg/m


News Article | December 6, 2016
Site: www.eurekalert.org

Unemployed workers use prescription opioids for nonmedical reasons; those out of the workforce use prescription stimulants December 6, 2016 -- Researchers at Columbia University's Mailman School of Public Health found that employment status is a factor in nonmedical use of prescription opioids and prescription stimulants. Unemployed workers had the highest risk of misusing prescription opioids, and those out of the workforce entirely were most at risk for misusing prescription stimulants. The study is among the first to analyze the relationship between employment status and nonmedical prescription drug-users over the age of 25 and show how social characteristics influence nonmedical prescription drug use. The findings are published online in the journal Social Psychiatry and Psychiatric Epidemiology. Epidemiologist Silvia Martins, MD, PhD, associate professor at the Mailman School and senior author, sampled 58,486 adults 25 years and older based on combined data from 2011 to 2013 from the National Survey on Drug Use and Health. People who were unemployed reported the highest odds of misusing prescription opioids at 7 percent. Those out of the workforce reported the highest odds of misusing prescription stimulants at 2 percent. Overall, there were more users of nonmedical prescription opioids (3.5 percent) compared with nonmedical users of prescription stimulants (.72 percent). Nonmedical prescription opioid use is defined as any self-reported use of prescription pain relievers that were not prescribed or that a person takes for the experience or sensation they impart. Nonmedical prescription drug use, particularly nonmedical use of prescription opioids, has declined in the U.S. in recent years, yet is still an important public health problem. Using prescription opioids for recreational purposes alone costs the U.S. about $42 billion in lost productivity, $8.2 billion in criminal justice costs, and $1 billion in medical complications. "Our results confirm the need for adult prevention and deterrence programs that target nonmedical prescription drug use, especially among those unemployed or not in the workforce," said Dr. Martins. Of particular concern are adults ages 26-34 who are unemployed, since the odds of nonmedical prescription opioid use are higher in this age group as compared to older adults. The study also showed higher odds of prescription stimulants misuse among those only employed part-time compared with persons employed full time. "Our findings on these associations between employment status and nonmedical prescription drug use parallel other research about emerging adulthood and taking on new social roles, such as marriage and parenthood," noted Martins. The observation that unemployment is associated with a host of diseases--mental disorders in particular, which Dr. Martins and colleagues also found--is of utmost importance to those instituting policies regulating control of nonmedical prescription drugs. "Physicians, in particular, should be aware of patients' employment status and the elevated risk between unemployment and non-medical drug use and drug and mental disorders prior to prescribing," noted Dr. Martins. Associations between employment status, and misuse of opioids and stimulants yield important public health implications, says Martins. "By improving our understanding of these associations and the role of employment in drug use behaviors and modes of access, drug prevention and deterrence programs can target users more effectively, especially when combined with regulation." Sensitivity to non-full-time employed people--a population that the data suggests experiences greater social disadvantage--is imperative, according to Martins. "Non-full-time employed people may suffer disproportionately from the indirect harms of nonmedical use of prescription opioids and stimulants insomuch that they have less family- neighborhood-, and community-level social ties that would help mitigate harms related to misuse. With substance use disorders increasingly recognized as a public health issue -- and not one of criminal justice -- withholding social support, including treatment, from those with the highest need will contribute to increasing social inequalities." Co-authors are Alexander S. Perlmutter (first author), Mailman School of Public Health and Centre de Recherche Epidemiologie et Statistique, Sorbonne, Universite´ Paris Descartes, Hopital Hotel-Dieu; Sarah C. Conner, Boston University School of Public Health; June H. Kim and Luis E. Segura, Mailman School of Public Health; and Mirko Savone, Mailman School of Public Health and Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Columbia University Medical Center. The study was supported by the U.S. National Institutes of Health, National Institute of Drug Abuse, grants R01DA037866, R01DA039454, 5T32DA031099-04, the Eunice Kennedy Shriver National Institute of Child and Human Development, R01HD060072, and Columbia University President's Global Innovation Fund. Founded in 1922, Columbia University's Mailman School of Public Health pursues an agenda of research, education, and service to address the critical and complex public health issues affecting New Yorkers, the nation and the world. The Mailman School is the third largest recipient of NIH grants among schools of public health. Its over 450 multi-disciplinary faculty members work in more than 100 countries around the world, addressing such issues as preventing infectious and chronic diseases, environmental health, maternal and child health, health policy, climate change & health, and public health preparedness. It is a leader in public health education with over 1,300 graduate students from more than 40 nations pursuing a variety of master's and doctoral degree programs. The Mailman School is also home to numerous world-renowned research centers including ICAP (formerly the International Center for AIDS Care and Treatment Programs) and the Center for Infection and Immunity. For more information, please visit http://www. .


Dreger P.,University of Heidelberg | Dohner H.,University of Ulm | McClanahan F.,University of Heidelberg | Busch R.,TU Munich | And 16 more authors.
Blood | Year: 2012

The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3- 12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015. © 2012 by The American Society of Hematology.


El-Mallawany N.K.,Oncology and Stem Cell Transplantation | Cairo M.S.,Children and Adolescent Cancer and Blood Diseases Center
Clinical Advances in Hematology and Oncology | Year: 2015

Burkitt lymphoma and diffuse large B-cell lymphoma represent the majority of mature B-cell non-Hodgkin lymphomas in children, adolescents, and young adults. Although they are characterized by specific clinical and biological nuances, the 2 diseases share significant clinicopathologic overlap and are treated with the same chemotherapy regimens in pediatrics. Modernday chemotherapy protocols achieve overall event-free survival rates of nearly 90%. The addition of the anti-CD20 monoclonal antibody rituximab to backbone chemotherapy holds great promise for improving long-term curative outcomes while diminishing acute and long-term toxicities. However, in the contemporary era, the long-term survival for patients with relapsed or refractory disease is meager. The role of hematopoietic stem cell transplantation in children, adolescents, and young adults with relapsed/ refractory disease is currently being defined. Meanwhile, novel humoral and cellular immunotherapies, as well as agents targeting specific molecular pathways that drive lymphomagenesis, are exciting developments that are being evaluated in clinical trials. © 2015, Millennium Medical Publishing, Inc. All rights reserved.


Bartram I.,Franklin University | Gokbuget N.,Goethe University Frankfurt | Schlee C.,Franklin University | Heesch S.,Franklin University | And 9 more authors.
Journal of Hematology and Oncology | Year: 2014

Background: Risk stratification, detection of minimal residual disease (MRD), and implementation of novel therapeutic agents have improved outcome in acute lymphoblastic leukemia (ALL), but survival of adult patients with T-cell acute lymphoblastic leukemia (T-ALL) remains unsatisfactory. Thus, novel molecular insights and therapeutic approaches are urgently needed. Methods. We studied the impact of B-cell CLL/lymphoma 11b (BCL11b), a key regulator in normal T-cell development, in T-ALL patients enrolled into the German Multicenter Acute Lymphoblastic Leukemia Study Group trials (GMALL; n = 169). The mutational status (exon 4) of BCL11b was analyzed by Sanger sequencing and mRNA expression levels were determined by quantitative real-time PCR. In addition gene expression profiles generated on the Human Genome U133 Plus 2.0 Array (affymetrix) were used to investigate BCL11b low and high expressing T-ALL patients. Results: We demonstrate that BCL11b is aberrantly expressed in T-ALL and gene expression profiles reveal an association of low BCL11b expression with up-regulation of immature markers. T-ALL patients characterized by low BCL11b expression exhibit an adverse prognosis [5-year overall survival (OS): low 35% (n = 40) vs. high 53% (n = 129), P = 0.02]. Within the standard risk group of thymic T-ALL (n = 102), low BCL11b expression identified patients with an unexpected poor outcome compared to those with high expression (5-year OS: 20%, n = 18 versus 62%, n = 84, P < 0.01). In addition, sequencing of exon 4 revealed a high mutation rate (14%) of BCL11b. Conclusions: In summary, our data of a large adult T-ALL patient cohort show that low BCL11b expression was associated with poor prognosis; particularly in the standard risk group of thymic T-ALL. These findings can be utilized for improved risk prediction in a significant proportion of adult T-ALL patients, which carry a high risk of standard therapy failure despite a favorable immunophenotype. © 2014 Bartram et al.; licensee BioMed Central Ltd.


PubMed | University of Leipzig, Saarland University, Oncology and Stem Cell Transplantation, Kantonsspital Graubunden and 2 more.
Type: Journal Article | Journal: Annals of hematology | Year: 2016

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3%) stopped treatment early. Infections (27%) and stomatitis (13%) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33%, respectively. Overall survival (OS) after 1 and 3years was 50 and 38%. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.


Murawski N.,Universitatsklinikum des Saarlandes | Pfreundschuh M.,Universitatsklinikum des Saarlandes | Zeynalova S.,University of Leipzig | Poeschel V.,Universitatsklinikum des Saarlandes | And 10 more authors.
Annals of Oncology | Year: 2014

Background: To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial. Patients and methods: Rituximab (375 mg/m2) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60. Results: One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0). Conclusions: Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Badawy S.M.,Oncology and Stem Cell Transplantation | Gust M.J.,Northwestern University | Liem R.I.,Oncology and Stem Cell Transplantation | Ball M.K.,Ohio State University | And 2 more authors.
Annals of Plastic Surgery | Year: 2016

Neonatal compartment syndrome is a rare, but devastating limb-threatening condition that requires early recognition and timely surgical intervention. We discuss the clinical presentation and management challenges of a neonate with forearm compartment syndrome and disseminated intravascular coagulation. © 2016 Wolters Kluwer Health, Inc. All rights reserved.


PubMed | University of Leipzig, Universitatsklinik Heidelberg, Universitatsklinikum Gottingen, Klinikum Grosshadern and 5 more.
Type: Clinical Trial, Phase II | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2014

To improve outcome of elderly patients with diffuse large B-cell lymphoma, dose-dense rituximab was evaluated in the prospective DENSE-R-CHOP-14 trial.Rituximab (375 mg/m(2)) was given on days 0, 1, 4, 8, 15, 22, 29, 43, 57, 71, 85, and 99 together with six CHOP-14 cycles. Results were to be compared with patients who had received the same chemotherapy in combination with eight 2-week applications of rituximab in RICOVER-60.One hundred twenty-four patients are assessable. Dose-dense rituximab resulted in considerably higher serum levels during the first 50 days of treatment, but rituximab exposure time was not prolonged. Grade 3 and 4 infections were exceptionally high in the first 20 patients without anti-infective prophylaxis, but decreased after introduction of prophylaxis with aciclovir and cotrimoxazole in the remaining 104 patients (from 13% to 6% per cycle and from 35% to 18% per patient; P = 0.007 and P = 0.125, respectively). Patients with international prognostic index = 3-5 had higher complete response/complete response unconfirmed rates (82% versus 68%; P = 0.033) than in the respective RICOVER-60 population, but this did not translate into better long-term outcome, even though male hazard was decreased (event-free survival: from 1.5 to 1.1; progression-free survival: from 1.7 to 1.1; overall survival: from 1.4 to 1.0).Dose-dense rituximab achieved higher rituximab serum levels, but was not more effective than eight 2-week applications in the historical control population, even though minor improvements in poor-prognosis and male patients cannot be excluded. The increased, though manageable toxicity, precludes its use in routine practice. Our results strongly support anti-infective prophylaxis with aciclovir and cotrimoxazole for all patients receiving R-CHOP.

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